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Stott, Holly Rosannah. "MMP-12 activity during vascular remodelling". Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/23609.
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Matrix metalloproteinases (MMPs) are required for tissue remodelling processes, including angiogenesis. MMP activity is generally proangiogenic but MMP-12 is suggested to be antiangiogenic and its precise role is still unclear. The work in this thesis describes the synthesis of an MMP-12 inhibitor and activity probe to address the hypothesis that MMP-12 inhibits angiogenesis. An inhibitor, synthesised in-house, selectively inhibited MMP-12 in in vitro recombinant enzyme assays. An activity probe, also synthesised in-house, was selective for MMP-12 in in vitro recombinant enzyme assays. The function of MMP-12 during angiogenesis was assessed using murine models of angiogenesis; the in vivo sponge implantation, and the ex vivo aortic ring assays. Angiogenesis and MMP activity were imaged in vivo in sponges in C57Bl6/J mice over 7 − 21 days (D) using commercial probes (MMPSense™ and AngioSense™). MMP-12 protein concentration and activity were higher in sponges during early angiogenesis (D 3 − 7) when gene expression of vascular endothelial growth factor (a proangiogenic marker) was also high. Gene expression for MMP-12 and platelet-derived growth factor receptor (a marker of vascular maturation) were both higher on D 21 as angiogenesis started to stabilise. The MMP-12 activity probe was unsuccessful in selectively detecting MMP-12 activity in sponge lysate mixtures from D 7 − 21. Administration of an MMP-12 inhibitor did not increase angiogenesis in the sponges in vivo. Additionally, sponges implanted in MMP-12-/- mice did not exhibit significant changes in angiogenesis or MMP activity when imaged in vivo using commercial probes (MMPSense™ and AngioSense™) on D 7. Supporting this, histological analysis of the sponges (removed on D 21) showed that deletion of MMP-12 also did not increase angiogenesis within the sponges.
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Eckelman, Brendan P. "The regulation of caspase activity by the inhibitor of apoptosis proteins". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC IP addresses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3288846.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed June 2, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 188-214).
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Gora, Kasia G. (Kasia Gabriela). "SciP : a novel inhibitor of CtrA transcriptional activity in Caulobacter crescentus". Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/68426.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, September 2011.Cataloged from PDF version of thesis. "August 8, 2011."
Includes bibliographical references.
Cells must sense changes in their environment and respond appropriately in order to survive. A common survival strategy is for cells to translate an environmental signal into the activity of a transcription factor they effects a change in gene expression. In this way, cells can express a gene just-in-time for its biological function. In addition, cells can coordinate the activity of many transcription factors to construct genetic regulatory networks that integrate many inputs to control complex cellular behaviors. In this thesis, I use the model system Caulobacter crescentus to examine the regulation of CtrA, the essential transcription factor at the core of the Caulobacter cell cycle regulatory network. CtrA regulates the activity of approximately 100 cell cycle genes many of which are critical for cell cycle progression. CtrA activity is regulated at the level of abundance, post-transcriptional modification, and here I show that CtrA is also regulated by a novel protein-protein interaction. I identify SciP, a GI specific inhibitor of CtrA transcriptional activity and show that SciP forms a complex with CtrA at CtrA dependent promoters. The SciP/CtrA interaction likely prevents CtrA from recruiting RNA polymerase thereby blocking the activation of transcription. In addition, I show that SciP is restricted to G1 by regulated proteolysis. I identify the Lon as the SciP protease and show that Lon is required for SciP proteolysis in vivo and that E. coli Lon degrades SciP in vitro. Finally I engineer a stable allele of sciP and show SciP proteolysis is critical for proper cell cycle progression.
by Kasia G. Gora.
Ph.D.
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Al-Yousuf, Karamallah. "Investigating the anti-melanoma activity of combinatorial paclitaxel and MEK inhibitor". Thesis, University of Dundee, 2018. https://discovery.dundee.ac.uk/en/studentTheses/1be821d2-2436-4c31-8485-e62b86d6d33b.
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Melanoma has increased considerably over the past forty years. Traditional and newly-developed anti-melanoma drugs do not produce a satisfactory therapeutic response for the treatment of late stage melanoma. Nanomedicine is a potent tool for clinicians to circumvent many of the existing shortcomings in cancer therapy. Combination of more than one drug may maximise the therapeutic response and minimise undesirable effects of the chemotherapeutic agents in cancer patients. I developed a novel combinatorial approach that can be loaded into targeted anti-melanoma nanocarriers. Our group have been working on the development of a theranostic superparamagnetic iron oxide nanoparticle (SPION), designed to accommodate the simultaneous encapsulation of two anti-melanoma compounds, with the addition of a melanoma cell-specific targeting moiety (α-MSH) attached to the surface of the nanoparticle (NP). The selection of PTX and SEL for being loaded on α-MSH-SPION takes into consideration the anti-melanoma potency, mechanism(s) of action, physicochemical properties of each drug and their ability for embedding in the hydrophobic pocket of the NP. The synergistic ratio of PTX-SEL combination exerted limited cytotoxic effect towards normal skin cells, but was potent in melanoma cells. Also, we have analysed the drug combination in vivo, where the combinatorial therapy had a statistically significant effect in blocking tumour growth. In a dose- and time-dependent manner, PTX-SEL co-treatment increased oxidative stress in melanoma cells. The pro-oxidant effect of PTX-SEL is specific to melanoma rather than normal cells. These effects accompanied by mitochondrial dysfunction and increased mitochondrial ROS production indicating that mitochondria are the key source of PTX-SEL-induced-ROS production. In addition, our findings show that antioxidants antagonise the drug combination-induced melanoma cell death. Overall, our findings establish the PTX-SEL drug combination is potent and selective anti-melanoma approach with mechanistic rationale offering therapeutic benefit when loaded to α-MSH-SPIONs that can wide the horizons of clinical pharmacology field.
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Sancho, Elena. "Conformation and activity of plasminogen activator inhibitor type 1 (PAI-1)". Thesis, University of Aberdeen, 1994. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU552562.
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Plasminogen activator inhibitor type 1 (PAI-1) is a unique member of the serpins in that it can adopt various conformations. It is synthesized as an active inhibitor which rapidly converts to a latent form that is not inhibitory. Conformational studies on this protein have been made difficult by this property. The production of recombinant PAI-1 was studied. The expression of r-PAI-1 by the bacterial strain MSD 1005 accounted for some 15-20% of the total cell protein, although some was produced in the form of inclusion bodies. As an attempt to improve the yields of PAI-1 antigen and activity, the cells were grown at low temperatures or under osmotic-stress conditions in the presence of betaine. These did not affect the distribution of r-PAI-1 between the soluble phase and inclusion bodies or the specific activity of the r-PAI-1. A quick protocol for the purification of r-PAI-1 from the strain MSD 1005 was developed. Approximately 26 mg of r-PAI-1 could be purified from 1.51 of bacterial culture in one step by ion exchange chromatography. The specific activity of the purified r-PAI-1 was found to be close to the theoretical maximum and to be unusually stable. The stability of the r-PAI-1 was found to be dependent on the low pH and the high NACl concentration used during the purification protocol. The effect of arginine was found to be comparable to that of NaCl. Vitronectin or aprotinin had no effect on the specific activity of r-PAI-1. Active, denaturant activated and latent r-PAI-1 were compared in terms of their binding to heparin and to a panel of monoclonal antibodies. Complex formation with t-PA was also assessed. Active and denaturant activated PAI-1 were indistinguishable in these studies.
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Grundy, Martin. "Activity of the aurora kinase B inhibitor AZD1152 in acute myeloid leukaemia". Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/12758/.
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Aurora kinases play an essential role in orchestrating chromosome alignment, segregation and cytokinesis during mitotic progression, with both aurora-A and B frequently over-expressed in a variety of human malignancies including those of leukaemic origin. Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells whose prognosis is particularly poor and where standard induction therapy has changed little over the past thirty years. This thesis evaluated the effects of AZD1152-hQPA (barasertib-hQPA), a highly selective inhibitor of aurora-B kinase, in AML cell lines and primary samples. Inhibition of phospho-Histone H3 (pHH3) on serine 10 can be used as a biomarker for AZD1152-hQPA activity and an assay was optimized to measure pHH3 in our cell lines and primary samples. AZD1152-hQPA inhibited pHH3 in our cell lines resulting in polyploid cells, apoptosis, and cell death, irrespective of cellular p53 status. Over-expression of the ATP-binding cassette (ABC) drug transporter proteins P-glycoprotein (Pgp) and Breast cancer resistance protein (BCRP) is a major obstacle for chemotherapy in many tumour types with Pgp conferring particularly poor prognosis in AML. A cell line which over-expresses Pgp was developed by selecting for daunorubicin (DNR) resistance in OCI-AML3 cells. Pgp and also BCRP expressing AML cell lines were found to be resistant to AZD1152-hQPA and it was found that AZD1152-hQPA is effluxed by these transporters. pHH3 inhibition by low dose AZD1152-hQPA was seen in all of the primary samples tested with Pgp and BCRP positive samples being less sensitive. However, 50% inhibition of pHH3 by AZD1152-hQPA was achieved in 94.6% of these samples. The FLT3-ITD-expressing MOLM-13 and MV4-11 cell lines were particularly sensitive to AZD1152-hQPA. Internal tandem duplications (ITDs) within the FLT3 tyrosine kinase receptor are found in approximately 25% of AML patients and are associated with a poor prognosis. It was demonstrated that AZD1152-hQPA directly targets phosphorylated FLT3 in the FLT3-ITD cell lines along with inhibiting its downstream target pSTAT5. FLT3-ITD primary samples were particularly sensitive to clonogenic inhibition and pSTAT5 down-regulation after treatment with AZD1152-hQPA compared with FLT3 wild-type (WT) samples.
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Sampathkumar, Yamuna. "Thermal processing effects on total phenolic content, antioxidant activity, trypsin inhibitor activity and in-vitro protein digestibility of lentils". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=107918.
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Heat pre-treatment of nutrient-rich lentil seeds prior to their processing into flour may enhance its use by reducing processing and preparation times in value added products. In this study, changes in trypsin inhibitor content, total phenolic content, antioxidant activity, and in-vitro protein digestibility of flours prepared from hulled red lentils and unhulled green lentils were determined subsequent to various processing methods such as oven roasting (OR), boiling and microwave heating (MH). The increasing interest in the phenolic content of plant based food-stuffs made us to assess two different lentil cultivars processed under fixed temperature and time combination. Total phenolic content and antioxidant activity (TAC) of 70% acetone lentil extracts were assayed spectrophotometrically at 760nm using Folin-Ciocalteu and DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity methods, respectively. Significant differences in phenolic content and antioxidant activity were noted between hulled red and unhulled green lentil varieties. MH (5 min) led to a significant increase (P ≤ 0.05) in total phenolic content in unhulled green lentil flours (GLF) [8.85 mg GAE/g dry weight (DW) while raw flour comparatively showed lower phenolic content [7.5 mg GAE/g DW]. A similar increase was found after oven-roasting this material for 20 min. The TAC of untreated unhulled green lentil range was around 86%, and it was higher than the value obtained for the flour from untreated hulled red lentils. The increase in TPC of OR samples and microwave-heated samples over untreated ones may reflect reductions in TAC. Flour samples obtained from boiled lentils showed a sharp decrease in TPC and TAC values, which may be attributable to a number of factors in the matrix.Though lentils are rich in protein, their anti-nutritional components, the length of the time required for their preparation, as well as their unfavorable flavor, and reduced protein digestibility have limited their frequency of use for human consumption. By applying heat, anti-nutritional factors such as trypsin inhibitors can be largely removed. Our results show that MH treatment produced significant reduction (P≤0.05) in trypsin inhibitor activity when compared to OR or boiling methods. In- vitro protein digestibility (IVPD) was improved after processing. Longer processing times associated with OR or boiling methods improved IVPD to a greater extent than MH.Keywords: TAC- Total antioxidant activity; GA- Gallic Acid equivalent; Lentils; TPC- Total phenolic content; IVPD- In-Vitro Protein digestibility; MH- Microwave heating; OR- Oven roasting; GLF- Green lentil flours; RLF- Red lentil floursLe prétraitment thermique de lentilles avant de les moudre en farine peut faciliter son utilisation dans la préparation de produits à valeur ajoutée. Cette étude porte sur l'évaluation des effets des prétraitments thermiques par chauffage par torréfaction(CT), par chauffage par microondes (CM), ou par l'eau bouillante (EB), sur la teneur en composés phénoliques totaux (CPT), sur l'activité anti-oxydante totale (AAOT), sur les teneurs en inhibiteur de trypsine, et sur la digestibilité in-vitro des protéines (DIVP). Les essais ont été faits sur des farines obtenues à partir de lentilles rouges décortiquées et de lentilles vertes non decortiquées après l'application des prétraitment thermiques. Les deux varieties de lentilles ont été prétraitées selon des combinaisons déterminées de températures et de durées de traitment. Les teneurs en CPT et l'AAOT ont été évaluées par spectrophotométrie à 760 nm en utilisant la méthode de Folin-Ciocalteu et la méthode DPPH (1, 1- diphényl-2-picrylhydrazyle) de piégeage des radicaux libres. Les résultats ont démontré des différences significatives entre les deux types de lentilles étudiées. Le prétraitement CM (5 min) a conduit à une augumentation significative (P≤0.05) de la teneur en CPT dans les échantillons de farine de lentilles vertes [8.85 mg GAE/g de poids sec (ps) lorsque comparé aux échantillons de farine de lentilles vertes non-traitées [7.5 JEU mg/g ps]. Une tendance similaire a été observée auprés des farines de lentilles vertes torréfiées au four pendant 20 min. L'AAOT des farines de lentilles vertes non-traitées était d'environ 86% et elle était supérieure à celle obtenue à partir de lentilles rouges non-traitées. Les teneurs en CPT observées dans les échantillons traités soit par CT soit par CM étaient plus élevées que celles des échantillons non traitées et peuvent refléter des réductions en AAOT obetnues. Les teneurs en CPT et en AAOT des échantillons obtenues à la suite du prétraitment EB étainet nettement inférieures et peut être attributées à plusieurs facteurs dans la matrice. Bien que les lentilles soit riches en protéines, plusiers facteurs limitent leurs utilisation pour la consommation humaine. Ces principaux facteurs sont : la présence de composants antinutritionnels, le temps nécessaire à la préparation, les saveurs désagréables, et la digestibilité réduites des protéines. On peut réduire l'impacte des facteurs antinutritionnels comme les inhibiteurs de la trypsine par des traitements thermiques. Les résultats ont demontré que l'utilisation du pretraitment CM permettait de réduire significativement (P≤0.05) l'activité des inhibiteurs de trypsine lorsque comparés aux prétraitments CT et EB. Il a aussi été démontré que l'augmentation de la dureé des prétraitments thermiques par CT ou par EB permettait d'accroitre la DIVP. Dans tous les cas étudiés, l'application d'un prétraitment thermique sur les lentilles a permis d'améliorer la DIVP.Mots clés : Lentilles vertes, lentilles rouges, farines, traitements thermiques, composés phénoliques totaux (CPT), activité anti-oxydante totale (AAOT), digestibilité in-vitro des protéines (DIVP), équivalent en acide gallique, chauffage par torréfaction (CT), chauffage par microondes (CM), chauffage par trempage dans l'eau bouillante (EB).
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Mendis, Mihiri Marini. "Variability in Arabinoxylan, Xylanase Activity and Xylanase Inhibitor Levels in Hard Spring Wheat". Thesis, North Dakota State University, 2012. https://hdl.handle.net/10365/26806.
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Arabinoxylans (AX), xylanase, and xylanase inhibitors have an important role in many cereal food processing applications. The effect of growing location (L), genotype (G), and their interactions (L ×G) on AX, apparent xylanase and apparent xylanase inhibition activities of National Science Foundation Grant (# HRD-0811239) to the NDSU Advance FORWARD program
North Dakota Wheat Commission
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Zwahlen, Hugo. "Effects of low-dose "Factor VIII Inhibitor Bypassing Activity (FEIBA)" in resistant heamophilia /". [S.l : s.n.], 1986. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Ren, Zhongyuan. "Small molecules regulated bone resorption and enzyme activity in osseous cells". Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10291/document.
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La Cathepsine K est parmi la plus efficace des collagénases de mammifère pour cliver la triple hélice de collagène de type-1. Nous avons développé une série d'azanitriles, (CKI-8 and CKI-13) inhibiteurs de cathepsine K. CKI-8 (un isomère de CKI-13) et CKI-13 ne sont pas toxiques sur les osteoblastes Saos-2 et les cellules RAW 264.7 jusqu' à une concentration de 1000 nM, tandis qu'ils ne le sont pas jusqu'à une concentration de 100 nM sur les osteoclastes. CKI-8 n'affecte pas l'activité de la phosphatase alkaline ainsi que la minéralisation induite par les Saos-2 et par les osteoblastes primaires. CKI-13 diminue de 35 % la minéralisation induite par les Saos-2 tandis qu'il n'affecte pas la minéralisation induite par les osteoblastes primaires. L'addition de CKI-13 diminue l'activité de la phosphatase alkaline d'environ 20% (Saos-2) et de 40 % (osteoblastes primaires). La résorption osseuse sur des tranches d'os d'origine bovine est diminuée avec 10 nM de CKI-13, 100 nM de CKI- 8 et 100 nM d'inhibiteur commercial E64. CKI-8 et CKI-13 diminuent la mobilité des osteoclastes. Nous avons développé un dosage d'hydrolyse de PPi par la phosphatase alkaline au moyen de l'IR, ayant l'avantage de fonctionner sur des vésicules matricielles et des cellules avec des substrats naturels à un pH physiologique. La bande de PPi localisée à 1107 cm-1 (∑= 2158 ± 211 M-1.cm-1) et celles de Pi localisées à 1076 cm-1 (∑= 1346 ± 116 M-1.cm- 1) et à 991 cm-1 (∑= 493 ± 49 M-1.cm-1) ont servis à mesurer les concentrations du substrat et du produitCathepsin K is among the most potent mammalian collagenase, capable of cleaving the triple helix in type-I collagen. We developed a series of azanitriles (CKI-8 and CKI-13) which are inhibitors of cathepsin K. CKI-8 (an isomer of CKI-13) and CKI-13 did not induce significant toxicity on osteoblasts Saos-2 and RAW 264.7 cells up to 1000 nM, while they were not toxic on mature osteoclasts up to 100 nM. Commercial E64 inhibitor was not toxic in primary osteoclast cells up to 1000 nM. CKI-8 did not affect alkaline phosphatase activity as well the mineralization induced by Saos-2 cells and by primary osteoblasts. CKI-13 decreased by 35% the mineralization induced by Saos-2 cells while it did not on mineralization induced by primary osteoblasts. Addition of CKI-13 decreased alkaline phosphatase activity by around 20% (Saos-2 cells) and 45% (primary osteoblasts). Bone resorption on bovine slices decreased significantly with 10 nM of CKI-13, with 100 nM of CKI-8 and commercial inhibitor E64. Our findings indicated that CKI-8 and CKI-13 inhibited bone resorption and affected the mobility of osteoclast. To monitor directly the PPi hydrolytic activity by alkaline phosphatase, we developed an infrared (IR) assay taking the advantage to use natural substrate under physiological pH in matrix vesicles and in living cells. PPi band located at 1107 cm-1 (∑= 2158 ± 211 M-1.cm-1) and Pi bands located at 1076 cm-1 (∑= 1346 ± 116 M-1.cm-1) and at 991 cm-1 (∑= 493 ± 49 M-1.cm-1) served to measure the substrate and the product concentrations
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Subedi, Yagya P. "Cost-Effective Synthesis, Bioactivity and Cellular Uptake Study of Aminoglycosides with Antimicrobial and Connexin Hemichannel Inhibitory Activity". DigitalCommons@USU, 2019. https://digitalcommons.usu.edu/etd/7699.
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Amphiphilic kanamycin is one of the promising class of compounds for the treatment of fungal infections in plants and animal. Factor that lead to the restricting of compounds for commercialization includes, the higher cost of production and poor stability of the compound. However, the new lead, identified from the synthesis and biological testing, can be synthesized on a large scale with a cost comparable to commercial antifungals. The newly reported lead is stable at the acidic and basic conditions. Additionally, this compound has an excellent activity towards Candida auris, a multidrug-resistant superbug.
Heart disease is the leading cause of death in the United States most of which are caused by cardiac ischemia and arrhythmias. Abnormal opening of Cx43 hemichannel can damage the heart muscles and lead to these conditions. A compound which can selectively inhibit the opening of Cx43 hemichannel may pave the way to reducing the mortality rate of heart disease. A selective inhibitor towards Cx43 hemichannel is explored from the synthesis and biological testing of kanamycin derivatives. The synthesis of the new inhibitor is scalable and cost-effective.
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Lau, Rosanna. "cIAP2 Negatively Regulates Proliferation and Tumourigenesis by Repressing IKK Activity and Maintaining p53 Function". Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22845.
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The cellular inhibitor of apoptosis protein (cIAP)-2 plays an important role in the protection against apoptosis by inhibiting the endogenous IAP inhibitor Smac, thus allowing other members of the IAP family, such as XIAP to block caspases. Additionally, cIAP2 functions as a ubiquitin ligase and mediates survival/proliferative signaling through NF-κB. cIAP2 is overexpressed in many human cancers and is believed to play an oncogenic role. This led to the development of small molecule IAP antagonists aimed at eliciting apoptosis in cancer cells. However, the loss of cIAP2 is also associated with multiple myeloma, in which constitutively active NF-κB signaling contributes to pathogenesis of the disease and suggests that cIAP2 may also perform a tumour suppressive function.
We demonstrate a novel role for cIAP2 in maintaining p53 levels in mammary epithelial cells that express wildtype p53. Downregulation of cIAP2 resulted in activation of IKKs, which led to increased Mdm2-mediated degradation of p53. cIAP2 depletion also led to increased phosphorylation of ERK1/2. Reduction of p53 levels, in combination with survival signaling provided by NF-κB and MEK-ERK pathways were associated with increased colony formation in vitro and increased DMBA-induced adenocarcinomas in cIAP2-null mice.
Treatment of cells with IAP antagonists resulted in significant cytotoxicity only in p53-mutant MDA-MB-231 cells, which was associated with autocrine production of TNF-α. We propose that the transcription of TNF-α is potentiated by gain-of-function mutation in p53 since downregulation of mutant p53 in MDA-MB-231 cells decreased TNF-α mRNA. Downregulation of cIAPs in p53-mutant cells resulted in a decrease in nuclear IKK-α, which may result in decreased IKK-α-mediated survival signaling. In contrast, cIAP downregulation in p53-wildtype cells resulted in no change in nuclear IKK-α, degradation of the corepressor SMRT and cell survival. We show that the effects of cIAP2 downregulation are context-dependent. Downregulation of cIAP2 in p53-wildtype cells results in a decrease in p53 and an increase in survival and proliferative signaling. These results suggest a tumour suppressor function for cIAPs that may account for cIAP mutation-associated cancers such as multiple myeloma. Moreover, our data also defines gain-of-function p53 mutation as a possible contributor to IAP antagonist sensitivity.
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Posarac, Vesna. "Characterization and anti-HIV activity of the proprotein convertase-directed serine protease inhibitor, Spn4A". Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/3434.
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HIV/AIDS is a global health problem of immense magnitude, with 33 million people living with HIV and 2 million AIDS-related deaths per year. As the development of drug resistance undermines treatment efficacy, the long-term success of anti-retroviral therapy depends upon the introduction of novel drugs aimed at additional targets essential for the viral life cycle. With a critical role in many viral diseases including the proteolytic maturation of the HIV-1 envelope glycoprotein gp160, the secretory pathway proprotein convertases (PCs) represent a potential anti-viral target.
Our laboratory has reported the identification of Spn4A, a potent naturally occurring secretory pathway serine protease inhibitor directed at the prototype PC member, furin. Because of the requirement for the PCs in the production of infectious HIV-1, we hypothesized that strategic manipulation of PC activity by Spn4A and Spn4A-engineered variants would provide a means of effectively limiting HIV-1 infection.
This thesis details the investigation of the anti-proteolytic activities and anti-HIV-1 properties of recombinant adenoviruses expressing Spn4A and Spn4A bio-engineered variants, including a secreted recombinant Spn4A (Spn4A S). Our data shows that the expression of Spn4A S in MAGI-CCR5 cells and furin-deficient LoVo cells inhibited the PC-dependent processing of the HIV-1 envelope precursor gp160. Furthermore, inhibition of processing resulted in a nearly complete reduction of productive HIV-1 infection as determined by HIV-1 Tat-driven β-galactosidase activity and multinuclear activation of a galactosidase indicator (MAGI) assays. Complementing the previously described anti-furin activity of Spn4A, our studies indicate that Spn4A S inhibits additional PCs involved in gp160 maturation, and that PC inhibition can serve as an effective means of limiting HIV-1 infection.
With the central role of the PCs in the replication and pathogenesis of numerous infectious agents, the identification of Spn4A S as an efficacious HIV inhibitor establishes Spn4A as a prospective broad-based agent for the inhibition of PC-related diseases.
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Ordway, Gregory A., W. D. Gill, J. B. Coleman, Hui Wang-Heaton i Russell W. Brown. "Anti-Inflammatory PARP Inhibitor Demonstrates Antidepressant Activity in Animal Model of Treatment Resistant Depression". Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/8643.
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Background: Major depressive disorder is associated with elevated levels of DNA oxidation, DNA damage, and gene expression of DNA repair enzymes including poly (ADP-ribose) polymerase-1 (PARP1). Elevated PARP1 activity is directly linked to neuroinflammation and PARP inhibitors are anti-inflammatory and neuroprotective. We previously showed that PARP inhibitors produce antidepressant-like effects equivalent to fluoxetine in rodent models. Here, we examined whether the PARP inhibitor 3-aminobenzamide (3AB) is effective in a rat model of treatment-resistant depression.
Methods: Treatment-resistant depression was modeled with injections of lipopolysaccharide (LPS; 0.1 ug/kg/day) and daily chronic unpredictable stress (CUS) for 28 days. Anhedonia and helplessness were indexed with sucrose preference and forced swim tests, respectively, in 5 groups of rats (n¼6-8 rats/group) including unstressed, CUS, and CUS+LPS rats treated with saline, and CUS+LPS rats treated with either 3AB or fluoxetine.
Results: Anhedonia induced by CUS+LPS was significantly attenuated by 3AB (p¼0.01), while fluoxetine failed to do so. Likewise, 3AB was superior to fluoxetine in reducing helplessness, where latency to immobility times were significantly lower in CUS+LPS rats treated with fluoxetine (p¼0.001) compared to unstressed rats, but not significantly different for 3AB-treated CUS+LPS rats.
Conclusions: The PARP inhibitor 3AB demonstrated robust and unique antidepressant activity superior to fluoxetine in the TRD rat model. PARP is linked to neuroinflammation through release of microglia-activating factors including poly (ADP-ribose) and HMGB1, and through NF-kB activation, pathways under investigation by our lab. PARP inhibitors are currently used clinically to facilitate cytotoxicity of DNA-damaging anti-cancer treatments. Further research could implicate re-purposing non-cytotoxic PARP inhibitors for treatment-resistant depression.
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Couto, Jason. "Biologic Activity of the Novel Small Molecule STAT3 Inhibitor Against Canine Osteosarcoma Cell Lines". The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373986927.
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Hewitt, Laura. "Using a novel small molecule inhibitor to investigate the role of Mps1 kinase activity". Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/using-a-novel-small-molecule-inhibitor-to-investigate-the-role-of-mps1-kinase-activity(fcacfefc-90d9-4e92-9af4-a57897737329).html.
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During mitosis, accurate chromosome segregation is essential: gain or loss of genetic information can be detrimental to cell viability, or promote tumourigenesis. The mitotic checkpoint (also known as the spindle assembly checkpoint or SAC) ensures accurate chromosome segregation by delaying cell cycle progression until accuracy can be guaranteed. Mps1 is a protein kinase that is crucial for mitotic checkpoint signalling and also for proper chromosome alignment at metaphase. However, the precise role of Mps1’s catalytic activity is still unclear. Here, I present AZ3146, a novel small molecule inhibitor of Mps1. AZ3146 inhibits recombinant Mps1 in vitro with an IC50 of ~35 nM, and has low activity against a panel of 50 kinases, suggesting a reasonable degree of selectivity. As predicted for an Mps1 inhibitor, AZ1346 treatment led to spindle checkpoint malfunction in cells, accelerated mitotic timing, and perturbed the kinetochore localisation of the checkpoint effector Mad2. AZ3146 has a negative effect on cell viability, suggesting it leads to detrimental missegregations. Thus, the cellular effects of AZ3146 are consistent with Mps1 inhibition, and I was able to use the compound confidently as a tool to further probe the role of Mps1 activity in cells.Strikingly, levels of Mps1 increased at unattached kinetochores following inhibition of its kinase activity, suggesting Mps1’s kinetochore localisation is regulated by its own activity. A kinase-dead GFP-Mps1 fusion protein only accumulated at kinetochores in the absence of endogenous, active Mps1, implicating intra-molecular interactions in regulation of Mps1’s kinetochore localisation. I confirm a role for Mps1 in the mechanism of chromosome alignment, but in contrast to previous reports I did not detect a decrease in Aurora B activity following Mps1 inhibition. On the contrary, both Mps1’s phosphorylation status and its kinetochore localisation were affected by treatment with the Aurora B inhibitor ZM447439, placing Mps1 downstream of Aurora B. As an alternative explanation for the alignment defect in cells with reduced Mps1 activity, I found that levels of the plus-end directed kinesin Cenp-E were markedly decreased at unaligned kinetochores. I propose a model in which catalytically active Mps1’s auto-release from kinetochores simultaneously promotes both mitotic checkpoint signalling and chromosome alignment by facilitating Mad2 dimerisation and Cenp-E binding at unattached kinetochores.
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Watanabe, Koji. "Pterin-6-aldehyde, an Inhibitor of Xanthine Oxidase, Has Superoxide Anion Radical Scavenging Activity". Kyoto University, 2000. http://hdl.handle.net/2433/151411.
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Bosc, Damien. "Synthèse et évaluation biologique d’hétérocycles à cinq chaînons, inhibiteurs de la protéine farnésyltransférase". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112200/document.
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La protéine farnésyltransférase (FTase) est une métalloenzyme à zinc catalysant le transfert d’une chaîne farnésyle provenant du pyrophosphate de farnésyle (FPP) sur le résidu cystéine de certaines protéines possédant un motif CaaX C-terminal où C est la cystéine farnésylée, a est un acide aminé aliphatique et X est Ser, Ala, Gln ou Met. Une fois additionné, le groupement farnésyle fait office de point d’ancrage rendant possible la fixation des protéines à la membrane cellulaire et de guide moléculaire facilitant la liaison de ces protéines prénylées à d’autres protéines. D’abord étudiée en oncologie, la FTase constitue aujourd’hui une cible potentielle pour la thérapie antiparasitaire qui manque cruellement de médicaments suite à l’apparition de phénomènes de résistance. La nécessité d’améliorer les thérapies existantes ouvre la voie de recherches innovantes pour trouver de nouvelles molécules bioactives.Lors de ces travaux de thèse, les deux stratégies de recherche pratiquées en chimie médicinale ont été utilisées.La première approche a consisté à synthétiser des analogues bisubstrats 1,2,3-triazoles pouvant se lier à la fois sur le site de liaison de la protéine et sur celui du FPP. Cette approche rationnelle a aussi permis d’ébaucher une synthèse monotope de triazoles 1,5-disubstitués à partir d’amines primaires. L’approche par criblage constitue la deuxième méthode de recherche de nouveaux inhibiteurs. Dans ce contexte, la chimiothèque de l’ICSN a été criblée et deux composés de type 3-arylthiophène ont révélé de bonnes activités et une structure originale dans l’inhibition de la FTase. Ainsi, des travaux de relations structure-activité ont été réalisés pour moduler les différentes positions du thiophène et la nature de l’hétérocycle central.Ce travail nous a permis d’élaborer une librairie de plus d’une centaine de composés. L’évaluation biologique de ces analogues sur FTases isolées humaine et de T. brucei et sur parasites T. brucei et P. falciparum a révélé des molécules particulièrement intéressantes et prometteusesProtein farnesyltransferase (FTase) is a zinc metalloenzyme which catalyzes the transfer of a farnesyl chain from farnesyl pyrophosphate (FPP) to the cysteine residue of some proteins possessing a C-terminal CaaX moiety where C is the farnesylated cysteine, a is an aliphatic amino-acid and X is Ser, Ala, Gln or Met. Once attached, the farnesyl group serves as anchors for fixing proteins to cell membrane and as molecular handles for facilitating binding of these prenylated proteins to other proteins.First studied in oncology, FTase constitutes nowadays a potential target for antiparasitic therapies, where drugs are missing due to the appearance of resistance phenomena. The necessity to improve the existing therapies paves the way of innovating researches to find new bioactive molecules.During this Ph.D work, two strategies of research used in medicinal chemistry were performed.The first approach consisted in the synthesis of bisubstrate analogues with a 1,2,3-triazole core deviced to tie up both to the protein and the FPP binding sites. This rational approach also allowed to draft a one-pot synthesis of 1,5-disubstituted triazoles from primary amines.The screening approach was the second strategy to search for new inhibitors. For this purpose, ICSN chemical library was screened and two 3-arylthiophene compounds disclosed good activities and an original scaffold for FTase inhibition. Therefore, a structure-activity relationship study was carried out to modulate the different positions of the thiophene and the nature of the central heterocycle.This work allowed us to create a above-hundred-molecule library. The biological evaluation of these analogues on human and T. brucei isolated FTase and on T. brucei and P. falciparum parasites revealed particularly interesting and promising molecules
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Li, Hao. "Design, Synthesis, and Structure-Activity Relationship Investigation of Selective Sphingosine Kinase Inhibitors". Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/100741.
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Sphingosine kinase 1 (SphK1) is the key enzyme catalyzing the formation of sphingosine-1-phosphate (S1P), which is an important signaling molecule that regulates multiple biological process including inflammatory responses. Elevated SphK1 activity as well as upregulated S1P levels is linked to various diseases such as cancer, fibrosis and sickle cell disease. Therefore, there is a growing interest in studying SphK1 as a potential target for these diseases. Through high-throughput screening, various SphK1 inhibitors have been discovered, among which PF-543 is the most potent and selective inhibitor reported to date (Ki=3.6 nM, >100 fold selectivity for SphK1). Previous research indicated that SphK1 inhibitor PF-543 is effective in reducing S1P levels and slowing down the development of sickle cell disease in vivo. However, the lack of in vivo stability of PF-543 still makes it necessary to develop inhibitors with an improved pharmacokinetic profile. In this study, PF-543 was employed as the lead compound, and the influence of different tails groups and head groups on binding affinity and in vivo stability were investigated. In brief, (R)-prolinol-based derivatives with various tail groups including alkyl, alkoxy and biphenyl groups were synthesized. Their inhibition potency was tested in a broken-cell assay, and hit compounds were further evaluated in a yeast cell assay to determine EC50 values. The U937 cell line and mice model were utilized for hit compounds to quantify S1P reduction in vitro and in vivo. Our preliminary results indicated compound 2.14d was the best hit discovered, with 88% SphK1 inhibition at 1 μM. In addition, compound 2.14d with a Ki of 0.68 μM and an EC50 of 0.15 μM, reduced the S1P of U937 cells by 90% at 1 μM. Its analog with a shorter tail group, 2.14a, reduced plasma S1P levels by 20% in mice (10 mg/kg, 3 h). Further modification of the head group of 2.14d produced compound 3.14c bearing a secondary benzylamine head group, with an EC50 value of 0.39 μM and less in vivo activity (14% plasma S1P reduction at 10 mg/kg, 6 h).Doctor of Philosophy
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Baker, Amanda F., Neale T. Hanke, Barbara J. Sands, Liliana Carbajal, Janet L. Anderl i Linda L. Garland. "Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models". BioMed Central, 2014. http://hdl.handle.net/10150/610318.
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BACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. METHODS: A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. RESULTS: CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC₅₀ values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC₅₀ values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CONCLUSIONS: CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.
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Chandrasekar, Balakumaran [Verfasser]. "From glycosidase activity profiling to inhibitor discovery in the plant pathogen Pseudomonas syringae / Balakumaran Chandrasekar". Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/1161462309/34.
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Yunus, Madiha. "Investigating the Effect of Regorafenib on the Expression and Activity of the Angiogenesis-Modulating Receptor Tyrosine Kinases". Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/29860.
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The past two decades have been vital for developing cancer treatments. Even though traditional chemotherapy remains the primary choice for most oral treatment regimens, the cancer treatment paradigm is shifting towards more personalised, mechanism-based and selective therapeutic strategies.
Tremendous advances have been made in understanding the aberrant signal transduction pathways in cancer, and a myriad of oncogenic drivers have been identified as promising candidates for molecule-targeted therapies. By using small low-molecular-weight compounds, specific alterations in oncogenic molecules driving cancer progression can be targeted precisely.
Neoangiogenesis is a complex process and one of the founding hallmarks of cancer. Therefore, targeting tumour angiogenesis is a key strategy in cancer treatment. The antiangiogenic agents currently available for gastric cancers are specific and predominantly target the vascular endothelial growth factor (VEGF) pathway. However, specific VEGF targeting has not proven 100% effective due to the emergence of several interconnected and compensatory pathways in response to VEGF targeting.
This thesis explores the efficacy of Regorafenib, a small molecule multikinase inhibitor with a broad antiangiogenic activity that targets multiple signalling pathways to maximise its potential therapeutic anti-cancer strategy. This thesis aims to build a profile of the kinases targeted by Regorafenib in gastric cancer and identify novel molecular pathways that may arise in response to Regorafenib’s multi-targeted mechanism of action.
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Wang, Haiyao. "Antiplasmin the main plasmin inhibitor in blood plasma : studies on structure-function relationships /". Stockholm : Department of Surgical Sciences, Division of Clincal Chemistry and Blood Coagulation, Karolinska University, 2005. http://diss.kib.ki.se/2005/91-7140-278-0/.
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Fernández, Cecilia A. 1969. "Functional and structural uncoupling of the angiogenic and enzymatic inhibitory activity of TIMPs : loop 6 of TIMP-2 is a novel inhibitor of angiogenesis". Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/31110.
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Thesis (Ph. D. in Applied Biosciences)--Massachusetts Institute of Technology, Biological Engineering Division, 2004.Includes bibliographical references (leaves 119-130).
Tissue inhibitors of metalloproteinases (TIMPs) regulate tumor growth, progression and angiogenesis in a variety of experimental cancer models and in human malignancies. However, numerous studies have revealed important differences between TIMP family members in their ability to inhibit angiogenic processes in vitro and angiogenesis in vivo despite their universal ability to inhibit matrix metalloproteinase (MMP) activity. To address these differences, structure-function studies were conducted to identify and characterize the anti-angiogenic domains of TIMP-2, the endogenous MMP inhibitor that uniquely inhibits capillary endothelial cell (EC) proliferation and angiogenesis in vivo. Only the carboxy-terminal domain of TIMP-2 (T2C) and not the MMP-inhibitory N-terminal domain (T2N), inhibited capillary EC proliferation. Although both T2N and T2C inhibited embryonic angiogenesis, only T2C potently inhibited mitogen-stimulated angiogenesis. These findings demonstrate that TIMP-2 possesses two distinct types of anti-angiogenic activities which can be uncoupled from each other. The anti-proliferative activity of T2C was further mapped to the 24-amino acid peptide, Loop 6, which proved to be a potent inhibitor of both embryonic and nitogen-stimulated angiogenesis in vivo. Initial studies into the mechanism(s) by which Loop 6 inhibits angiogenesis revealed that the anti-proliferative effects of Loop 6 are due, at least in part, to the inhibition of cell cycle progression and not to the induction of apoptosis. This inhibition was associated with increased levels of cell cycle inhibitor p27. Although Loop 6 did not compete with bFGF for binding to its receptor,
(cont.) five potential cell surface complexes were observed in crosslinking studies of capillary EC treated with ¹²⁵I-labeled T2C or Loop 6. Finally, given the high degree of homology between TIMP-2 and TIMP-4, we hypothesized that TIMP-4 might share anti-proliferative and MMP inhibition- independent anti-angiogenic activities with TIMP-2. Our results demonstrate that although TIMP-4 inhibits capillary EC migration, it does not inhibit capillary EC proliferation. Furthermore, TIMP-4 did not result in significant inhibition of embryonic angiogenesis in the CAM. These results suggest that TIMP-2 is unique among TIMP family members in its ability to inhibit angiogenesis via two distinct pathways. One of these activities, housed within Loop 6, results in the potent inhibition of angiogenesis in vivo.
by Cecilia A. Fernández.
Ph.D.in Applied Biosciences
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Natarajan, M. "Effects of amylase inhibitor albumin from wheat on the alpha-amylase activity in carp and tilapia". Thesis, University of Stirling, 1988. http://hdl.handle.net/1893/1919.
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The amylolytic activities of alpha-amylase extracted from Mirror carp (Cyprinus carpio) and Nile tilapia (Oreochromis niloticus) were significantly reduced by purified amylase inhibitor albumin of wheat when tested under in vitro conditions. The action of this inhibitor was rapid and maximum levels of inhibition were attained within 20 minutes. For both carp and tilapia, the enzyme residual activities after inhibition were found to be related inversely to inhibitor concentration and positively to the initial enzyme activity levels. The curvilinear relationships between these parameters were explained by deriving equations of the type: A2 = a+b A1 - c I + d I2 where a, b, c and d are constants, Ai = Initial amylase activity (mU/min), A2 = Residual amylase activity (MU/min), I= Inhibitor concentration as ug protein. Inhibitions were greatest for amylases from gut tissue and ýowest for amylases from gut fluids. 1ug of purified inhibitor was found to contain a potency, to reduce 298 Units of carp gut tissue alpha-amylase and 532 Units of tilapia intestinal tissue alpha-amylase, by 50%. When amylase inhibitor extracted from wheat was incorporated in the feed of carp in its active form for three weeks, it caused a significant reduction in the specific growth rate to only 0.16%/day, while in carp fed autoclaved inhibitort such reduction in growth was not seen and the SGR was maintained at over 1.00%/day. However, despite the presence of active inhibitor in the intestine, the fish were able to maintain alpha-amylase activities in the gut contents at a level similar to that in fish fed denatured inhibitor. This was achieved by hyperactivation of enzyme secretions in the tissues of hepatopancreas and intestine. Hepatopancreas from fish fed active inhibitor exhibited more than two-fold increase in amylase, activity compared to those fed denatured inhibitor. By the third week of the experiment this difference in enzyme activity levels was not apparent but there were also no indications of adaptation or improvement in growth rate. Degenerations in hepatopancreas were also not apparent. Feeding carp with diet containing wheat with its inherent content of inhibitor also caused pancreas hyperactivity and some reduction in growth rate for a short period in comparison to those fish fed autoclaved wheat. In carp, the alpha-amylase activity did not vary depending on the raw or gelatinized nature of starch, both forms elicited equal increases in enzyme activity. However, autoclaving wheat, though effective in inactivating the inhibitor, was found to lower the biological value and digestibility of wheat proteins. Contrary to the result of the carp trials in Nile tilapia, the growth was not significantly reduced by feeding on diet containing active inhibitor and a SGR of 1.57%/day was recorded in comparison to 1.81i/day in tilapia fed denatured inhibitor. Samples of stomach and intestinal contents collected 4 hours after feeding did not reveal the presence of active inhibitor. Apparently the acidic protease, pepsin, in the stomach of tilapia caused the total destruction of the inhibitor in the diet before the contents were passed into the intestinal region. The presence of active amylase inhibitor in tilapia feed did not affect the digestibilities of starch and protein in the diet. Both the groups were able to digest carbohydrates and protein to levels of over 90%. The implications of these results are discussed in relation to feed formulation and fish nutrition.
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Glas, Carina [Verfasser], i Franz [Akademischer Betreuer] Bracher. "Structure-activity relationship analysis of the subtype-selective Sirt5 inhibitor balsalazide / Carina Glas ; Betreuer: Franz Bracher". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1228270929/34.
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Tanaka, Ruriko. "Activity of the multi-targeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL positive leukemic cells". Kyoto University, 2011. http://hdl.handle.net/2433/142109.
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Batman, Angela. "MODULATION OF COCAINE-LIKE BEHAVIOURAL ACTIVITY BY SEROTONIN UPTAKE INHIBITION RELATIVE TO THE EFFECTS OF THE NOVEL AND SELECTIVE DOPAMINE TRANSPORTER INHIBITOR, D-84". VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2181.
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Cocaine dependence is a major health concern worldwide, but despite this high rate of abuse there are currently no approved therapies for cocaine dependence. Replacement pharmacotherapies are one possible approach for treating cocaine dependence, and identification of such therapeutics for cocaine abuse is the long-term goal of this research. Cocaine binds to, and inhibits uptake at the dopamine (DAT), serotonergic (SERT) and noradrenaline (NET) uptake transporters, but studies have shown that cocaine produces its strong behavioural and positive reinforcing effects through inhibition of the DAT. To this end a great number of diverse, non-selective DAT-inhibiting compounds have been investigated as potential cocaine replacement therapies. It was the initial objective of this research to determine whether the behavioral profile of a novel, selective DAT inhibitor, D-84, fit with that thought for an ideal cocaine replacement therapy. Results indicated that D-84 stimulated locomotor activity, incompletely generalized to the cocaine cue in discrimination tests, attenuated cocaine-self-administration and was self-administered. These observations provide a profile consistent, although perhaps not ideal, with one possible treatment strategy for cocaine dependence. Although it is well established that cocaine predominantly produces its abuse-related effects through inhibition of the DAT, recent evidence suggests that inhibition at the SERT may have modulating effects on the pharmacology of cocaine-like compounds. The second part of this dissertation investigated what effects that increasing SERT inhibition had on the cocaine-like behavioural effects of DAT inhibitors, as a method of determining the fruitfulness of incorporating this feature into future drug candidates to improve them. RTI-55 (DAT Ki 2.7 nM SERT Ki 3 nM) and GBR-12909 (DAT Ki 4.3 nM SERT Ki 73 nM) were selected based on their high and intermediate SERT inhibitory effects, respectively. They were compared in behavioural studies with D-84, which is considered to be a selective DAT inhibitor. The results indicated that although increasing SERT inhibition attenuated locomotor activity effects, it had less effect on cocaine-like discriminative stimulus and reinforcing effects, at least with the doses tested
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Debord, Jean. "Relation structure chimique-activité biologique pour quelques phosphoramides et benzamides". Poitiers, 1988. http://www.theses.fr/1988POIT2331.
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Les constantes d'inhibition reversible de la butylcholinesterase par une serie de 16 phosphoramides aliphatiques ont ete determinees par spectrophotometrie et par microcalorimetrie. L'activite des substituants amines augmente avec la lipophilie. L'inhibition irreversible de la butylcholinesterase par le thio-tepa et le methyl-parathion a ete etudiee en suivant l'hydrolyse d'une faible concentration de substrat en presence de l'inhibiteur
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Ren, Huan. "Biological activity of the 2-phenylaminopyrimidine class receptor tyrosine kinase inhibitor imatinib mesylate (STI571) in malignant glioma". Thesis, University of Liverpool, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419008.
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Zyryanova, Alisa. "A molecule-inhibitor of the integrated stress response regulates activity of mammalian eukaryotic translation initiation factor 2B". Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/284208.
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The Integrated Stress Response (ISR) is a conserved eukaryotic translational and transcriptional program implicated in mammalian metabolism, memory and immunity. Although mainly considered to be a protective mechanism, prolonged and severe ISR can result in cell death. The ISR is activated by diverse stress pathways converged on phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2) that inhibits the guanine nucleotide exchange activity of its partner eIF2B and attenuates overall rates of protein synthesis. Numerous mutations in eIF2B are linked to a fatal neurodegenerative disease of vanishing white matter. A new chemical inhibitor of the ISR (ISRIB), a bis-O-arylglycolamide, can reverse the attenuation of mRNA translation by phosphorylated eIF2 protecting mice from prion-induced neurodegeneration and traumatic brain injury. The work presented in this dissertation describes identification of mammalian eIF2B as a cellular target of ISRIB by implementing biochemical, biophysical, structural and chemogenetic methods. The herein reported cryo-electron microscopy-based structure of eIF2B uncovers a novel allosteric site on the translation factor capturing the ISRIB-binding pocket at the interface between its β and δ regulatory subunits. The extensive CRISPR/ Cas9-based screen for ISRIB-resistant and analogue-sensitive phenotypes revealed residues on the eIF2B dimer interface important for ISRIB binding. Based on the results reported in this dissertation along with the similar findings of others the potential molecular basis of ISRIB action, and its implication for the regulation of eIF2B's activity is broadly discussed. The identification of the ISRIB binding pocket away from the known interaction sites between eIF2B and eIF2 is also put into the context of a possible molecular mechanism of eIF2B's guanine exchange inhibition by phosphorylated eIF2. The work described in this dissertation provides new insight into the translational regulation and points to the importance of fine-tuning the activity of translation factors by small chemical molecules.
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Harrington, Bonnie K. "Activity of the Second Generation BTK Inhibitor Acalabrutinib in Canine and Human B-cell Non-Hodgkin Lymphoma". The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1531911818180297.
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Garrido, Christian M. "Avicin is a potent sphingomyelinase inhibitor that blocks K-Ras plasma membrane interaction and its oncogenic activity". Wright State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=wright1545974237243977.
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Khanwalkar, Harshal. "In vitro and in vivo analysis of anti-tumour activity of UVI5008, a novel chromatin enzyme inhibitor". Strasbourg, 2010. http://www.theses.fr/2010STRA6266.
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De plus en plus de données indiquent que le cancer n’est pas uniquement la conséquence d’altérations génétiques, mais résulte également en partie d’altérations épigénétiques. De façon intéressante, cette dérégulation épigénétique est réversible, faisant des enzymes responsables des cibles thérapeutiques potentielles. En effet, les enzymes de modification de la chromatine et en particulier les Histones Déacétylases (HDACs) et les ADN Méthyltransférases (DNMTs), ont récemment émergé comme de nouvelles cibles prometteuses appelées « drogues épigénétiques » pour le traitement des cancers. Le but de ce projet a été de caractériser l’activité de UVI5008, un dérivé de la psammaplin A qui a initialement été isolée de l’éponge marine Psammaplysilla. Ce composé a été synthétisé dans le laboratoire de l’un de nos collaborateurs, le professeur Angel R. De Lera (Université de Vigo, Espagne), et nous avons pu montrer que ce composé cible spécifiquement plusieurs enzymes épigénétiques et présente une activité anti-tumorale in vitro et in vivo. Nous avons évalué l’activité anti-tumorale potentielle de UVI5008 in vitro sur des lignées de cellules cancéreuses et ex vivo sur des blastes issus de patients leucémiques. Nos résultats indiquent que UVI5008 réduit la prolifération cellulaire en induisant un arrêt du cycle cellulaire en phase G1-M et l’apoptose dans des lignées cellulaires de leucémie myéloïde aiguë (AML) établies et dans des blastes issus de patients AML en culture ex vivo. Des essais enzymatiques in vitro ont permis de mettre en évidence que UVI5008 bloque l’activité de HDAC1, 4 et 6 et augmente l’acétylation globale et spécifique des histones. Outre son activité d’inhibition des HDACs, ce nouvel inhibiteur bloque également la méthylation des îlots CpG situés sur les promoteurs des gènes suppresseurs de tumeur p16/INK4 et RAR-Beta, un récepteur de l’acide rétinoïque. Enfin, nous avons observé que UVI5008 possède des capacités inhibitrices des sirtuines, le niveau d’acétylation de p53 sur le résidu lysine 382 étant augmenté suite à un traitement avec ce composé. Nous avons également pu mettre en évidence une activité antitumorale de UVI5008 in vivo dans des xénogreffes de cellules HCT116 (issues de cancer du colon humain) et de cellules MCF7 (provenant de cancer du sein humain) dans des souris nues, de même que dans un modèle murin de cancer mammaire, les souris MMTV-Myc. Dans ces différents modèles, une augmentation de l’acétylation des histones et de p53K382 a pu être observée in tumouri. De façon importante, l’activité de UVI5008 est spécifique des cellules cancéreuses et sans toxicité importante pour les cellules normales. De plus, son activité est indépendante de p53, ce qui représente un avantage, la majorité des cancers ayant une mutation ou une extinction de l’expression de p53. ErbB2 joue un rôle important dans de nombreuses pathologies humaines. Son niveau est augmenté par amplification génique ou surexpression dans environ 30 % des cancers mammaires humains, de même que dans d’autres pathologies humaines, et cette marque est associée à un mauvais pronostique pour les patients. Nous avons donc choisi de tester l’activité anti-tumorale de UVI5008 sur un autre modèle de tumorigenèse chez la souris par la surexpression de l’oncogène ErbB2 dans la glande mammaire, les souris MMTV-ErbB2, et nous avons pu montrer une efficacité similaire de UVI5008 sur ces tumeurs mammaires. À l’heure actuelle, il n’existe pas de traitement qui cible simultanément l’ensemble de ces 3 familles d’enzymes que sont les HDACs, les DNMTs et les SIRTs. Nos résultats suggèrent fortement que ces enzymes peuvent être ciblées simultanément par un composé unique, ce qui pourrait représenter un avantage pour les nouvelles thérapies contre le cancerIt is becoming increasingly clear that cancer is a consequence not only of genetic but also of epigenetic alterations. Interestingly, this epigenetic deregulation is reversible making the corresponding enzymes promising drug targets. Chromatin modifying enzymes, in particular histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), have recently emerged as new promising targets of the so-called “epigenetic drugs” for the treatment of cancer. The aim of this project is to characterize the activities of UVI 5008, a derivative of psammaplin A, a natural product that was originally isolated from the marine sponge Psammaplysilla sp. This compound was synthesized by one of our collaborators, Prof. Angel. R de Lera’s lab (Vigo University, Spain) and we were able to show that it targets several epigenetic effector enzymes and displays anti-tumour activity in vitro and in vivo. We have assessed the tumoricidal activity of UVI5008 both in vitro in a panel of cancer cell lines as well as ex vivo in leukemia patient’s blasts. Our results indicate that UVI5008 reduces cell proliferation by inducing G1-M arrest and apoptosis in established acute myeloid leukemia (AML) cells and AML patient’s blasts in ex vivo culture. In vitro enzymatic assays showed that UVI5008 blocks HDAC1, 4 and 6 as well as increases the global and site-specific histone acetylation. Apart from its HDAC inhibitory activity, the novel inhibitor blocks CpG island methylation of the promoters of p16/INK4 and retinoic acid receptors (RAR)-beta tumor suppressors. Moreover, we have observed that UVI5008 has sirtuin inhibitory capacity as it increases the acetylation levels of p53 on lysine 382 residue. We could also show that UVI5008 exerts its antitumor effect in vivo in HCT-116 (human colon cancer) and MCF-7 (human breast cancer) xenografted tumours in nude mice as well as in a mouse breast cancer model MMTV-myc, which was accompanied by increased histone and p53K382 acetylation in tumouri. Importantly, UVI5008 anti-tumoral activity is selective for cancer cells, without significant toxicity to normal cells and is p53-independent which is also promising, as in the majority of cancers p53 is either silenced or mutated. It is well documented that ErbB2 gene plays an important role in human malignancies. It is amplified and /or overexpressed in approximately 30% of human breast carcinomas and in many other types of human malignancies and individuals with ErbB2-overexpressing tumours have significantly poor clinical outcome. Taking into consideration this fact, we have assessed the anti tumour activity of UVI5008 in one more mouse breast cancer model MMTV-ErbB2, which revealed that UVI5008 is equally active in ErbB2 overexpressing breast tumours. To date there is not a single drug that simultaneously targets all these three families of enzymes namely HDACs, DNMTs and SIRTs. Taken together, our data strongly suggest that targeting these enzymes simultaneously by a single drug is a feasible and an attractive paradigm for new cancer therapies
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ARNO', BARBARA. "Investigation of human topoisomerase 1b activity through a domain substitution and interaction with a new synthetic inhibitor". Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2013. http://hdl.handle.net/2108/210054.
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Il Plasmodium falciparum è l’agente eziologico della malaria umana. La diffusione di ceppi multi- resistenti ai farmaci ha reso necessaria l’identificazione di nuovi bersagli molecolari per la terapia antimalarica. Le DNA topoisomerasi, responsabili della regolazione della topologia del DNA durante fondamentali processi biologici, possono essere considerate possibili candidati. La DNA topoisomerasi 1 (Top1) risolve i superavvolgimenti accumulati dalla doppia elica del DNA catalizzando il processamento di uno dei due filamenti, la rotazione e la risaldatura. La Top1 umana (hTop1) ha una struttura bilobata costituita da tre domini proteici e un dominio linker che si estende dal dominio C-terminale, contenente il sito attivo. Il dominio linker svolge un ruolo fondamentale nel meccanismo catalitico dell'enzima. E’ stato dimostrato che in seguito alla delezione del linker nella hTop1, si perdono interazioni inter-dominio, evidenziando così la sua importanza nel controllo della risaldatura del DNA e nella modulazione della sensibilità verso la camptotecina (CPT), noto inibitore della hTop1. La topoisomerasi 1 del Plasmodium falciparum (PfTop1) presenta un linker di lunghezza maggiore rispetto all’omologo enzima umano; il ruolo strutturale e funzionale del dominio linker della PfTop1 è stato analizzato mediante il clonaggio di una Top1 chimera umana/plasmodio, hTop1(Pf-linker), in cui il dominio linker della hTop1 è stato sostituito con il relativo dominio della PfTop1. Inoltre, è stato sintetizzato un composto penta ciclico-dichinoide, Et-Kuq , ed analizzato il suo effetto sulla hTop1 mediante saggi di attività e docking molecolare, per mezzo dei quali è stato possibile comprenderne il meccanismo d’inibizione ed evidenziare elementi fondamentali della reazione di risaldatura.Plasmodium falciparum infection is one of the most frequent acquired red blood cell disease worldwide. The spread of multi-drug-resistant strains has increased the need to identify new molecular targets for antimalarial therapy. DNA topoisomerases may be considered possible candidates, due to their important role in cellular activities, including DNA replication. DNA topoisomerase I (Top1) relaxes supercoiled DNA by a transient DNA strand breakage, rotation, and religation. The human Top1 (hTop1) comprises a conserved protein clamp, tightly wrapped about the DNA duplex, formed by three protein domains and an extended coiled-coil linker domain that appropriately positions the C-terminal active site tyrosine against the core to form the catalytic pocket. The linker has been shown to be important in controlling the enzyme catalytic mechanism. After removal of the linker domain, hTop1 loses inter-domain communication, thus highlighting the importance of linker in controlling the religation and modulating CPT sensitivity. The Plasmodium falciparum topoisomerase I (PfTop1) contains a longer linker, compared to the human homologue. This finding pushed us in exploiting its structural and functional properties in enzyme activity and drug sensitivity swapping the hTop1 linker domain with the corresponding one of PfTop1. Moreover, as the linker domain specifically affects the religation reaction, a pentaciclic-diquinoid synthetic compound, KuQ, has been designed and its effect has been analyzed through activity assays and molecular docking, identifying crucial elements for this step of the hTop1 activity.
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Boisson, Julien. "Synthèse de nouveaux iminosucres et évaluation de leur activité inhibitrice de glycosidases". Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENV027/document.
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Le travail présenté dans ce manuscrit concerne la synthèse et une évaluation biologique de 10 nouveaux iminosucres. Les iminosucres sont une classe importante d'inhibiteurs de glycosidases (enzymes catalysant l'hydrolyse d'oligosaccharides), et l'activité inhibitrice de nos produits a été évaluée vis-à-vis d'un panel de 7 glycosidases différentes.Notre laboratoire a récemment décrit la préparation de cétonitrones cycliques polyalcoxylées à partir de cétoses tels que le D-fructose ou le L-sorbose (des sucres naturels abondants). Nous avons imaginé utiliser ces cétonitrones comme intermédiaires clés pour la synthèse de nouveaux iminosucres de structure originale, comportant un centre quaternaire en alpha de leur atome d'azote. Une partie de ce travail de thèse a consisté à améliorer la synthèse de ces cétonitrones, puis à trouver des conditions de C-vinylation diastéréosélective afin d'accéder sélectivement et efficacement à quatre pipéridines diastéréoisomères après réduction de la fonction N-hydroxylamine formée. La N-allylation de ces dernières a permis l'accès à des bis-alcénylpipéridines qui ont pu être aisément transformées en N-propylpipéridines,alpha-gem-disubstituées tétrahydroxylées après hydrogénation (des deux chaînes insaturées) et débenzylation.Les bis-alcénylpipéridines ont également été employées pour une réaction de métathèse cyclisante qui conduit au squelette indolizidine avec une double liaison en C1-C2. L'hydrogénation ou la dihydroxylation de cette double liaison, suivie par une étape de débenzylation a permis la synthèse d'indolizidines polyhydroxylées (tétra- et hexahydroxylées) inédites, substituées en jonction de cycle (position 8a). Un des composés synthétisés (une indolizidine) s'est révélé être un inhibiteur puissant et sélectif d'-glucosidases avec une concentration inhibitrice médiane de 52 nM (sur alpha-glucosidase de riz) et un mode d'inhibition peu répandu dans cette famille de molécules (inhibition non compétitive mixte)This manuscript describes the synthesis and bioevaluation of 10 new iminosugars. Iminosugars are an important class of compounds, which can inhibit the activity of glycosidases (enzymes which catalyze oligosaccharide hydrolysis). The inhibitory activity of our products was assessed towards a panel of 7 glycosidases.Our laboratory has recently succeeded in the preparation of polyalkoxylated cyclic ketonitrones from ketoses such as D-fructose or L-sorbose (abundant natural sugars). Herein, we envisaged their utilization as precursors of new, structurally original iminosugars, bearing a quaternary center in of their nitrogen atom. We firstly improved the synthesis of these ketonitrones, and then we optimized conditions for their diastereoselective C-vinylation, in order to access selectively and efficiently four diastereoisomeric piperidines after reduction of the formed N-hydroxylamine function. The N-allylation of these piperidines gave access to the corresponding bis-alkenylpiperidines, which were readily transformed into ,alpha-gem-disubstituted tetrahydroxylated N-propylpiperidines after hydrogenation (of both unsaturated chains) and debenzylation.The bis-alkenylpiperidines were also engaged in a ring closing metathesis reaction, providing the indolizidine skeleton with a double bond in C1-C2. Hydrogenation or dihydroxylation of the latter, followed by a debenzylation step, produced original polyhydroxylated indolizidines (tetra- and hexahydroxylated), which are substituted at their ring junction (8a position). One of the synthesized compounds (an indolizidine) was found to be a highly potent and selective inhibitor of -glucosidases with a median inhibitory concentration of 52 nM (rice alpha-glucosidase) and an uncommon mode of inhibition for this class of molecules (mixed non-competitive inhibition)
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Kutlesa, Nicole J. "The insecticidal activity of a herbicidal inhibitor of glutamine synthetase tested on larvae of Calpodes ethlius (Lepidoptera: hersperiidae)". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ42166.pdf.
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Henderson, Sally E. "Translating the Anti-Tumor/Anti-Cachectic Activity of AR-42, a Novel HDAC Inhibitor, into Pancreatic Cancer Therapy". The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1495801301660324.
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Christadore, Lisa M. "Discovery of a small molecule dihydroquinolinone inhibitor with potent antiproliferative and antitumor activity results in catastrophic cell division". Thesis, Boston University, 2013. https://hdl.handle.net/2144/12733.
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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.A family of dihydroquinolinones that inhibited the proliferation of a number of cancer cell lines and targeted the oncogenic activities of the late simian virus 40 factor (LSF) was discovered. The lead quinolinone inhibitors, 8-(2-propoxyphenyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one, FQI1, and 8-(2-propoxyphenyl)-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one, FQI2, were determined by a comprehensive SAR study. The lead compounds had low micromolar to nanomolar Gi50S and IC50S (concentrations that induced 50% inhibition) in cell growth and LSF-directed luciferase reporter assays, respectively. A distinct correlation between the GI50 and IC50 values indicated antiproliferative effects resulted from inhibition of LSF activity. FQI1 had no growth effects on immortalized human hepatocytes or primary mouse hepatocytes. Overall, FQI1 proved a good drug candidate for hepatocellular carcinoma (HCC). It possessed a low molecular weight and moderate solubility, which was improved by substitution of the amide with a triazole bioisostere. FQI1 showed excellent microsomal stability, high in vivo volume of distribution and half-life in rodents, and was a potent inhibitor of HCC tumorigenesis in immunocompromised mice. FQI1 induced mitotic catastrophe in the HCC cell line, QGY-7703, the cervical carcinoma cell line, HeLa, and the NIH-3T3 fibroblasts, as evidenced by widespread multinucleated cell morphologies. Excessive micronucleation in NIH-3T3 cells treated with higher FQI1 concentrations further supported severe chromosome segregation defects. Mitotic slippage into interphase and subsequent endoreduplication was also induced by FQI1 in NIH-3T3 cells. These phenotypes have been seen with chemicals such as the microtubulin poisons and Aurora B kinase inhibitors. Together these results suggested that FQI1-induced evasion or adaptation of the spindle assembly checkpoint and abnormal chromosome segregation resulted in mitotic catastrophe, and in the case of NIH-3T3 cells, polyploid cell progeny. Expression profiling in QGY-7703 cells with FQI1 cells revealed an upregulation of multiple genes along the TGF-β/SMAD signaling cascade compared to the untreated cell population. This supported a model where the induction of p21Cip1 activity as a result of mitotic slippage activated the G1/S checkpoint in response to aberrant exit out of mitosis in QGY-7703 cells. These results together elucidated FQI1's mechanism of action in mitosis and also strongly suggested that LSF regulated genes required for the proper execution of mitosis.
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Elkovich, Andrea J. "The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth". VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5792.
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Myeloid Derived Suppressor Cells (MDSC) represent a significant hurdle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous studies have reported on the myelo-depletive effects of certain chemotherapies. Using guadecitabine, a next-generation DNA methyltransferase inhibitor (DNMTi), we observed significantly reduced tumor burden in the 4T1 murine mammary carcinoma model. Guadecitabine treatment prevents excessive tumor-induced myeloid proliferation and systemic accumulation, and skews remaining MDSCs toward a beneficial antigen-presenting phenotype. Together, this alters the splenic environment to improve T cell activation and interferon-gamma (IFNg) production. Additionally, guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. Based on these findings, the immune-modulatory effects of guadecitabine can help rescue the anti-tumor immune response and could contribute to the overall effectiveness of current cancer immunotherapies.
Allergies and asthma are common ailments that are on the rise around the world. Mast cells play a direct role in the signs and symptoms characteristic in allergic patients. The family of A Disintegrin And Metalloproteinases (ADAMs) are involved in regulating many cellular processes by cleaving surface receptors, ligands, and signaling molecules. We sought to determine the role of ADAM17 in mast cell activity. In studies using ADAM17-deficient mast cells, percent degranulation and cytokines released by IgE-mediated activation were significantly reduced. Interestingly, ionomycin-activation was unchanged, suggesting ADAM17 may be involved in IgE-mediated mast cell activation upstream of calcium release. Additionally, ADAM17MC-/- mice showed protection from IgE-, but not histamine-, mediated passive systemic anaphylaxis (PSA). The underlying mechanism behind the reduced degranulation occurs through signaling deficiencies downstream of Lyn phosphorylation. Together, the data suggest that ADAM17 is required for proper mast cell signaling through its interaction with the Src family kinase, Lyn.
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Crosby, Brendan. "Exercise as an adjunct therapy in melanoma patients undergoing checkpoint inhibitor therapy". Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2022. https://ro.ecu.edu.au/theses/2569.
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Extensive research has shown that exercise can improve physical, functional, and psychosocial outcomes during cancer treatment. Despite the prevalence of melanoma, exercise as a therapy in the management of this disease remains understudied and underrepresented in current exercise oncology guidelines. Our systematic literature review identified six studies (882 patients) reporting the effects of physical activity and exercise on objectively-measured and patient-reported outcomes among patients with melanoma. Studies presented heterogeneity of design with two cross-sectional surveys, two retrospective analyses, and two non-randomised intervention trials. Findings from this review indicate that physical activity or exercise did not negatively impact quality of life, objectively measured or patient-reported outcomes in patients with melanoma. In our intervention study, ten patients (5 female, 62.2 ± 13.6 years) with advanced melanoma receiving checkpoint inhibitors completed the 8-week single-group telehealth intervention. Intervention sessions were undertaken three times per week (24 sessions) and included supervised comprehensive balance, aerobic, and resistance exercises. The completion rate was 91%, program attendance 88%, average session intensity 76%, with no severe or life-threatening adverse events. Physical function outcomes, aerobic capacity (17.6%, p < 0.001), lower body power (23.2%, p = 0.006), upper body strength (39.6%, p = 0.010), and balance (3.8%, p = 0.007) improved following the intervention. There was no change in quality of life (p = 0.888) or fatigue (p = 0.440), although the decrease in fatigue [(median and IQR, 44.4 (22.2 – 66.7) to 33.3 (19.4 – 47.2)] was clinically meaningful. These findings show that supervised exercise delivered via telehealth to patients with advanced melanoma receiving checkpoint inhibitors is feasible and can improve physical function. Supervised telehealth exercise is safe and can be delivered by an accredited exercise physiologist to improve physical outcomes and preserve quality of life in patients undergoing checkpoint inhibitor treatment.
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Souza, Pedro Filho Noronha de. "Purification, biochemical characterization and antimicrobial activity of a novel 2s albumin from castor bean(ricinus cmmunis L.) cake displaying trypsin inhibitory activity". Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=8867.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorConselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico
FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico
Castor bean (Ricinus communis L.) is an important crop for the Northeast of Brazil, which recently has been used to produce biodiesel. Around 90% of the castor bean production in Brazil is concentrated at Northeast region and the state of Cearà is the second largest producer. During the oil extraction process from the castor bean seeds, a resulting residue, called castor cake, is underutilized. However, this byproduct is rich in protein and micronutrients such as nitrogen, phosphorus and potassium, an attribute that qualifies it as a stuff that could be used as organic fertilizer or as animal feed, for example, bringing added value to it. Unfortunately, its use as food has not been possible because of the presence of toxic elements and allergens (ricin, ricinine, complex allergens) in its composition, unless it were previously submitted to a detoxification process. To date, the existing technologies to this end are not economically viable on an industrial scale. Therefore, studies to add value to this abundant byproduct generated in the castor bean biodiesel productive chain is of paramount importance. Thus, in this context, this study was performed to identify, isolate, purify and characterize new bioactive molecules of de-oiled castor cake with biotechnological potential. Through extraction of soluble proteins with 50 mM Tris-HCl pH 7.5, fractionation with ammonium sulfate (50-75%), following by hydrophobic interaction chromatography in Phenyl-Sepharose column and ion exchange chromatography (DEAE-Sepharose), a protein, named Rc-2S-Alb, able to inhibit trypsin was purified. Rc-2S-Alb has a molecular mass of approximately 75.8 kDa, as determined by SDS-PAGE, and under reducing conditions showed a large and a small protein band of 15.8 kDa and 10.5 kDa, respectively. Its NH2-terminal sequence showed similarity with the following proteins: putative 2S albumin precursor (89%), chain A of RicC3 (89%), and chain A of mabilin-1 (89%), all from R. communis seeds; and with the short chain of a "napin-like" protein from Brassica napus (89%). In addition, these similar proteins have two highly conserved domains: QEVQRKDLS and YLRQS. Comparison of the partial primary structure of Rc-2S-Alb generated by the ESI-Q-TOF MS/MS analysis of 17 tryptic peptides, showed 43% similarity to Mabinlin-1 (pI/Mr 6.7 and 29.3 kDa) from R. communis. There were also high similarities among the three-dimensional structures of Rc-2S-Alb, RicC3 and Mabinlin-1. Rc-2S-Alb did not inhibit the spore germination of the phytopathogenic fungi Fusarium oxysporum and Rizoctonia solani, but promoted aggregation of their respective spores. Moreover, Rc-2S-Alb did not inhibit the mycelial growth of Fusarium oxysporum, Fusarium solani, Rizoctonia solani and Collethotricum gloeosporioides. Contrary, Rc-2S-Alb was effective in inhibiting the growth of the human pathogenic bacteria Pseudomonas aeruginosae, Klebsiella pneumoniae and Bacillus subtilis, at low concentrations. In conclusion, it was established a protocol to purify a new 2S albumin from castor bean cake, which inhibits trypsin and has important antibacterial activity. Thus, the Rc-2S-Alb should be further studied in order to verify its effectiveness as new alternative therapeutic agent against resistant bacteria to commercial antibiotics, which will contribute to improve the human health.
A mamoneira (Ricinus communis L.) à uma cultura importante para a regiÃo Nordeste do Brasil, onde, recentemente, tem sido utilizada para produÃÃo de biodiesel. O Nordeste detÃm 90% da produÃÃo brasileira de mamona, sendo o CearÃ, o segundo maior produtor. No processo de extraÃÃo de Ãleo das sementes de mamoneira para produÃÃo de biodiesel, o resÃduo resultante, denominado de torta da mamona, representa um subproduto pouco utilizado. Apesar disso, essa torta à rica em proteÃnas e micronutrientes, como nitrogÃnio, fÃsforo e potÃssio, atributo que a qualifica como um insumo que poderia ser utilizado como adubo orgÃnico, ou mesmo como raÃÃo animal, o que lhe agregaria valor comercial. Todavia, seu uso como alimento nÃo tem sido possÃvel por causa da presenÃa de elementos tÃxicos e alergÃnicos (Ricina, Ricinina, Complexos AlergÃnicos) na sua composiÃÃo, a nÃo ser que passasse por processamento para sua destoxificaÃÃo. Infelizmente, tecnologia economicamente viÃvel para esse fim, em escala industrial, ainda à inexistente. Portanto, hà necessidade de pesquisas que venham a agregar valor a esse subproduto abundante da cadeia produtiva do biodiesel. Assim, nesse contexto, o presente trabalho està inserido num projeto cujo objetivo maior à identificar, isolar, purificar e caracterizar novas molÃculas bioativas da torta delipidada de sementes de mamoeira com potencial biotecnolÃgico. AtravÃs de extraÃÃo de proteÃnas solÃveis com tampÃo Tris-HCl, 50 mM, pH 7,5, e fracionamento do extrato obtido com sulfato de amÃnio (50-75%), cromatografia de interaÃÃo hidrofÃbica em coluna Phenyl-Sepharose e cromatografia de troca iÃnica (DEAE-Sepharose) foi possÃvel purificar uma albumina 2S, denominada Rc-2S-Alb, capaz de inibir tripsina. A Rc-2S-Alb apresentou massa molecular de, aproximadamente, 75,8 kDa, determinada por SDS-PAGE, mas, em condiÃÃes redutoras, apareceu como uma banda maior de 15,8 kDa e outra menor com 10,5 kDa. Sua sequÃncia NH2-terminal revelou haver similaridade (89%) com o precursor putativo da albumina 2S de R. communis jà descrita, com a cadeia A da estrutura da RicC3 (89%), com a cadeia A da mabilin-1, ambas, tambÃm, de R. communis (89%), com a cadeia pequena de uma proteina ânapin-likeâde Brassica napus (89%). Em todas essas proteÃnas similares, dois domÃnios, QEVQRKDLS e YLRQS, sÃo altamente conservados. ComparaÃÃo da estrutura primÃria gerada por ESI-Q-TOF MS/MS, a apartir de 17 peptÃdeos trÃpticos da Rc-2S-Alb, mostrou similaridade de 43% com a Mabinlin-1 (pI/Mr de 6,7 e 29.3 kDa) de R. communis. Em relaÃÃo à estrutura tridimensional da Rc-2S-Alb, ela apresentou similaridade com a de Ric C3 e Mabinlin-1. A Rc-2S-Alb foi incapaz de inibir a germinaÃÃo de esporos dos fungos fitopatogÃnicos Fusarium oxysporum e Rizoctonia solani, mas foi capaz de promover a aglomeraÃÃo dos mesmos. A Rc-2S-Alb tambÃm nÃo foi capaz de inibir o crescimento micelial dos fungos Fusarium oxysporum, Fusarium solani, Rizoctonia solani e Collethotricum gloeosporioides. Por outro lado, a Rc-2S-Alb foi eficiente em inibir o crescimento de Pseudomonas aeruginosae, Klebsiella pneumoniae e Bacillus subtilis, todas as bactÃrias patogÃnicas a seres humanos, quando em baixas concentraÃÃes. Como conclusÃo, foi possÃvel a purificaÃÃo de uma nova albumina 2S da torta da mamona, capaz de inibir tripsina e com atividade antibacteriana importante. Assim, a Rc-2S-Alb deve ser explorada no sentido de verificar sua eficÃcia como um novo agente terapÃutico alternativo no combate a bactÃrias resistentes aos produtos disponÃveis, hoje, no mercado, o que, se confirmado, poderà contribuir para a melhoria da saÃde humana.
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Byberg, Liisa. "Plasminogen Activator Inhibitor-1 and the Insulin Resistance Syndrome". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5307-4/.
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Böhm, Miriam [Verfasser]. "Targeting the Final Step of Blood Coagulation : Structure-Activity-Relationship Studies on the Factor XIIIa Inhibitor Tridegin / Miriam Böhm". Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1077290438/34.
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Shimura, Kazuya. "Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137)". Kyoto University, 2008. http://hdl.handle.net/2433/135828.
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Blanco, Aparicio Carmen. "El Inhibidor de carboxipeptidasa de patata (PCI): un antagonista del EGF con actividad antitumoral". Doctoral thesis, Universitat de Girona, 1998. http://hdl.handle.net/10803/96759.
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In this work we report that potato carboxypeptidase inhibitor suppresses the growth of several human and mouse pancreatic adenocarcinoma cell lines. The inhibitor also reduces the growth of solid tumors obtained by subcutaneous injection of human adenocarcinoma cell line in nude mice and the appearance of metastasis in mice injected intraesplenically with B16H10 melanoma cells. A transgenic line has been characterized, mice develop choroid plexus carcicomas and insulinomas. Lifespan of animals immunized with PCI I s significantly higher than control mice. To further characterize the effects of PCI on tumor cell growth, analyses of cell cycle phase distribution have been performed. A significant increase in the G0/G1 phase is also detected. This finding is correlated with an increase in the mRNA expression of p53. Moreover, we have demonstrated that PCI is easily internalized by the cells and the inhibitor remain altered after the internalizationEn el presente trabajo se ha demostrado que el inhibidor de carboxipeptidasa de patata (PCI) tiene un efecto inhibitorio sobre el crecimiento tumoral tanto in vitro como in vivo, y se ha estudiado su mecanismo de acción, lo que ha llevado a descubrir que el PCI es un antagonista del EGF. Con dicho fin se han utilizado técnicas de cultivo celular en conjunción con técnicas bioquímicas, de biología molecular, de análisis computacional y ensayos con modelos animales
En el present treball s’ha demostrat que l’inhibidor de carboxipeptidasa de patata (PCI) té un efecte inhibitori sobre el creixement tumoral tant in vitro com in vivo i s’ha estudiat el seu mecanisme d’acció, que ha permès descobrir que el PCI és un antagonista de l’EGF. Amb aquest fi s’han utilitzat tècniques de cultiu cel·lular amb tècniques bioquímiques, de biologia molecular, d’anàlisi computacional i assajos amb models animals
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GALBIATI, ANDREA. "DESIGN AND SYNTHESIS OF NOVEL ENZYME INHIBITORS AS ANTIPROLIFERATIVE COMPOUNDS WITH ANTIPROTOZOAL AND ANTICANCER ACTIVITY". Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/827428.
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This dissertation describes the research carried out as part of a PhD program in Chemistry
from the 1st October 2017 until 30th November 2020. The PhD project investigated the
development of inhibitors of enzymes involved in important metabolic pathways, with the
final aim to produce an antiproliferative effect. The present thesis combines the works
performed at the University of Milan and Vrije Universiteit of Amsterdam.
Part A describes the research performed in Amsterdam, NL during my period abroad from
January to September 2019 in the research group of Professor Rob Leurs, at the Division of
Medicinal Chemistry of the Amsterdam Institute for Molecules, Medicines and Systems,
Vrije Universiteit of Amsterdam. In particular, this part outlines the design, synthesis and
pharmacological evaluation of two novel series of potent antitrypanosomal agents,
identified through SAR exploration and scaffold hopping approach starting from cyclic
nucleotide Trypanosoma brucei phosphodiesterase (PDE) inhibitors. PDE enzymes provide
a fine control on several biochemical pathways and have recently been demonstrated to
be essential for parasite proliferation. Their disruption by RNA interference (RNAi)
dramatically increase intracellular cAMP and, consequently, causes complete mortal
trypanosome cell lysis.
Part B describes the research done at the Department of Pharmaceutical Sciences,
University of Milan, under the supervision of Professor Paola Conti, on the design and
synthesis of novel covalent inhibitors targeting the glycolytic enzyme Glyceraldehyde-3-
phosphate dehydrogenase (GAPDH). Due to its pivotal role in the glycolysis, GAPDH
represents a rate-limiting enzyme in those cells that mostly, or exclusively rely on this
pathway for energy production. In this context, GAPDH inhibition represents a valuable
approach for the development of anticancer and antiparasitic drugs. Due to the presence
of a druggable nucleophilic cysteine residue in the catalytic pocket of the target, I focused
my attention on the development of covalent GAPDH inhibitors, presenting an electrophilic
warhead with a finely tuned reactivity. In particular, Section B2 reportsthe work conducted
on the development of Plasmodium falciparum GAPDH inhibitors and the in vitro
antiplasmodial activity. Section B3 shows the work performed on the design and synthesis
of human GAPDH inhibitors, with in vitro antitumor activity.
48
Dias, Lucas Pinheiro. "PurificaÃÃo e caracterizaÃÃo de um inibidor de tripsina das flores de Cassia fistula Linn. com atividade antimicrobiana". Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=16457.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorAs plantas sintetizam proteÃnas que possuem propriedades antimicrobianas, podendo ser utilizadas em substituiÃÃo aos defensivos quÃmicos no campo e como fonte de novas drogas para o controle de infecÃÃes bacterianas em humanos. Dentre as diversas estruturas vegetais, ÃrgÃos reprodutivos como as flores parecem ser uma fonte promissora de tais molÃculas ativas contra patÃgenos, particularmente se considerado o seu relevante papel fisiolÃgico, o qual deve ser preservado. Nesse contexto, a presente pesquisa experimental teve como objetivos a prospecÃÃo de proteÃnas com aÃÃo antimicrobiana em flores silvestres e posterior purificaÃÃo, caracterizaÃÃo bioquÃmica e avaliaÃÃo da atividade antimicrobiana de um inibidor de tripsina presente em flores de Cassia fistula Linn. (Chuva-de-ouro). O extrato total das flores de C. fistula foi preparado em tampÃo fosfato de sÃdio 50 mM, pH 7,5. Esse extrato apresentou atividade inibitÃria de tripsina (42,41 Â 0,35 UI/mgP) e de papaÃna (27,10 Â 0,23 UI/mgP), alÃm de mostrar a presenÃa de peroxidase (20,0 Â 0,18 UAP/mgP) e quitinase (1,70 Â 0,21 ηkatal/mgP), estando ausentes as atividades hemaglutinante, β-1,3-glucanÃsica, ureÃsica e proteÃsica. O inibidor de tripsina de C. fistula, denominado CfTI, foi purificado do extrato total por fracionamento com Ãcido tricloroacÃtico (2,5%), seguido de cromatografias de afinidade (anidrotripsina-Sepharose-4B) e fase reversa (Vydac C-18TP 522). CfTI Ã uma glicoproteÃna com massa molecular aparente de 22,2 kDa, pI 5,0 e sequÃncia NH2-terminal exibindo alta similaridade com o inibidor de tripsina da soja do tipo Kunitz (SBTI). O inibidor mostrou-se pouco estÃvel ao calor, reduzindo sua atividade inibitÃria para 23,4% quando incubado a 60 ÂC, durante 15 minutos. No entanto, ele se mostrou bastante estÃvel a variaÃÃes no pH. CfTI (100 Âg/mL) retardou o crescimento dos fungos fitopatogÃnicos de importÃncia agrÃcola, Colletotrichum lindemuthianum e Fusarium solani, alÃm de apresentar atividade antibacteriana frente Ãs bactÃrias patogÃnicas ao homem, Staphylococcus aureus e Enterobacter aerogenes. Os resultados obtidos demonstram o potencial das flores como fonte diversificada de proteÃnas bioativas, evidenciando o inibidor de tripsina presente em flores de C. fistula, fomentando sua aplicaÃÃo biotecnolÃgica frente a fungos e bactÃrias de relevÃncia para a Agricultura e SaÃde.
Plants synthesize proteins that have antimicrobial properties, which can be used to substitute chemical pesticides in agriculture and as new drugs for the control of bacterial infections in humans. Among the various plant structures, the flowers seem to be a promising source of active molecules against pathogens, particularly if considered its important physiological role, which should be preserved. Therefore, this experimental research aimed at the prospection of novel proteins with antimicrobial activity in wild flowers and to subsequent purification, biochemical characterization and evaluation of antimicrobial activity of a trypsin inhibitor present in flowers of Cassia fistula Linn (the golden shower tree). The total extract of C. fistula flowers was prepared in 50 mM sodium phosphate buffer, pH 7.5. This extract presented trypsin inhibitory activity (42.41 Â 0.35 IU/mgP) and papain (27.10 Â 0.23 IU/mgP), besides to the presence of peroxidase (20.0 Â 0.18 UAP/mgP) and chitinase (1.70 Â 0.21 ηkatal/mgP). On the other hand, the hemagglutinating, β-1,3-glucanase, protease and urease activities were not detected. The trypsin inhibitor of C. fistula, named CfTI, was purified by fractionating the crude extract with trichloroacetic acid (2.5%) followed by affinity (anidrotripsina-Sepharose-4B) and reverse phase (Vydac C-18TP 522) chromatographies. CfTI is a glycoprotein with an apparent molecular mass of 22.2 kDa, pI 5.0 and NH2-terminal sequence showing high similarity with Kunitz soybean trypsin inhibitor (SBTI). The inhibitor was not stable to heat, and loss 23.4% when incubated at 60 ÂC for 15 minutes. However, it proved to be stable to changes of pH. CfTI (100 Âg/mL) slowed the growth of pathogenic fungi of agricultural importance, Colletotrichum lindemuthianum and Fusarium solani, and also presented antibacterial activity against the human pathogenic bacteria, Staphylococcus aureus and Enterobacter aerogenes. The results demonstrate the potential of the flowers as a source of diverse bioactive proteins, as the trypsin inhibitor present in C. fistula flowers, promoting its biotechnological potential application against fungi and bacteria of relevance to Agriculture and human health.
49
Dias, Lucas Pinheiro. "Purificação e caracterização de um inibidor de tripsina das flores de Cassia fistula Linn. com atividade antimicrobiana". reponame:Repositório Institucional da UFC, 2012. http://www.repositorio.ufc.br/handle/riufc/18870.
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DIAS, Lucas Pinheiro. Purificação e caracterização de um inibidor de tripsina das flores de Cassia fistula Linn. com atividade antimicrobiana. 2012. 83 f. Dissertação (Mestrado em Bioquímica)-Universidade Federal do Ceará, Fortaleza-CE, 2012.Submitted by Eric Santiago (erichhcl@gmail.com) on 2016-07-19T13:34:23Z No. of bitstreams: 1 2012_dis_lpdias.pdf: 2004862 bytes, checksum: cd42d65281498494806d7ca987015da7 (MD5)
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Plants synthesize proteins that have antimicrobial properties, which can be used to substitute chemical pesticides in agriculture and as new drugs for the control of bacterial infections in humans. Among the various plant structures, the flowers seem to be a promising source of active molecules against pathogens, particularly if considered its important physiological role, which should be preserved. Therefore, this experimental research aimed at the prospection of novel proteins with antimicrobial activity in wild flowers and to subsequent purification, biochemical characterization and evaluation of antimicrobial activity of a trypsin inhibitor present in flowers of Cassia fistula Linn (the golden shower tree). The total extract of C. fistula flowers was prepared in 50 mM sodium phosphate buffer, pH 7.5. This extract presented trypsin inhibitory activity (42.41 ± 0.35 IU/mgP) and papain (27.10 ± 0.23 IU/mgP), besides to the presence of peroxidase (20.0 ± 0.18 UAP/mgP) and chitinase (1.70 ± 0.21 ηkatal/mgP). On the other hand, the hemagglutinating, β-1,3-glucanase, protease and urease activities were not detected. The trypsin inhibitor of C. fistula, named CfTI, was purified by fractionating the crude extract with trichloroacetic acid (2.5%) followed by affinity (anidrotripsina-Sepharose-4B) and reverse phase (Vydac C-18TP 522) chromatographies. CfTI is a glycoprotein with an apparent molecular mass of 22.2 kDa, pI 5.0 and NH2-terminal sequence showing high similarity with Kunitz soybean trypsin inhibitor (SBTI). The inhibitor was not stable to heat, and loss 23.4% when incubated at 60 °C for 15 minutes. However, it proved to be stable to changes of pH. CfTI (100 µg/mL) slowed the growth of pathogenic fungi of agricultural importance, Colletotrichum lindemuthianum and Fusarium solani, and also presented antibacterial activity against the human pathogenic bacteria, Staphylococcus aureus and Enterobacter aerogenes. The results demonstrate the potential of the flowers as a source of diverse bioactive proteins, as the trypsin inhibitor present in C. fistula flowers, promoting its biotechnological potential application against fungi and bacteria of relevance to Agriculture and human health.
As plantas sintetizam proteínas que possuem propriedades antimicrobianas, podendo ser utilizadas em substituição aos defensivos químicos no campo e como fonte de novas drogas para o controle de infecções bacterianas em humanos. Dentre as diversas estruturas vegetais, órgãos reprodutivos como as flores parecem ser uma fonte promissora de tais moléculas ativas contra patógenos, particularmente se considerado o seu relevante papel fisiológico, o qual deve ser preservado. Nesse contexto, a presente pesquisa experimental teve como objetivos a prospecção de proteínas com ação antimicrobiana em flores silvestres e posterior purificação, caracterização bioquímica e avaliação da atividade antimicrobiana de um inibidor de tripsina presente em flores de Cassia fistula Linn. (Chuva-de-ouro). O extrato total das flores de C. fistula foi preparado em tampão fosfato de sódio 50 mM, pH 7,5. Esse extrato apresentou atividade inibitória de tripsina (42,41 ± 0,35 UI/mgP) e de papaína (27,10 ± 0,23 UI/mgP), além de mostrar a presença de peroxidase (20,0 ± 0,18 UAP/mgP) e quitinase (1,70 ± 0,21 ηkatal/mgP), estando ausentes as atividades hemaglutinante, β-1,3-glucanásica, ureásica e proteásica. O inibidor de tripsina de C. fistula, denominado CfTI, foi purificado do extrato total por fracionamento com ácido tricloroacético (2,5%), seguido de cromatografias de afinidade (anidrotripsina-Sepharose-4B) e fase reversa (Vydac C-18TP 522). CfTI é uma glicoproteína com massa molecular aparente de 22,2 kDa, pI 5,0 e sequência NH2-terminal exibindo alta similaridade com o inibidor de tripsina da soja do tipo Kunitz (SBTI). O inibidor mostrou-se pouco estável ao calor, reduzindo sua atividade inibitória para 23,4% quando incubado a 60 °C, durante 15 minutos. No entanto, ele se mostrou bastante estável a variações no pH. CfTI (100 µg/mL) retardou o crescimento dos fungos fitopatogênicos de importância agrícola, Colletotrichum lindemuthianum e Fusarium solani, além de apresentar atividade antibacteriana frente às bactérias patogênicas ao homem, Staphylococcus aureus e Enterobacter aerogenes. Os resultados obtidos demonstram o potencial das flores como fonte diversificada de proteínas bioativas, evidenciando o inibidor de tripsina presente em flores de C. fistula, fomentando sua aplicação biotecnológica frente a fungos e bactérias de relevância para a Agricultura e Saúde.
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Recasens, Zorzo Clara. "Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma". Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663897.
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Constitutive activation of the chemokine receptor CXCR4 is associated with tumor progression, invasion and resistance to treatment. Overexpression of CXCR4 in diffuse large B-cell lymphoma (DLBCL) confers a reduced prognosis. However, the biological relevance of this receptor in DLBCL progression remains underexplored. In this thesis, the new CXCR4 inhibitor IQS-01.01 has been preclinicaly evaluated in in vitro and in vivo models of DLBCL. It has been concluded that 1) inhibition of CXCR4 presents antitumor properties in DLBCL, 2) that IQS-01.01RS holds better pharmacological properties than the reference CXCR4 inhibitor, AMD3100 3) that treatment with IQS- 01.01RS reduces the levels of the oncogene MYC and 4) that the combinantion of IQS- 01.01RS with the BET-bromodomain inhibitor, CPI203, is synergistic in DLBCL. The results of this doctoral thesis unravel a cooperation between CXCR4 and MYC in DLBCL, and indicate that CXCR4 inhibition in combination with inhibition of MYC is a promising novel therapeutic approach in DLBCL.La activación constitutiva del receptor de quemocinas CXCR4 está asociada a la progresión tumoral, invasión y resistencia al tratamiento. En el linfoma difuso de células grandes (LDCG) la sobreexpresión de CXCR4 concede un peor pronóstico, pero la relevancia biológica de este receptor no se ha estudiado en profundidad. En esta tesis se ha evaluado un nuevo inhibidor de CXCR4 (IQS-01.01) en modelos preclínicos de LDCG. Usando tanto modelos in vitro como in vivo de LDCG se ha concluido 1) que la inhibición de CXCR4 en LDCG tiene un efecto antitumoral, 2) que IQS-01.01RS tiene mayores propiedades farmacológicas que el inhibidor de referencia, AMD3100 3) que el tratamiento con IQS-01.01RS reduce los niveles del oncogén MYC y 4) que la combinación de IQS-01.01 RS con el inhibido de BET, CPI203, confiere un efecto antitumoral sinérgico. Los resultados de esta tesis doctoral ponen en evidencia una cooperación entre MYC y CXCR4 en LDCG e indican que la inhibición de CXCR4 en combinación con un inhibidor de MYC es una terapia prometedora contra el LDCG.