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Frett, Brendan. "Discovery and Development of Novel Ret Inhibitors for the Treatment of Pervasive Malignancies." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/325495.
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Targeted cancer therapeutics represent the advent of a new therapeutic age, brought forth by the small molecule tyrosine kinase inhibitor (TKI) imatinib (Gleevec®). Imatinib is able to cause complete and sustained remissions in patients with chronic myelogenous leukemia (CML) driven by the Abelson (ABL) kinase, which caused a massive paradigm shift in how cancer is treated. The following research has been completed to extend the principles of imatinib therapy to the rearranged during transfection (RET) kinase. The RET kinase is involved in driving the pathology of medullary thyroid cancer (MTC), papillary thyroid carcinoma (PTC), certain non-small cell lung cancers (NSCLC), chronic myelomonocytic leukemia (CMML), tamoxifen resistant breast cancer, and Spitz melanoma. A heavily diverse population of solid and liquid carcinomas are driven by the RET oncogene, and patients presenting with these cancers could significantly benefit from a RET inhibitor. Previous drug discovery campaigns identified RET activity after therapeutic development for an unrelated kinase, as the case with vandetanib (Calpresa®) and cabozantinib (Cometriq®). Both agents fail to achieve dominant activity on RET and are more active on the vascular endothelial growth factor receptor 2 (VEGFR2), yet still achieve efficacy in RET driven tumors. This likely results from interrupting the oncogene cooperation between RET and VEGFR2; VEGFR2 provides the nutrients through angiogenesis that RET requires to promote proliferation and survival. We hypothesized that an equipotent RET/VEGFR2 dual inhibitor could maximize inhibiting the cooperation between RET and VEGFR2 in RET driven cancers. The inhibitor should be developed to maintain activity on all known RET mutations for treatment durability. In that case, the RET oncogene, despite mutating, will always be inhibited. Through research efforts, Pz-1 was identified as a sub-nanomolar, equipotent inhibitor of both RET (IC₅₀<0.001 µM) and VEGFR2 (IC₅₀<0.001 µM). Pz-1 was found active on every known, clinically relevant RET mutant tested at an IC₅₀≤0.001 µM. Through RET-driven xenograft models, Pz-1 was found active at an oral dose as low as 0.3 mg/kg/day.
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Myers, Samuel Harry. "Development of novel receptor tyrosine kinase inhibitors by a chemocentric approach." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28769.
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In recent years, there has been a major movement in the pharmaceutical industry towards the development of molecules that selectivity inhibit a previously-validated specific target. This is referred to as target-based drug discovery. It was hoped that adopting this approach would usher in a new golden age of drug discovery. However, this has not been the case, with issues arising such as the target’s mechanism of action being poorly understood, with it not playing the expected role in the disease progression, or feedback resistance mechanisms causing the target to lose its role in the disease. In contrast to this, in the past 20 years it has been argued that developing drugs in a target-agnostic way and screening them against an expressed phenotype i.e. phenotypic drug discovery, has been more successful, despite fewer programs being run in the manner. The AXL kinase is a receptor tyrosine kinase (RTK) and a member of the TAM family, along with MER and TYRO3. AXL has long been associated with numerous types of cancer. Having been first discovered in 1991 in acute myeloid leukaemia (AML), it has gone on to be more associated with advanced solid tumours such as brain, breast, and lung, with the trend being that increased AXL correlates with a poorer prognosis for the patient. Upon the activation of AXL by the vitamin K ligand GAS6, a series of downstream pathways are activated that go on to encourage cell survival, proliferation, and migration. In addition to this, AXL has been shown to be involved in crosstalk with other kinase pathways, resulting in AXL expression being associated with chemoresistance and survival mechanisms. Despite the promising outlook for AXL inhibitors, to date only one selective AXL inhibitor, BGB324 (formally R428) has entered clinical trials, with selective AXL inhibitors being difficult to develop due to a lack of a crystal structure or a reliable homology model. To address the aforementioned issues that target-based approaches can suffer from, and due to AXL lacking a crystal structure, the work in this thesis utilised a pragmatic drug design method that started from ligands/existing scaffolds known to inhibit the target from the literature (publications, clinical trials and patents). A series of small libraries were prepared and then tested against a selected phenotype e.g. cell viability, in at least two cell types: one that expressed the target (e.g. AXL) and one that did not. Hits were optimised for potency against the desired phenotype. The compounds then went through target deconvolution (kinase screening) to confirm the target of the inhibitors. Employing this approach, we initially synthesised two small libraries of potential AXL inhibitors. The potency of these compounds was tested using cell-based phenotypic assays, by evaluating cell viability in both native and chemo-resistant breast cancer cells. These libraries were optimised through focused combinatorial synthesis and phenotypic screening, to yield a small collection of antiproliferative hits. These hits were then profiled against a panel of twelve select kinases. The first library, while giving some important structural information, did not inhibit the kinases screened in a meaningful manner. However, the second library gave several potent compounds, inhibiting AXL, FLT3, and RET, with one compound being selective for AXL. The leads from this series were optimised further, through SAR studies, gaining important structural information in order to improve potency and selectivity of the compounds. The flexibility of the phenotypic cell-based approach allowed the pursuit of FLT3 inhibitors, resulting in the synthesis of one of the most potent FLT3 inhibitors synthesised to date.
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Vargas, Carla Vaz Ferreira. "O papel dos marcadores de angiogênese no feocromocitoma." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/143794.
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Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.
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SARONNI, DAVIDE. "TYROSINE KINASE INHIBITORS IN NEUROENDOCRINE TUMORS: FROM IN VITRO TO ZEBRAFISH MODEL." Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/917967.
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(1) Background: Neuroendocrine neoplasms (NENs) are a group of tumors that arise from neuroendocrine cells throughout the body, with the lungs and gastrointestinal tract being the most common sites of origin. In patients with NENs and distant metastases, surgery is generally not curative. Although well-differentiated and low-grade NENs, classified as neuroendocrine tumors (NETs), are usually less aggressive than poorly-differentiated NENs, they can develop distant metastases in about 15% of cases. These patients require chronic medical management. However, the clinical efficacy of these treatments is limited by the low objective response rate, due to the occurrence of tumor resistance and the high biological heterogeneity of these neoplasms.
(2) Research problem: We addressed this study on two rare NETs: lung neuroendocrine tumors (LNETs) and medullary thyroid carcinoma (MTC). LNETs represent about 2% of lung tumors, while MTCs are rare thyroid tumors caused by mutations in the RET proto-oncogene. Both NETs are well-differentiated neoplasms and are known to be highly vascularized. Therefore, they represent a potential target for tyrosine kinase inhibitors (TKIs) selective for receptors involved in angiogenesis. The aim of this project was to evaluate the antitumor activity of several new TKIs both in vitro, using LNETs (NCI-H727, UMC-11 and NCI-H835) and MTC (TT and MZ-CRC-1) cell lines, and in vivo, adopting a novel zebrafish xenograft model to study angiogenesis. In LNETs we tested: sulfatinib, a small molecule that inhibits the Vascular Endothelial Growth Factor Receptor (VEGFR) 1, 2, and 3, and the Fibroblast Growth Factor Receptor type 1 (FGFR1); cabozantinib, a multi-target inhibitor selective for VEGFR2, c-Met, Kit, Axl and Flt3; and axitinib, a multi-target TKI of VEGFR1, 2, 3 and Platelet-Derived Growth Factor Receptor-beta (PDGFRβ). In MTC we tested: sulfatinib; SPP86, a RET-specific inhibitor; and SU5402, an inhibitor of the FGFR1 and VEGFR2.
(3) Methodology: In LNETs and MTC cells the effects of selected TKIs have been evaluated in vitro through: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays, for assessing cell viability; flow-cytometer analysis, for the evaluation of cell cycle and apoptosis; and wound-healing assay, to study cell migration. In vivo we took advantage of the transgenic zebrafish line of Tg(fli1a:EGFP)y1. Through the xenotransplantation of NET cells in the subperidermal space near the subintestinal vein, we assessed the effects of TKIs on tumor-induced angiogenesis and cancer dissemination.
(4) Key Results: In LNET cell lines we observed a dose-dependent decrease in cell viability after incubation with all TKIs. This effect seems to be related to the perturbation of the cell cycle and induction in apoptosis. In NCI-H727 wound healing assay showed a significant reduction in cell migration only after incubation with cabozantinib. In the zebrafish model, we found a significant reduction of the tumor-induced angiogenesis in implanted LNET cell lines after treatment with all TKIs. Cabozantinib and axitinib were more potent than sulfatinib in inhibition of angiogenesis, while cabozantinib was the most efficient in reducing cell migration from the transplantation site to the tail. In MTC cell lines, sulfatinib, SU5402 and SPP86 showed a decrease in cell viability, confirmed by the significant reduction in S phase cell population. Moreover, sulfatinib and SPP86 showed for both cell lines a significant induction of apoptosis. Sulfatinib and SPP86 inhibited the migration of TT and MZCRC-1 cells, evaluated through the wound healing assay, while SU5402 was able to inhibit migration only in TT cells. In vivo we observed a significant reduction of TT cells-induced angiogenesis in zebrafish embryos after treatment with sulfatinib and SPP86.
(5) Conclusions: Despite sulfatinib resulted the most potent compound in terms of inhibition of LNET cell proliferation, cabozantinib showed in vivo the most effective impact in reducing tumor-induced angiogenesis. Cabozantinib was the only TKI able to inhibit in vivo the dissemination of implanted LNET cells. According to these data, cabozantinib could represent a potential candidate in the therapy of patients with highly vascularized LNET. In MTC cell lines, SPP86 and sulfatinib displayed a similar antitumor activity both in vitro and in vivo, suggesting a good efficacy of specific RET inhibitors (SPP86) with potentially less adverse effects than multitarget TKIs (sulfatinib). In addition, this study showed that the zebrafish model for NETs represents an innovative tool for drug screening with several advantages compared with rodent models: rapidity of procedure, animal immune suppression is not required, lower number of tumor cells for implant and the optical transparency provides a real-time monitoring of cell-stromal interactions and cancer progression in living animals.
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Lakshmanan, Aparna. "Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914.
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Lee, David. "Age-Related Differences in In-vitro Sensitivity to Inhibition of Human Red Blood Cell Acetylcholinesterase and Plasma Butyrylcholinesterase by the Cholinesterase Inhibitors Physostigmine (PHYS), Pyridostigmine (PYR), Donepezil (DON) and Galantamine (GAL)." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1937.
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Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder, characterized clinically by a progressive loss of memory, cognitive function, ability to care for oneself and psychiatric symptoms. First-line agents for the treatment of AD are ChE inhibitors (DON, GAL), whose modest clinical efficacy and the high incidence of dose-limiting toxicities limit their clinical utility. In addition to AD, ChE inhibitors (PYR) are used for other medical conditions, such as myasthenia gravis (MG). Furthermore, ChE inhibitors (PYR) are used by military personnel prophylactically if impending exposure to chemical warfare agents, e.g., soman, is suspected. The purpose of this research project was to understand the effect of age on the in-vitro sensitivity of ChE inhibitors in human RBCs and plasma. Understanding possible covariates, such as age and gender, may assist in optimizing dosing regimens of ChE inhibitors and/or developing newer ChE inhibitors with better adverse effect profiles. Plasma PHYS concentrations were measured by a validated HPLC-FD method. RBC AChE activity and plasma BuChE activity were measured by a modified Ellman’s colorimetric method using the model substrates, acetylthiocholine and butyrylthiocholine, respectively. The kinetics of RBC and plasma ChE activity followed Michaelis-Menten kinetics. Acetylthiocholine was found to be a nonselective substrate (RBC AChE Km = 73 μM; plasma BuChE Km = 117 μM); while butyrylthiocholine was a selective substrate for plasma BuChE (RBC AChE Km = 130,000 μM; plasma BuChE Km = 72 μM). For the following studies, RBC AChE activity was measured using acetylthiocholine as the substrate and plasma BuChE activity was measured using butyrylthiocholine as the substrate. This research project was performed in two parts: First, mechanistic studies of PHYS, PYR, DON and GAL, explored and determined the mechanism of in-vitro inhibition of RBC AChE and plasma BuChE inhibition, as well as the in-vitro degradation of PHYS in human whole blood, plasma and RBC. PHYS was rapidly degraded in human whole blood, RBC and plasma and followed Michaelis-Menten kinetics but its degradation clearance - scaled to whole blood clearance - was only predicted to account for 4-6% (i.e., 195-261 ml/min) of the reported total body clearance for PHYS (4500 ml/min). RBCs were responsible for 60% of the whole blood clearance while plasma accounted for 40% of the whole blood clearance. Inhibition results indicated that both PHYS and PYR were nonselective and rapid suicide ChE inactivators. PYR inactivated RBC AChE more rapidly at low concentrations and inactivated plasma BuChE more rapidly at high concentrations, but inactivated both more rapidly than PHYS. PHYS was a more potent inactivator than PYR with a Ki for RBC AChE of 0.011 μM and 0.063 μM, respectively, and 0.023 μM and 0.036 μM, respectively for plasma BuChE. DON was found to be a noncompetitive inhibitor for RBC AChE (Ki,noncomp = 114 μM), but a competitive inhibitor for plasma BuChE (Ki,comp = 213 μM). GAL was found to be a competitive inhibitor for both RBC AChE (Ki,comp = 66 μM) and plasma BuChE (Ki,comp = 358 μM). The second part involved a clinical study with ten young and nine elderly healthy subjects, balanced for gender, who donated blood for an in-vitro study in order to assess any age- and gender-related differences in in-vitro sensitivity to RBC AChE and plasma BuChE inhibition to all four ChE inhibitors. Elderly adults were found to be 2-3-fold less sensitive compared to the young adults for PHYS (BuChE Ki,pss; 0.010 and 0.015 μM, young and elderly, respectively) and PYR (AChE Ki,pss; 0.12 and 0.25 μM, young and elderly, respectively) only, while neither DON nor GAL showed any age-related differences in sensitivity. The observed differences for PHYS and PYR may be due to kinetic differences in ChE inactivation between young and aged adults, rather then a difference in binding affinities/potencies. These carbamate ChE inhibitors, presumably, have a slower decarbamoylation rate in younger adults than elderly adults, which leads to the observed difference in in-vitro sensitivity. The above in-vitro results were consistent with results of a meta-analysis: In a study by Knapp et al. (1991), young males (n=6), receiving 18 mg, 24 mg and 30 mg PHYS tablets, showed similar ex-vivo plasma BuChE sensitivity to (28 %/(ng/ml)) as the in-vitro sensitivity for young males in the current study (33 %/(ng/ml)). On the other hand, in the study by Men (2004), elderly males (n=8) and females (n=8), receiving 6.7 μg/kg PHYS as 30-minute infusion, showed similar ex-vivo RBC AChE sensitivity (12 %/(ng/ml)) as the in-vitro sensitivity for elderly subjects in the current study (9.7 %/(ng/ml)). This suggests that in-vitro measurement of ChE sensitivity is predictive of ex-vivo sensitivity in clinical studies. The study results suggest that elderly adults may require a 2-3-fold higher blood concentration than young adults to achieve the same ChE inhibition. This may explain why for epistigmine, an investigational carbamate ChE inhibitor for the treatment of AD, the maximum tolerated dose observed in young adults (40 mg single dose) was lower than for older adults (90 mg/day). Higher sensitivity in young adults prevented further dose escalation, while all elderly subjects tolerated higher doses. This research may have implications for other diseases and conditions, most notably MG and as a prophylaxis of nerve gases poisoning. As patients with MG age, they may become less sensitive to PYR, the most common symptomatic treatment for MG, and an increase in dose may be required. Further, older military personnel assigned to receive PYR, may require increased doses to achieve the targeted 10% RBC AChE inhibition, necessary to protect against nerve gas poisoning.
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Murata, Toru. "Inhibitory effect of Y-27632,a ROCK inhibitor,on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells." Kyoto University, 2002. http://hdl.handle.net/2433/149343.
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Gemmill, R. J. "The passivation of aluminium in inhibited red fuming nitric acid." Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376493.
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Nelson, Kathryn Jane. "Conditioned inhibition in the rat from incomplete reductions in reinforcement." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329276.
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Otto, Anne. "The protection of rosuvastatin and ramipril against the development of nitrate tolerance in the rat and mouse aorta." Doctoral thesis, Universite Libre de Bruxelles, 2006. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210861.
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Organic nitrates, such as nitroglycerine (NTG), are widely used for their potent vasodilator capacity in the management of coronary artery disease and heart failure. Unfortunately, their beneficial effect is rapidly lost due to the development of nitrate tolerance, which is translated by an impaired vasorelaxation to NTG and an increased oxidative stress production. Although the mechanisms of the development of nitrate tolerance are still not fully elucidated, much interest has been focused in treating nitrate-receiving patients together with other drugs in order to overcome the development of nitrate tolerance. The Nitric Oxide generating enzyme, eNOS, and the superoxide anion generating enzyme, NAD(P)H oxidase, have been suggested to play a role in the development of nitrate tolerance. The aim of this study was to analyse the underlying mechanism by which ramipril, an ACE inhibitor and rosuvastatin, a new molecule of the statin class, are able to protect against the development of nitrate tolerance in the aortas isolated from rats, wild-type (wt) and eNOS-/- mice. These results show that ramipril as well as rosuvastatin are able to protect against the development of nitrate tolerance in the wt and eNOS-/- mice aortas suggesting that eNOS is not necessary for their protective effect. The aortas from nitrate tolerant rats and mice showed a significant increase in the NAD(P)H oxidase activation compared to the aortas from the control and from the co-treated ramipril+NTG or rosuvastatin+NTG animals. In line with these findings were the results obtained by RT-PCR analysis: the mRNA expression of the different subunits of the NAD(P)H oxidase, such as gp91phox, p22phox, were significantly decreased after rosuvastatin or ramipril treatment in wt and eNOS-/- mice aortas. Apocynin, the NAD(P)H oxidase inhibitor was also able to inhibit the development of nitrate tolerance in the rat and mouse aortas.
In conclusion, these results suggest that rosuvastatin and ramipril are able to protect against the development of nitrate tolerance by counteracting the nitrate-induced oxidative stress. The mechanism of protection involves a direct interaction with the NAD(P)H oxidase pathway and seems to be completely independent of the eNOS pathway.
Doctorat en sciences pharmaceutiques
info:eu-repo/semantics/nonPublished
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Hussain, Sabar. "Inhibitory and excitatory neurotransmission in the rat cerebellum." Thesis, University of Southampton, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328659.
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Beňková, Daniela. "Hodnocení vlivu protinádorové léčby na elektrickou aktivitu srdce v experimentální telemetrické studii." Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2018. http://www.nusl.cz/ntk/nusl-378034.
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This master´s thesis deals with the analysis of experimental telemetrical ECG records with intention to determine the long-term influence of anticancer drug sunitinib on the electrical activity of heart. A laboratory rat was chosen as a model organism for the experimental study carried out at the Department of Physiology at Faculty of Medicine, Masaryk university. The sunitinib was applied to the rats at an early age and the ECG was measured with a 20-week delay using the Stellar telemetry system. To measure the effect of sunitinib on the electrical activity of the heart chambers, an analysis of the duration of the RR and QT interval and the width of the QRS complex was chosen. These parameters were detected by the wavelet transform method. Statistical analysis was performed using nonparametric tests - the Wilcoxon signed rank test, the MannWhitney test and the Friedman Test. The obtained results suggest that the use of sunitinib has no long-term effect on the observed parameters for the chosen animal model. After extension of the study, the results obtained could contribute to assess the effect of drugs on electrical activity of the human heart several decades after sunitinib treatment termination.
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Longman, S. D. "Cardiovascular studies with angiotensin converting enzyme inhibitors in the rat." Thesis, University of Bradford, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375102.
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Kumarasamy, Vishnu, and Daekyu Sun. "Demonstration of a potent RET transcriptional inhibitor for the treatment of medullary thyroid carcinoma based on an ellipticine derivative." SPANDIDOS PUBL LTD, 2017. http://hdl.handle.net/10150/624673.
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Dominant-activating mutations in the RET (rear-ranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as the binding site for transcriptional factors. As we have recently shown, this stretch of nucleotides in the promoter region is highly dynamic in nature and tend to form non-B DNA secondary structures called G-quadruplexes, which suppress the transcription of the RET gene. In the present study, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Circular dichroism (CD) spectroscopic studies revealed that the incorporation of a piperidine ring in an ellipticine derivative, NSC311153 improves its binding with the G-quadruplex structure and the stability induced by this compound is more potent than ellipticine. Furthermore, this compound also interfered with the transcriptional mechanism of the RET gene in an MTC derived cell line, TT cells and significantly decreased the endogenous RET protein expression. We demonstrated the specificity of NSC311153 by using papillary thyroid carcinoma (PTC) cells, the TPC1 cell line which lacks the G-quadruplex forming sequence in the promoter region due to chromosomal rearrangement. The RET downregulation selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. In the present study, we also showed that the systemic administration of a water soluble NSC311153 analog in a mouse MTC xenograft model inhibited the tumor growth through RET downregulation.
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Poisson, Jessica. "Synthesis and In Vitro Applications of Ice Recrystallization Inhibitors." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39466.
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Recent advances in the clinical diagnosis and treatment of diseases using cell transplantation have emphasized the urgent need to cryopreserve many types of cells. In transfusion medicine, red blood cell (RBC) transfusions are used to treat anemia and inherited blood disorders, replace blood lost during or after surgery and treat accident victims and mass casualty events. In regenerative medicine, mesenchymal stem cell (MSC) therapy offers promising treatment for tissue injury and immune disorders. Current cryoprotective agents (CPAs) utilized for RBCs and MSCs are 40% glycerol and 10% dimethyl sulfoxide (DMSO), respectively. Although glycerol is required for successful cryopreservation of RBCs, it must be removed from RBCs post-thaw using costly and time-consuming deglycerolization procedures to avoid intravascular hemolysis. Unfortunately, while DMSO prevents cell damage and increases post-thaw MSC viability and recovery, recent reports have suggested that MSCs cryopreserved in DMSO display compromised function post-thaw. As a result, improvements to the current cryopreservation protocols such as reducing post-thaw RBC processing times and improving MSC function post-thaw are necessary in order to meet the increasing demands of emerging cellular therapies. Ice recrystallization has been identified as a significant contributor to cellular injury and death during cryopreservation. Consequently, the ability to inhibit ice recrystallization is a very desirable property for an effective CPA, unlike the conventional CPAs such as DMSO and glycerol that function via a different mechanism and do not control or inhibit ice recrystallization. Over the past few years, our laboratory has reported several different classes of small molecules capable of inhibiting ice recrystallization such as lysine-based surfactants, non-ionic carbohydrate-based amphiphiles (alkyl and aryl aldonamides) and O-linked alkyl and aryl glycosides. The use of these small molecule ice recrystallization inhibitors (IRIs) as novel CPAs has become an important strategy to improve cell viability and function post-thaw. With the overall goal to identify highly effective inhibitors of ice recrystallization, the first part of this thesis examines the IRI activity of three diverse classes of small molecules including carbohydrate-based surfactants bearing an azobenzene moiety, fluorinated aryl glycosides and phosphate sugars. While the majority of the carbohydrate-based surfactants and fluorinated aryl glycosides were not effective inhibitors of ice recrystallization, this work revealed that monosaccharides possessing a phosphate group could be effective IRIs. Our laboratory has previously demonstrated that small molecule IRIs β-PMP-Glc and β-pBrPh-Glc can protect human RBCs from cellular injury during freezing using reduced concentrations of glycerol (15% w/v). This was significant as reducing the concentration of glycerol can drastically decrease deglycerolization times. Consequently, structure- function studies were conducted on β-PMP-Glc and β-pBrPh-Glc to elucidate key structural features that further enhance their IRI activity and may increase their cryoprotective ability. In particular, the influence of an azido moiety on the IRI activity of β-PMP-Glc and β-pBrPh-Glc was investigated and it was determined that the position of the azide substituent on the pyranose ring is crucial for effective inhibition of ice recrystallization. Furthermore, the presence of an azido group at C-3 was found to increase the IRI activity of β-PMP-Glc and β-pBrPh-Glc. Despite the discovery that β-PMP-Glc and β-pBrPh-Glc are beneficial additives for the freezing of RBCs, a significant amount of cellular damage occurred during deglycerolization, resulting in very low cell recoveries. Thus, IRI active azido aryl glucosides were explored for their cryopreservation potential in RBCs to determine whether they could function as effective additives that reduce cellular damage post-thaw and improve cell recovery. One of the most significant results of this thesis is the discovery that azido aryl glucosides can successfully cryopreserve RBCs in the presence of 15% glycerol with significantly improved cell recovery. This thesis also explores the use of small molecule IRIs to improve the cryopreservation of MSCs. In particular, the addition of an N-aryl-aldonamide (2FA) to the standard 10% DMSO solution was found to enhance the proliferative capacity of MSCs post-thaw. Lastly, the ability of small molecule IRIs to cross the cell membrane and behave as permeating CPAs was evaluated in two different cell models, RBCs and human umbilical vein endothelial cells (HUVECs). These studies demonstrated that small molecule IRIs are capable of permeating the cell membrane and controlling intracellular ice recrystallization.
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Brice, Edmund Andrew William. "Rat angiotensin-converting enzyme : tissue specific expression during pharmacological inhibition." Doctoral thesis, University of Cape Town, 1995. http://hdl.handle.net/11427/27042.
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The renin-angiotensin system plays a central role in the maintenance of blood pressure. Angiotensin II, the main effector of this system, results from the action of angiotensin-converting enzyme (ACE) on angiotensin I. Angiotensin II, maintains vasomotor tone via its vasoconstrictor action, and also increases salt and water retention by stimulating the release of aldosterone. ACE inhibitors, such as captopril, enalapril and lisinopril, are highly effective in the treatment of hypertension and congestive cardiac failure. Previous studies have suggested that angiotensin converting enzyme (ACE) production may be enhanced during pharmacological inhibition of the enzyme. Little is known, however about the mechanism of this induction. After demonstrating increases in circulating ACE protein in cardiac failure patients receiving the ACE inhibitor captopril, a rat model was used to study this effect. A sensitive enzyme linked immunosorbent assay for rat ACE was developed and a partial cDNA for rat ACE cloned to enable examination of ACE mRNA and protein expression during enzyme inhibition with enalapril. Rat lung ACE mRNA increased by 156% (p<0.05) and ACE protein doubled within 3 hours of administering a single dose of enalapril. Testicular ACE mRNA also increased by 300% (p<0.05) within 2 hours and returned to pretreatment levels by 6 hours. The angiotensin II antagonist saralasin similarly caused a significant (p<0.0001) 800% enhancement of mRNA expression. Aldosterone pretreatment of rats prior to enalapril administration was found to abolish this mRNA induction. These findings indicate that increased ACE expression during inhibition results from reduced levels of angiotensin II with consequent reduced stimulation of the angiotensin 11 receptor and its effects, such as aldosterone release. This suggests that ACE levels are regulated by a negative feedback loop involving the distal components of the renin-angiotensin system, namely angiotensin II and aldosterone. In situ hybridisation and immunohistochemical techniques were employed to localise the site of this inductive response in rat tissue sections. It was found that lung macrophages were markedly induced to produce ACE, as was ACE in seminiferous tubules. ACE induction was also noted in the expected sites of renal tubular epithelium and glomerular tissue. Interestingly, ACE expression was also enhanced in cardiac valves. In these studies it has been conclusively demonstrated that new ACE expression is induced by enzyme inhibitor therapy. A variety of techniques have been developed that will allow futher study of ACE in rat tissues.
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Volenec, Andreja. "Studies of gene expression in rat brain in response to antidepressants." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249611.
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Brandt, Wiebke [Verfasser], and Conrad [Akademischer Betreuer] Kunick. "Neue Inhibitoren der Proteinkinasen PfGSK-3 und RET / Wiebke Brandt ; Betreuer: Conrad Kunick." Braunschweig : Technische Universität Braunschweig, 2009. http://d-nb.info/117582934X/34.
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Mears, Ryan Phillip. "NEUROPHYSIOLOGY OF AUDITORY INHIBITORY GATING IN RAT MEDIAL PREFRONTAL CORTEX." Bowling Green State University / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1151343744.
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Wong, Chui-shan. "Interactions of multiple proteins during specialized junctions formation in the rat seminiferous epithelium /." Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B20567431.
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Fontaine, David. "Analyse pharmacologique comparative de l'action vasculaire du ramipril et d'inhibiteurs de l'HMG-COA réductase sur l'aorte isolée de rat: perspectives d'applications cliniques." Doctoral thesis, Universite Libre de Bruxelles, 2004. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211194.
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La prévention des maladies cardiovasculaires constitue actuellement une approche capitale dans la diminution de la mortalité au sein de nos pays industrialisés. Tous les facteurs de risques étant associés à une dysfonction endothéliale, nous nous sommes intéressés à deux classes de médicaments dont l’action bénéfique se situe, du moins en partie, au niveau de l’endothélium vasculaire :les inhibiteurs de l’enzyme de conversion de l’angiotensine (IECA) et les inhibiteurs de l’hydroxy-3-méthyl-3-glutaryl-Coenzyme A (HMG-CoA) réductase (statines).Le présent travail contribue à l’étude in vitro des effets protecteurs vasculaires de l’administration chronique, chez le rat, de deux statines (la pravastatine et l’atorvastatine) vis-à-vis de la toxicité aiguë des LDL humaines oxydées et vis-à-vis de la tolérance à la nitroglycérine. Une comparaison est menée par rapport au ramipril dans ces deux modèles expérimentaux.
Les effets de ces médicaments se manifestent au niveau vasculaire par une amélioration de la disponibilité du NO. Toutefois, dans nos modèles, des mécanismes singulièrement différents ont été identifiés entre les agents étudiés :alors que le ramipril engendre une augmentation de l’expression de la eNOS, enzyme synthétisant le NO, les statines permettent une meilleure disponibilité de ce radical par un mécanisme post-traductionnel. Outre cette action, elles semblent agir directement sur des enzymes oxydatives comme les NAD(P)H oxydases.
Une action antioxydante des statines pourrait expliquer tous les effets observés, ce qui n’est pas le cas pour le ramipril. Vu que le stress oxydatif intervient dans tous les facteurs de risques cardiovasculaires, diverses perspectives cliniques sont envisagées afin d’améliorer l’approche thérapeutique de la maladie athéroscléreuse.
Doctorat en sciences pharmaceutiques
info:eu-repo/semantics/nonPublished
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Cornett, Evan M. "Light-activated binary nucleotide reagent for inactivation of DNA polymerase." Master's thesis, University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5172.
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This work explores a binary reagent approach to increase the specificity of covalent inhibitors. In this approach, two ligand analogs equipped with inert pre-reactive groups specifically bind a target biopolymer. The binding event brings the pre-reactive groups in proximity with each other. The two groups react, generating active chemical intermediates that covalently modify and inactivate the target. In the present study we compare the new approach with the traditional single-component reagent strategy using DNA polymerase from bacteriophage T4 as a model target biopolymer. We report the design and synthesis of two analogs of deoxythymidine triphosphate, a natural DNA polymerase substrate. Together, the analogs function as a binary nucleotide reagent which is activated by light with wavelengths 365 nm and longer. However, the active analog functions as a traditional single component reagent when activated by light with wavelengths at 300 nm and longer. The traditional single-component reagent efficiently inactivated DNA polymerase. However, in the presence of non-target protein the inactivation efficiency is greatly diminished. Under the same conditions, the binary nucleotide reagent also inactivated DNA polymerase, and the inactivation efficiency is not affected by the presence of the non-target protein. Our results validate that a binary approach can be employed to design highly specific covalent inhibitors. The binary reagent strategy might be useful as a research tool for investigation of ligand-protein interactions in complex biological systems and for drug design.ID: 031001303; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Title from PDF title page (viewed March 15, 2013).; Thesis (M.S.)--University of Central Florida, 2012.; Includes bibliographical references (p. 26-29).
M.S.
Masters
Molecular Biology and Microbiology
Medicine
Biotechnology
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Brockdor, F. F. "The effect of oestradiol-17#beta# on the ribonucleases and ribonuclease inhibitor of immature rat uterus." Thesis, University of Glasgow, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379306.
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Nylund, Göran M. "Epibiosis of red algae and algal metabolites as settlement inhibitors of the barnacle Balanus improvisus Darwin." Göteborg [Sweden] : Dept. of Marine Botany, Göteborg University, 1999. http://bibpurl.oclc.org/web/20311.
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Thesis (master's)--Göteborg University, 1999.Title from PDF t.p. (viewed on Sept. 25, 2007). At head of title: Tjärno Marine Biological Laboratory. Includes bibliographical references (p. 13-14).
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Yeung, Yuen-ting Yukiona, and 楊菀婷. "Effects of HIV protease inhibitors and non-nucleoside reverse transcriptase inbibitors on vasomotor function in rat mesentericarteries." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46942117.
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Akula, Kavitha. "Expanding the Spiroligomers Toolbox as Protein-Protein Interaction Inhibitors." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/422281.
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ChemistryPh.D.
This work presents the application of spiroligomers as inhibitors of protein-protein interactions. After the discovery of an acyl-transfer coupling reaction by Dr. Zachary Brown, a previous graduate student of Schafmeister group, the synthesis of highly functionalized spiroligomers that mimic the helical domain of p53 was undertaken before each molecule was tested for binding to HDM2, a natural binding partner of p53. A library of molecules was synthesized on solid support that altered the stereochemistry along the spiroligomer as well as the presented functional groups. It was determined that spiroligomers enter human liver cancer cells through passive diffusion and induces a biological response in both a dose- and time-dependent manner. The synthesis of additional spiroligomer analogues achieved low micromolar to high nanomolar range activity during screening in direct and competitive binding assays. In parallel to the project above, a series of spiroligomers that mimic the side chains of the leucine zipper region of Max were synthesized in an effort to disrupt the interaction of the protein with c-Myc. The series of compounds contained various stereocenter combinations and different functional groups as before but were made in solution before testing for inhibition. Initial binding assays resulted in low micromolar activity, however, secondary assays (ELISA and cellular assays) did not confirm the inhibitory effect of spiroligomers on the c-Myc/Max heterodimer. In summary, this work illustrates that spiroligomers are capable mimics of helical peptides and can induce a biological response.
Temple University--Theses
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Wong, Chui-shan, and 黃翠珊. "Interactions of multiple proteins during specialized junctions formation in the rat seminiferous epithelium." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31221907.
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Leonard, Maureen Barbara. "Peripheral nerve changes in experimental diabetes and the effects of an aldose reductase inhibitor." Thesis, University of Aberdeen, 1986. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU367566.
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The object of this study was to investigate the effects of an aldose reductase inhibitor, sorbinil (Pfizer inc), in relation to some of the biochemical, structural and functional changes associated with diabetic nerves. An animal model, the streptozotocin-induced diabetic rat was used and the following studies were performed: Motor nerve conduction velocity (MNCV) was measured in the tibial nerve over a 6 month period. A group of rats were examined at the onset of the experiment (OC) to provide a baseline for comparison to all other groups. Age matched control (AMC) animals showed a 13% increase in MNCV during the first 3 months of the experiment with little increase thereafter. The diabetic animals (DC) did not significantly differ over the experimental period from the OC animals and were thus slower conducting than the corresponding AMC group. Administration of sorbinil (25 mg/Kg) to rats from the onset of diabetes had no effect on MNCV by 3 months but had normalised values by 6 months. Nerve glucose, sorbitol, fructose and myo-inositol levels were examined by GLC. Sorbinil had no effect on nerve glucose values but prevented the 10-fold increase in nerve sorbitol values observed with the DC animals. Sorbinil partially normalised nerve fructose values after 3 months of treatment and fully normalised them after 6 months. Myo-inositol (MI) levels showed a 45% reduction by 3 months of diabetes but were normal after 6 months. Sorbinil showed a tendency to restore the reduced MI values by 3 months. Morphometric profiles were examined in the tibial nerve. Axon areas demonstrated a 14% reduction at both 3 and 6 months of diabetes while myelin areas were increased by 13 and 22% respectively. Sorbinil treatment allowed normal axon growth and normalised myelin areas. MNCV was examined in the tibial and gastrocnemius nerves. As above, diabetes prevented the normal MNCV maturation in the tibial nerve. Sorbinil administration (25 mg/Kg) to rats initially diabetic for 2 months, was ineffective in restoring MNCV in the tibial nerve though a partial recovery was observed after 4 months of treatment. MNCV in the gastrocnemius nerve of the DC animals continued to fall as the experiment progressed, reaching a 33% reduction below the OC animals by 3 months. A spontaneous recovery was observed thereafter. Sorbinil partially normalised MNCV in the gastrocnemius nerve after 1 month. These changes exactly paralleled the changes in nerve MI levels. Sorbinil reversed the already elevated nerve sorbitol levels after 1 month of treatment though nerve fructose levels were only partially normalised after 4 months. A morphometric evaluation of the triceps surae nerve (containing fibres to gastrocnemius and soleus muscles) after 4 months of the experiment demonstrated an 18% increase of myelin area in the DC animals. Axon areas were unaffected by diabetes. Sorbinil treatment for 2 months partially normalised myelin areas. Sorbinil administration at doses of 7.5, 12.5 and 25 mg/Kg to rats that had been diabetic for 2 months did not normalise MNCV in the tibial nerve. However, 12.5 and 25 mg/Kg produced a significant improvement in MNCV of the gastrocnemius nerve after 1 month of treatment. 7.5 mg/Kg had no effect in this nerve. All doses of sorbinil produced a trend towards reversing the already elevated nerve sorbitol levels, though 25 mg/Kg was effective after 1 month of treatment whereas 12.5 mg/Kg required 2 months. 7.5 mg/Kg did not fully normalise nerve sorbitol levels. Nerve fructose values remained elevated, though treatment with 25 mg/Kg of sorbinil produced a reduction towards normal values. All 3 doses partially normalised MI levels. For all DC groups, sciatic nerve water content was significantly elevated after a 1 month experimental period. Sorbinil treatment, either given from the induction of diabetes or given after rats were initially diabetic for 2 months, had only a small effect on water content and values remained elevated compared with the controls.
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Joseph, Emlyn Clive. "Pathogenesis of arteriopathy induced by PDE III inhibitors in the rat and dog." Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307684.
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Clarke, Anna B. "Mitochondrial toxicity of nucleoside reverse transcriptase inhibitors in a rat phaeochromocytoma cell line." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430314.
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Reyskens, Kathleen Maria Simone Elise. "The maladaptive effects of HIV protease inhibitors (Lopinavir/Ritonavir) on the rat heart." Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/85782.
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Thesis (PhD)--Stellenbosch University, 2013.ENGLISH ABSTRACT: Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term effects include onset of insulin resistance and cardiovascular diseases. Increased oxidative stress and dysregulation of the ubiquitin-proteasome system (UPS) are implicated in protease-inhibitor (PI)-mediated cardio-metabolic pathophysiology. We hypothesized that PI treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the UPS, thereby attenuating cardiac function. Lopinavir/Ritonavir was dissolved in 1% ethanol (vehicle) and injected into mini-osmotic pumps that were surgically implanted into Wistar rats for eight weeks vs. vehicle and sham controls. Subsequently, we evaluated metabolic parameters and heart function (ex vivo and in vivo methods) at baseline and following ischemia-reperfusion. PI-treated rats exhibited weight gain, increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. It also upregulated hepatic gene expression of acetyl-CoA carboxylase β and 3-hydroxy-3-methylglutaryl-CoA-reductase, key regulators of fatty acid oxidation and cholesterol synthesis, respectively. Further, PI-treated hearts displayed impaired UPS, increased superoxide dismutase (SOD) activity and unaltered superoxide levels, and elevated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) peptide levels. Perfusion data revealed contractile dysfunction at baseline and following ischemia-reperfusion, while post-ischemic hearts exhibited decreased ATPase specific activity vs. matched controls. Early changes initiated by PI treatment resemble the metabolic syndrome and reflect a pre-atherogenic profile. Moreover, the effects of PIs on cardiac contractile function may in part be triggered by impaired UPS activity together with strain on the mitochondrial energetic system. Our study alerts to cardio-metabolic side effects of PI treatment and raises the question of the most appropriate co-therapies for patients on chronic antiretroviral treatment.
AFRIKAANSE OPSOMMING: Alhoewel anti-retrovirale behandeling MIV-VIGS morbiditeit/mortaliteit verlaag, bestaan daar langtermyn effekte soos die aanvang van insulienweerstandigheid en kardiovaskulêre siektes. Verhoogde oksidatiewe stres en wanregulering van die ubikwitien-proteosoomsisteem (UPS) word geïmpliseer met protease-inhibeerder (PI) gemediëerde kardio-metaboliese patofisiologie. Ons hipotetiseer dat PI behandeling (Lopinavir/Ritonavir) miokardiale oksidatiewe stres verhoog, en gevolglik die UPS inhibeer waardeur dit kardiale funksie verander. Lopinavir/Ritonavir is in 1% etanol (draer) opgelos en in ‘n mini-osmotiese pomp ingespuit wat chirurgies in Wistar rottes ingeplant is vir agt weke vs. draer en valskontroles. Gevolglik het ons die metabolise parameters en hartfunksie (ex vivo en in vivo metodes) op basislyn en na afloop van ischemie-reperfusie ondersoek. PI-behandelde rotte het ‘n toename in massa getoon asook verhoogde serum LDL-cholesterol, hoër weefseltrigliseriede (hart, lewer), maar geen bewys van insulienweerstandigheid nie. Dit het ook hepatiese asetielko-ensiem A karboksilase β en 3-hidrokise-3-metielglutariel KoA reduktase geenuidrukking opwaarts gereguleer, wat sleutel reguleerders van vetsuuroksidasie en cholesterolsintese onderskeidelik is. Verder, het PI-behandelde harte ingeperkte UPS, verhoogde SOD aktiwiteit en onveranderde superoksiedvlakke vertoon, asook verhoogde peroksisoomproliferator-geaktiveerde reseptor-γ ko-aktiveerder 1-α (PGC-1α) peptiedvlakke. Perfusie data toon kontraktiele wanfunskionering gedurende basislyn en na afloop van ischemie-reperfussie, terwyl post-ischemiese harte verlaagde ATPase spesifieke aktiwiteit vs gepaarde kontrole vertoon. Vroeë veranderinge wat deur PI behandeling veroorsaak word, kom ooreen met die metabolise sindroom en reflekteer op ‘n pre-aterogeniese profiel. Bowendien kan die effekte van PIs op kardiale kontraktiele funksie deels veroorsaak word deur die ingeperkte UPS aktiwiteit tesame met die las op die mitochondriale energie sisteem. Ons studie waarsku teen kardio-metaboliese newe effekte met PI behandeling en rig die vraag; wat die mees gepaste ko-behandeling vir pasiënte op chroniese anti-retrovirale behandeling is.
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Duong, Hoan Quoc. "ASYMMETRIC SYNTHESIS OF SILANEDIOL INHIBITORS FOR ACE, FXIa, AND CHYMASE." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/227165.
Full textAbstract:
ChemistryPh.D.
Dialkylsilanediols, a novel class of non-hydrolyzable analogues of the tetrahedral intermediate of amide hydrolysis, have been shown to be good inhibitors of the HIV-1 protease, angiotensin converting enzyme (ACE), thermolysin, and the serine protease α-chymotrypsin. Synthesis and biological evaluation of silanediols are therefore a priority in this research. Asymmetric intramolecular hydrosilylation (AIH) of allyl silyl ethers gives silafurans which can be used directly to make chiral β-silyl acids needed for the silanediol peptide mimics. Absolute configuration determination of AIH products remains a challenge. Proton nuclear magnetic resonance (1H NMR) of the Mosher ester derivative was used to confirm the absolute configuration. This has proven to be a simple method to determine the absolute configuration of silicon-containing primary carbinols. Dialkylsilanediols (1.52) are known as good inhibitors of angiotensin converting enzyme (ACE), with inhibition constants from 3.8 to 207 nM. However, the synthesis of these silandiol peptide mimics involved a long synthetic route. A short, asymmetric synthesis of silanediol ACE inhibitors was developed using asymmetric hydrosilylation and addition of a silyllithium to a sulfinimine, 8 linear steps with an 8% over all yield. Specific inhibitors of the FXIa protease could inhibit thrombosis without completely interrupting normal hemostasis, and prevent or minimize the risk of hemostasis complications. Based on the FXIa substrate, the design and synthesis of the first five guanidine-containing silanediol FXIa inhibitors was developed: Ac-Arg-[Si]-Ala-NHMe (4.15), Ac-Ala-Arg-[Si]-Ala-NHMe (4.16), Ac-Leu-Ala-Arg-[Si]-Ala-NHMe (4.17), Ac-Pro-Ala-Arg-[Si]-Ala-NHMe (4.18), and Ac-Arg-[Si]-Ala-Ala-NHMe (4.19). Synthesis of these targets was achieved using our newly developed silyllithium preparation and silyl dianion addition to the Davis sulfinimine, 11 linear steps, gave silanediol precursor 4.60 in 1.7% yield. Inhibition constant of the FXIa inhibitors was good in range of 76 - 980μM. Human heart chymase (HHC), a chymotrypsin-like serine protease present in the left ventricular tissues of the human heart, converts angiotensin I to angiotensin II, raising blood pressure. Although the physiological role of HHC has not been fully elucidated, it may be involved in various pathological states, particularly in cardiovascular diseases. Synthesis of silanediol inhibitors of HHC, therefore, may contribute to the understanding of its physiological functions and a better treatment for cardiovascular diseases. Synthesis of a silanediol chymase inhibitor has been investigated.
Temple University--Theses
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Nuttall, Robert Kristofer. "Expression and regulation of matrix metalloproteinases and their inhibitors during decidualization in the rat." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0018/NQ58182.pdf.
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Jackson, P. J. "The control of ATP synthesis in heart mitochondria : Functions of a naturally-occurring inhibitor protein." Thesis, University of Leeds, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381278.
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Pendleton, Cullen Nelson. "The inhibitor of apoptosis ch-IAP1 is a direct transcriptional target of v-Rel and c-Rel /." Full text (PDF) from UMI/Dissertation Abstracts International, 2000. http://wwwlib.umi.com/cr/utexas/fullcit?p3004356.
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Kammula, Rao Karunakara. "Purification, characterization and inhibitor studies of rat liver nuclear spermidine N-acetyltransferase." Scholarly Commons, 1994. https://scholarlycommons.pacific.edu/uop_etds/2783.
Full textAbstract:
Polyamines are ubiquitously present in all living cells. The abnormal metabolism of polyamines that is associated with certain types of cancers has been the focus of several investigations. Enzymes that are involved in the transacetylation of polyamines have been studied extensively, so as to develop inhibitors of these enzymes which may be used as drugs in cancer therapy. Based on indirect evidence, the nuclear spermidine acetyltransferase has been thought to be a critical enzyme that is associated with genetic derepression leading to cancerous growth. In the present study a novel, rapid, sensitive and highly reproducible radio chemical procedure has been developed for assaying spermidine (polyamine) acetylation. The study contains data showing range of linearity of the procedure, percent product recovery, as well as low interference from the unreacted acetyl coenzyme A. Rat liver nuclear spermidine acetyltransferase has been purified using the biochemical procedures annmonium sulfate precipitation, DEAE chromatography, Hydroxyapatite chromatography, Diaminobutyl agarose chromatography and Polyacrylamide P-300 gel filtration. The enzyme obtained at the end of such procedures was found to be essentially homogeneous as seen on native gel electrophoresis. The purified enzyme has been shown to have an isoelectric point of 5.2. Bicine and Hepes were found to be more suitable as buffering species for good enzyme activity. The enzymatic reaction velocity was found to increase with temperature upto 36$\sp\circ$C and was found to increase linearly up to four minutes under non limiting conditions in the presence of 20% glycerol. Using the purified enzyme it has also been established that of the three nuclear polyamines, spermidine is the preferred substrate. The apparent Km for acetyl Co A with spermidine as substrate was found to be about 5 mM. The purified enzyme does acetylate histones. All the substrate analogs containing aminobutylamino group are acetylated by the enzyme.
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Ayanruoh, Kris Odafe. "THE NIGERIA DIASPORA AND INVESTING IN NIGERIA: MOTIVATORS & PERCEIVED INHIBITORS." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/506673.
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Business Administration/Strategic ManagementD.B.A.
This dissertation investigates the motivating factors as well as the perceived inhibitors to the Nigeria diaspora investing in Nigeria. Two studies address (1) the motivation for the Nigeria diaspora to invest in their country of origin (2) the perceived factors inhibiting them. Not much is known about what motivates diaspora to invest in their country of origin or why investment intensity varies among diaspora communities. To this end, the relationship between the causal factors and Nigerian born diaspora investment interest is examined using Nielsen & Riddle (2007) investment motivation framework. Using this interdisciplinary approach, an individual level conceptual model of diaspora homeland investment is generated. The study shows that members of the Nigeria diaspora community do not invest in their homeland for financial reward. They invest for perceived emotional returns and this is positively moderated by the degree of their social embeddedness in their country of origin as well as in their country of residence. They also invest for perceived social rewards. This is also moderated by their social embeddedness. The second study examined the perceived inhibitors to diasporic investment using the Galetto conceptual framework (Galetto, 2011). According to Galletto, investment is contingent on four main proximate factors; a minimum amount of money remitted or saved; minimum level of local development; the presence of suitable investment opportunities and the existence of specific household arrangement. The study shows that the perceived inhibitors to diasporic investment are: poor physical infrastructure; weak financial system and political instability and risk and that the dominant inhibitor is political instability and risk. Collectively, these two studies examine why the Nigeria diaspora would want to invest in their homeland and what prevents them from doing so. They seek to identify ways to turn diaspora investment and entrepreneurship interest into meaningful investment in the country-of-origin. Understanding why the nascent Nigeria diaspora investor or entrepreneur invest in their homeland and the obstacles they face is an important first step to identifying ways that governments can attract diasporic investment and entrepreneurship through marketing and other promotional efforts. Finally, this research lays a foundation for a stream of future research, building on the findings and data generated in the process of addressing the research questions.
Temple University--Theses
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Fenning, Andrew S. "Cardiac remodelling in rat models of chronic cardiovascular disease : angiotensin-converting enzyme inhibition in heart failure and diabetes /." [St. Lucia, Qld], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18264.pdf.
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Cyril, Vidusha. "A solid phase assay for topoisomerase I interfacial poisons and catalytic inhibitors." Master's thesis, University of Central Florida, 2011. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4750.
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We report a mechanism based screening technique to rapidly identify eukaryotic topoisomerase I targeting agents. The method is based on genetic tagging of topoisomerase I to immobilize the enzyme on a solid surface in a microtiter well format. DNA is added to the wells and retained DNA is detected by Picogreen fluorescence. Compounds that result in an increase in Picogreen staining represent potential topoisomerase interfacial poisons while those that reduce fluorescence report catalytic inhibitors; therefore, the solid phase assay represents a 'bimodal' readout that reveals mechanisms of action. The method has been demonstrated to work with known interfacial poisons and catalytic inhibitors. In addition to specific topoisomerase targeting drugs, the method also weakly detects other relevant anticancer agents, such as potent DNA alkylating and intercalating compounds; therefore, topoisomerase I HTS represents an excellent tool for searching and identifying novel genotoxic agents. This method is rapid, robust, economical and scalable for large library screens.ID: 031001489; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Title from PDF title page (viewed July 24, 2013).; Thesis (M.S.)--University of Central Florida, 2011.; Includes bibliographical references (p. 47-54).
M.S.
Masters
Molecular Biology and Microbiology
Medicine
Molecular and Microbiology
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Capicciotti, Chantelle. "The Rational Design of Potent Ice Recrystallization Inhibitors for Use as Novel Cryoprotectants." Thèse, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/30634.
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The development of effective methods to cryopreserve precious cell types has had tremendous impact on regenerative and transfusion medicine. Hematopoietic stem cell (HSC) transplants from cryopreserved umbilical cord blood (UCB) have been used for regenerative medicine therapies to treat conditions including hematological cancers and immodeficiencies. Red blood cell (RBC) cryopreservation in blood banks extends RBC storage time from 42 days (for
hypothermic storage) to 10 years and can overcome shortages in blood supplies from the high demand of RBC transfusions. Currently, the most commonly utilized cryoprotectants are 10%
dimethyl sulfoxide (DMSO) for UCB and 40% glycerol for RBCs. DMSO is significantly toxic
both to cells and patients upon its infusion. Glycerol must be removed to <1% post-thaw using
complicated, time consuming and expensive deglycerolization procedures prior to transfusion to prevent intravascular hemolysis. Thus, there is an urgent need for improvements in
cryopreservation processes to reduce/eliminate the use of DMSO and glycerol.
Ice recrystallization during cryopreservation is a significant contributor to cellular injury and
reduced cell viability. Compounds capable of inhibiting this process are thus highly desirable as novel cryoprotectants to mitigate this damage. The first compounds discovered that were ice recrystallization inhibitors were the biological antifreezes (BAs), consisting of antifreeze proteins and glycoproteins (AFPs and AFGPs). As such, BAs have been explored as potential cryoprotectants, however this has been met with limited success. The thermal hysteresis (TH)activity and ice binding capabilities associated with these compounds can facilitate cellular damage, especially at the temperatures associated with cryopreservation. Consequently,
compounds that possess “custom-tailored” antifreeze activity, meaning they exhibit the potent ice recrystallization inhibition (IRI) activity without the ability to bind to ice or exhibit TH activity,are highly desirable for potential use in cryopreservation.
This thesis focuses on the rational design of potent ice recrystallization inhibitors and on
elucidating important key structural motifs that are essential for potent IRI activity. While
particular emphasis in on the development of small molecule IRIs, exploration into structural
features that influence the IRI of natural and synthetic BAs and BA analogues is also described as these are some of the most potent inhibitors known to date. Furthermore, this thesis also
investigates the use of small molecule IRIs for the cryopreservation of various different cell types to ascertain their potential as novel cryoprotectants to improve upon current cryopreservation protocols, in particular those used for the long-term storage of blood and blood products.
Through structure-function studies the influence of (glyco)peptide length, glycosylation and
solution structure for the IRI activity of synthetic AFGPs and their analogues is described. This thesis also explores the relationship between IRI, TH and cryopreservation ability of natural
AFGPs, AFPs and mutants of AFPs. While these results further demonstrated that BAs are
ineffective as cryoprotectants, it revealed the potential influence of ice crystal shape and growth progression on cell survival during cryopreservation.
One of the most significant results of this thesis is the discovery of alkyl- and phenolicglycosides as the first small molecule ice recrystallization inhibitors. Prior to this discovery, all reported small molecules exhibited only a weak to moderate ability to inhibit ice recrystallization.
To understand how these novel small molecules inhibit this process, structure-function studies
were conducted on highly IRI active molecules. These results indicated that key structural
features, including the configuration of carbons bearing hydroxyl groups and the configuration of
the anomeric center bearing the aglycone, are crucial for potent activity. Furthermore, studies on the phenolic-glycosides determined that the presence of specific substituents and their position on the aryl ring could result in potent activity. Moreover, these studies underscored the sensitivity of IRI activity to structural modifications as simply altering a single atom or functional group on this substituent could be detrimental for activity.
Finally, various IRI active small molecules were explored for their cryopreservation potential
with different cell types including a human liver cell line (HepG2), HSCs obtained from human
UCB, and RBCs obtained from human peripheral blood. A number of phenolic-glycosides were
found to be effective cryo-additives for RBC freezing with significantly reduced glycerol
concentrations (less than 15%). This is highly significant as it could drastically decrease the
deglycerolization processing times that are required when RBCs are cryopreserved with 40%
glycerol. Furthermore, it demonstrates the potential for IRI active small molecules as novel
cryoprotectants that can improve upon current cryopreservation protocols that are limited in terms of the commonly used cryoprotectants, DMSO and glycerol.
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Edwards, Jeffrey Earl. "THE TRANSPORT AND MODULATION OF HIV PROTEASE INHIBITORS INTO THE RAT CENTRAL NERVOUS SYSTEM AND MILK." UKnowledge, 2004. http://uknowledge.uky.edu/gradschool_diss/468.
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The objective of this dissertation is to study the mechanism by which HIV protease inhibitors enter into the central nervous system (CNS) and breast milk of rats, and what effects MDR modulators have on the distribution and metabolism of HIV protease inhibitors. The transporter P-glycoprotein (P-gp) has been shown to limit the distribution of HIV protease inhibitors into the CNS of rodents. This thesis examined the effects of GF120918, an MDR modulator, on the CNS distribution of amprenavir, an HIV protease inhibitor, in rats. GF120918 significantly increased the unbound CNS concentrations of amprenavir without altering the unbound blood concentrations of amprenavir. The results of these studies show that GF120918 can inhibit P-gp at the blood brain barrier (BBB) to increase the unbound CNS concentration of amprenavir and potentially other HIV protease inhibitors. Many first generation MDR modulators inhibited both P-gp transport and CYP3A metabolism. Therefore, a principal goal of this thesis was to determine if GF120918 could selectively inhibit P-gp transport without inhibiting CYP3A metabolism. Using in vitro (human) and in vivo (rat) studies, GF120918 selectively inhibited P-gp at the BBB without inhibiting CYP3A metabolism. The transporter MRP1 has been shown to both transport HIV protease inhibitors and expressed in the CNS. Studies contained in the thesis have shown that mrp1 is not localized to the BBB of rats, therefore, mrp1 is unlikely to play a significant role in the distribution of HIV protease inhibitors into the CNS of rats. The distribution of nelfinavir, an HIV protease inhibitor, into rat breast milk was studied in the thesis as a first approach in understanding the extent to which HIV protease inhibitors can accumulate into milk. The concentration of nelfinavir in rat milk was approximately half that of plasma. P-gp protein expression was detected in lactating rat mammary tissue. However, GF120918 showed no effect on the distribution of nelfinavir into rat milk suggesting that P-gp does not play a significant role in the distribution of HIV protease inhibitors into milk.
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Komorowski, Joanna Irena. "Influence of protein kinase C activators and inhibitors on rat granulosa cell steroidogenesis in vitro." Thesis, University of Ottawa (Canada), 1993. http://hdl.handle.net/10393/6745.
Full textAbstract:
The present studies were undertaken to determine the involvement of protein kinase C (PKC) in the regulation of rat granulosa cell steroidogenesis in vitro. The effects of PKC activators (1-oleoyl-2-acetylglycerol (OAG); 1,2-dioctanoylglycerol (DiC$\sb8$) and phorbol 12-myristate 13-acetate (TPA)) and inhibitors (DL-Sphingosine (ESP) and 1-(5-Isoquinolinylsulfonyl)-3-methylpiperazine free base (H$\sb7)\rbrack$ on basal and FSH-, (Bu)$\sb2$cAMP-, forskolin- and calcium ionophore A23187-stimulated pregnenolone (P$\sb5$), progesterone (P) and 20$\alpha$-hydroxy-pregn-4-en-3-one (20$\alpha$-OH-P) secretion by granulosa cells were studied. OAG, when continually present in the culture medium (MEM), significantly stimulated P$\sb5$, P and 20$\alpha$-OH-P secretion during 6 to 24 h culture periods. It also markedly increased the conversion of exogenous P$\sb5$ to P and 20$\alpha$-OH-P and exogenous P to 20$\alpha$-OH-P during 24 h cultures. Pretreatment of granulosa cells with TPA for 1 h or treatment for up to 6 h resulted in a significant increase in P$\sb5$, P and 20$\alpha$-OH-P secretion. Except for 20$\alpha$-OH-P production, which was stimulated by the phorbol ester during all culture periods studied, secretion of P$\sb5$ and P (in the presence or absence of exogenous hormones and the inhibitors of steroidogenic enzymes) were substantially inhibited by TPA during a 24 h incubation. However, when granulosa cells were incubated with both OAG (20 $\mu$g/ml) and TPA (40 ng/ml), progestin secretion was increased irrespective of the duration of incubation. PKC inhibitors dose-dependently suppressed the stimulatory effect of OAG (20 $\mu$g/ml) and TPA (40 ng/ml) with complete inhibition noted at 100 $\mu$M of H$\sb7$ and 10 $\mu$M of ESP. Diacylglycerols and TPA exerted divergent effects on FSH-, (Bu)$\sb2$cAMP- and forskolin-stimulated progestin secretion. FSH-stimulated accumulation of P$\sb5$ throughout the culture periods (1-24 h) was markedly increased by OAG (20 $\mu$g/ml) but inhibited by TPA (40 ng/ml). OAG (5-80 $\mu$g/ml) and DiC$\sb8$ (20 $\mu$g/ml) significantly enhanced FSH-induced progestin secretion during 6 h and 24 h culture periods and increased steroid synthesis in 24 h cultures in the presence of (Bu)$\sb2$cAMP or forskolin. In contrast, TPA significantly inhibited FSH- and (Bu)$\sb2$cAMP-stimulated progestin secretion during both 6 h and 24 h of incubation. Pretreatment of granulosa cells with TPA (40 ng/ml) for 20 h to down-regulate PKC, decreased progestin secretion during subsequent incubation with FSH (150 ng/ml) and prevented any stimulation by OAG (20 $\mu$g/ml). The effects of OAG (20 $\mu$g/ml) and TPA (40 ng/ml) on FSH-induced steroid secretion appeared to be additive when both PKC activators were present together and differed significantly from those when OAG and TPA were present with FSH separately. Diolein (a nonpermeable diacylglycerol), 4$\alpha$-phorbol 12,13-didecanoate and phorbol 13-monoacetate (two phorbol esters with no tumor promoting activity) did not influence basal or FSH-stimulated steroid secretion by granulosa cells. (Abstract shortened by UMI.)
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McCarry, W. J. "The influence of monoamine oxidase inhibitors on some pharmacological responses of the rat anococcygeus muscle." Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373269.
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Dobie, Frederick Andrew. "Molecular and cellular mechanisms of inhibitory synapse formation in developing rat hippocampal neurons." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/41933.
Full textAbstract:
The proper functioning of the brain and central nervous system (CNS) requires the precise formation of synapses between neurons. The two main neurotransmitter systems for fast synaptic communication in the CNS are excitatory glutamate and inhibitory gamma-aminobutyric acid. A growing body of evidence has begun to uncover several shared and divergent rules for the establishment of each of these two types of synapses.
At the molecular level, a number of key proteins have been shown to be involved in the initial formation and subsequent development of synaptic connection, including cell adhesion molecules (CAMs). Among the CAMs, neurexins and neuroligins are important synaptogenic proteins that act trans-synaptically to organize synapses: binding of axonal beta-neurexins by neuroligins is sufficient to cause development of a presynaptic specialization at that site, while binding of dendritic neuroligin-1 or neuroligin-2 by beta-neurexins is sufficient to cause development of postsynaptic excitatory or inhibitory specializations, respectively. In Chapter 2, we explore the role of alpha-neurexins in synapse organization. We find alpha-neurexins are able to specifically induce the formation of inhibitory synapses, presumably through clustering of postsynaptic neuroligin-2. Moreover, we find that the expression of various splice variants of alpha- and beta-neurexins is regulated both during development and by activity, suggesting a physiological role for alternative splicing in the modulation of synapse assembly.
At the cellular level, it is now clear from live imaging studies that synapses and their formation are highly dynamic processes. A number of studies have established the temporal recruitment of pre- and postsynaptic components to nascent synapses and how synapse formation can influence neuron growth. However, these studies have focused on excitatory synapses. In Chapter 3, we explore the cellular mechanisms of inhibitory synapse formation and modulation. We find that entire synapses are highly mobile and can undergo dynamic structural modulation. New synapses are formed by gradual accumulation of components from diffuse cytoplasmic pools, with a significant contribution of presynaptic vesicles from previously recycling sites. These results provide new insights into the mechanisms of inhibitory synapse formation and how it is both similar and different from excitatory synapse formation.
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Farrant, M. "Inhibitory neurotransmission and amino acid release in the substantia nigra of the rat." Thesis, University College London (University of London), 1987. http://discovery.ucl.ac.uk/57623/.
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Harris, Dorothy Patrice. "Regulation of growth inhibitory mechanisms following cortical injury in the adult rat brain." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1490070821&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Lau, Sin-nga, and 劉善雅. "The role of RAB(rat sarcoma-related proteins in brain) Gtpases in regulating testicular junction dynamics." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31245535.
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Stone, Erica. "EFFECTS OF ORTHOPHOSPHATE CORROSION INHIBITOR IN BLENDED WATER QUALITY ENVIRONMENTS." Doctoral diss., University of Central Florida, 2008. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/2961.
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This study evaluated the effects of orthophosphate (OP) inhibitor addition on iron, copper, and lead corrosion on coupons exposed to different blends of groundwater, surface water, and desalinated seawater. The effectiveness of OP inhibitor addition on iron, copper, and lead release was analyzed by statistical comparison between OP treated and untreated pilot distribution systems (PDS). Four different doses of OP inhibitor, ranging from zero (control) to 2 mg/L as P, were investigated and non-linear empirical models were developed to predict iron, copper, and lead release from the water quality and OP doses. Surface characterization evaluations were conducted using X-ray Photoelectron Spectroscopy (XPS) analyses for each iron, galvanized steel, copper, and lead/tin coupon tested. Also, a theoretical thermodynamic model was developed and used to validate the controlling solid phases determined by XPS. A comparison of the effects of phosphate-based corrosion inhibitor addition on iron, copper, and lead release from the PDSs exposed to the different blends was also conducted. Three phosphate-based corrosion inhibitors were employed; blended orthophosphate (BOP), orthophosphate (OP), and zinc orthophosphate (ZOP). Non-linear empirical models were developed to predict iron, copper, and lead release from each PDS treated with different doses of inhibitor ranging from zero (control) to 2 mg/L as P. The predictive models were developed using water quality parameters as well as the inhibitor dose. Using these empirical models, simulation of the water quality of different blends with varying alkalinity and pH were used to compare the inhibitors performance for remaining in compliance for iron, copper and lead release. OP inhibitor addition was found to offer limited improvement of iron release for the OP dosages evaluated for the water blends evaluated compared to pH adjustment alone. Empirical models showed increased total phosphorus, pH, and alkalinity reduced iron release while increased silica, chloride, sulfate, and temperature contributed to iron release. Thermodynamic modeling suggested that FePO4 is the controlling solid that forms on iron and galvanized steel surfaces, regardless of blend, when OP inhibitor is added for corrosion control. While FePO4 does not offer much control of the iron release from the cast iron surfaces, it does offer protection of the galvanized steel surfaces reducing zinc release. OP inhibitor addition was found to reduce copper release for the OP dosages evaluated for the water blends evaluated compared to pH adjustment alone. Empirical models showed increases in total phosphorus, silica, and pH reduced copper release while increased alkalinity and chloride contributed to copper release. Thermodynamic modeling suggested that Cu3(PO4)2•2H2O is the controlling solid that forms on copper surfaces, regardless of blend, when OP inhibitor is added for corrosion control. OP inhibitor addition was found to reduce lead release for the OP dosages evaluated for the water blends evaluated compared to pH adjustment alone. Empirical models showed increased total phosphorus and pH reduced lead release while increased alkalinity, chloride, and temperature contributed to lead release. Thermodynamic modeling suggested that hydroxypyromorphite is the controlling solid that forms on lead surfaces, regardless of blend, when OP inhibitor is added for corrosion control. The comparison of phosphate-based inhibitors found increasing pH to reduce iron, copper, and lead metal release, while increasing alkalinity was shown to reduce iron release but increase copper and lead release. The ZOP inhibitor was not predicted by the empirical models to perform as well as BOP and OP at the low dose of 0.5 mg/L as P for iron control, and the OP inhibitor was not predicted to perform as well as BOP and ZOP at the low dose of 0.5 mg/L as P for lead control. The three inhibitors evaluated performed similarly for copper control. Therefore, BOP inhibitor showed the lowest metal release at the low dose of 0.5 mg/L as P for control of iron, copper, and lead corrosion.Ph.D.
Department of Civil and Environmental Engineering
Engineering and Computer Science
Environmental Engineering PhD
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Guan, Xiaotao. "IMPACT OF ZINC ORTHOPHOSPHATE INHIBITOR ON DISTRIBUTION SYSTEM WATER QUALITY." Doctoral diss., University of Central Florida, 2007. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/3294.
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This dissertation consists of four papers concerning impacts of zinc orthophosphate (ZOP) inhibitor on iron, copper and lead release in a changing water quality environment. The mechanism of zinc orthophosphate corrosion inhibition in drinking water municipal and home distribution systems and the role of zinc were investigated. Fourteen pilot distribution systems (PDSs) which were identical and consisted of increments of PVC, lined cast iron, unlined cast iron and galvanized steel pipes were used in this study. Changing quarterly blends of finished ground, surface and desalinated waters were fed into the pilot distribution systems over a one year period. Zinc orthophosphate inhibitor at three different doses was applied to three PDSs. Water quality and iron, copper and lead scale formation was monitored for the one year study duration. The first article describes the effects of zinc orthophosphate (ZOP) corrosion inhibitor on surface characteristics of iron corrosion products in a changing water quality environment. Surface compositions of iron surface scales for iron and galvanized steel coupons incubated in different blended waters in the presence of ZOP inhibitor were investigated using X-ray Photoelectron Spectroscopy (XPS), Scanning Electron Microscopy (SEM) / Energy Dispersive X-ray Spectroscopy (EDS). Based on surface characterization, predictive equilibrium models were developed to describe the controlling solid phase and mechanism of ZOP inhibition and the role of zinc for iron release. The second article describes the effects of zinc orthophosphate (ZOP) corrosion inhibitor on total iron release in a changing water quality environment. Development of empirical models as a function of water quality and ZOP inhibitor dose for total iron release and mass balances analysis for total zinc and total phosphorus data provided insight into the mechanism of ZOP corrosion inhibition regarding iron release in drinking water distribution systems. The third article describes the effects of zinc orthophosphate (ZOP) corrosion inhibitor on total copper release in a changing water quality environment. Empirical model development was undertaken for prediction of total copper release as a function of water quality and inhibitor dose. Thermodynamic models for dissolved copper based on surface characterization of scale that were generated on copper coupons exposed to ZOP inhibitor were also developed. Surface composition was determined by X-ray Photoelectron Spectroscopy (XPS). The fourth article describes the effects of zinc orthophosphate (ZOP) corrosion inhibitor on total lead release in a changing water quality environment. Surface characterization of lead scale on coupons exposed to ZOP inhibitor by X-ray Photoelectron Spectroscopy (XPS) was utilized to identify scale composition. Development of thermodynamic model for lead release based on surface analysis results provided insight into the mechanism of ZOP inhibition and the role of zinc.Ph.D.
Department of Civil and Environmental Engineering
Engineering and Computer Science
Environmental Engineering PhD
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HENDRON, EUNAN. "Potent and specific actions of 2-Aminoethoxydiphenyl borate (2-APB) derivatives on Orai channel function." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/235040.
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BiochemistryPh.D.
In an effort to dissect the mechanism of SOCe activation, I used two novel 2-APB analogs (DPB162-AE and DPB163-AE) which are ~50-100 times more potent at modifying SOCe than 2-APB. In the presence of STIM1, both compounds (2 µM) differentially affected Orai subtypes, fully blocking endogenous Orai1, but not Orai2 or Orai3 mediated SOCe in DT40 Orai-specific knockout cells. Neither analog directly activated Orai3 over-expressed alone in HEK293 cells. Analysis of constitutively active Orai1 mutant, Orai1V102C, showed an increase in Ca2+ entry after application of DPB162-AE independent of STIM1. When STIM1 was co-expressed with Orai1V102C, there was no inhibitory effect of the analog on the mutant channel complex. DPB162-AE appeared to have a long term effect on the channel complex revealed a lack of SOCe 10 minutes after washout of the analog. STIM1ct-Orai1 Ca2+ entry was moderately increased by DPB162-AE yet constitutively active Stim1ct4EA-Orai1 Ca2+ entry was robustly inhibited. The activation of mutant Orai1V102C indicated the analogs are capable of interacting with Orai1, perhaps to widen the pore, and pointing to a putative mechanism of action for inhibition. FRET analysis indicated no effect on STIM1-Orai1, STIM1ct-Orai1 or SOAR-Orai1 coupling. Thus, the inhibitory effect on STIM1-Orai may be through physical alteration of Orai1 gating. Previously reported as having biphasic effect on SOCe proteins, DPB163-AE appeared to effect its potentiation exclusively via STIM2 with no evident inhibition of STIM2 SOCe. Inhibition by both analogs was mediated by STIM1. DPB162-AE and DPB163-AE had remarkable specificity on Orai1 as opposed to other Ca2+ permeant channels. Neither compound affected Ca2+ entry through TRPC3, TRPC6, or strontium entry through Cav1.2 channels at concentrations (2 µM) that completely inhibited Orai1-mediated SOCe. In summary, DPB162-AE and DPB163-AE are highly specific inhibitors of Orai1 SOCe, with little effect on Orai2 and Orai3, and no effect on other Ca2+ channels. They do not disrupt STIM-Orai coupling but may modify functional Orai1 channel structure to effect their inhibitory action on SOCe.
Temple University--Theses