Tolfenamic acid (TA), betulinic acid (BA) and acetylsalicylic acid (aspirin) are anticancer drugs, and Sp1, Sp3, Sp4 transcription factors and growth factor 2 (EGFR2, HER2 / ErbB2) are important molecular markers in cancer cells. In this study the molecular mechanisms by which these anticancer drugs target downregulation of Sp1, Sp3, Sp4 and ErbB2 are investigated in breast cancer cells. TA inhibits growth of ErbB2-overexpressing BT474 and SKBR3 breast cancer cells by inhibiting ErbB2 expression. In cells treated with TA, ErbB2 mRNA expression and promoter activity were decreased, and this was due to decreased mRNA stability in BT474 cells. In both cell lines, TA also decreased expression of the YY1 and AP-2 transcription factors that are required for basal ErbB2 expression. These effects were accompanied by decreased ErbB2-dependent kinase activities, induction of p27, and decreased expression of cyclin D1. In addition, TA also inhibited tumor growth in BT474 cells orthotopic mouse model. However, Sp proteins were not the major target of TA in these breast cancer cells and this contrasts to results in pancreatic cancer cells where TA decreased expression of Sp proteins. BA inhibits growth of ErbB2 –overexpressing BT474 and MDA-MB-453 and induced apoptosis in these cells. BA induced proteasome-independent downregulation of specificity protein (Sp) transcription factors Sp1, Sp3, Sp4 and survivin, an Sp-regulated gene, and BA also decreased expression of ErbB2, ErbB2-regulated kinases and also YY1, a transcription factor that regulates ErbB2 expression in these cells. Knockdown of Sp1, Sp3, Sp4 and their combination by RNA interference was accompanied by decreased expression of ErbB2, YY1 and luciferase activity in cells transfected with a construct containing the GC-rich YY1 promoter linked to a luciferase reporter gene. BA-dependent repression of Sp1, Sp3, Sp4 and Sp regulated genes was due in part to induction of the Sp repressor ZBTB10 and downregulation of microRNA-27a (miR-27a) which constitutively inhibits ZBTB10 expression. The effects of BA on the miR-27a:zBTB10-Sp transcription factor axis were inhibited in cells cotreated with the cannabinoid 1 (CB1) and CB2 receptor antagonists AM251 and AM630 respectively. However, in vitro binding studies with ≤ 10 mM BA and a radiolabeled cannabinoid did not indicate direct competitive binding of BA to the CB1 and CB2 receptors, suggesting a possible role for other CB-like G protein-coupled receptors. Aspirin inhibits growth, induces apoptosis and decreases cell migration in BT474 and MDA-MB-453 breast cancer cells that overexpress the ErbB2 oncogene. Aspirin also downregulated ErbB2 expression in these cells and this was accompanied by inhibition of downstream kinases including phospho-Akt (p-Akt) and phospho-mitogen-activated protein kinase (p-MAPK). Aspirin also decreased expression of survivin, vascular endothelial growth factor (VEGF) and YY1 which regulates ErbB2 expression in these cell lines. Aspirin also downregulates Sp1, Sp3 and Sp4, and further investigation of the underlying mechanism of action showed that aspirin-induced downregulation of Sp transcription factors and Sp-regulated genes could be inhibited in part by proteasome inhibitior lactacystin and phosphatase inhibitors including sodium orthovanadate (SOV). These results were consistant with the induction of several phosphatases by aspirin in BT474 and MDA-MB-453 cells and these include mitogen-activated protein kinase phosphatase-5 (MKP-5) and MKP-1. Aspirin-induced downregulation of Sp1, Sp3 and Sp4 are reversed in cells transfected with an oligonucleotide (siMKP5) that knocks down MKP5 by RNA interference whereas siMKP-1 did not block Sp protein downregulation demonstrating for the first time a linkage between a drug-induced phosphatase (MKP-5) and Sp downregulation. These results suggest that TA, BA and aspirin represent novel and promising new anticancer drugs for cancer treatment by targeting Sp proteins and ErbB2 oncogene.

Abstract In the course of human medical history, if there¡¦s a drug that encompasses historic position and future possibilities, it is without a doubt, the aspirin. In the past ten years, new researches related to aspirin developed and opened new area and usages for this wonder drug. Treatments for newly diagnosed disease are also being expanded with new aspirin researches. Usage of medicine against infection can be traced back to 1500. Ebers Papyrus suggested the practice of using dried leaves to treat rheumatism pains and fight against infection through the salicylic acid effect. Later, it was discovered that salicylic acid from the tree bark contains medical value. This was how salicylic acid was obtained until a German named Herman Klobe discovered attaining salicylic acid chemically. Salicylic acid can assist in resisting rheumatism, which was confirmed in a clinical research in 1876. In Germany, 1887, while working in Bayer¡¦s paramedical factory, Felix Hoffman wanted to improve the terrible smell of salicylic acid, so his father, with rheumatism can better take the medicine. He added Acteyl to salicylic acid, which produced acetylsalicylic acid. With animal research, Heinrich Dressler found that this drug has the function of relieving pain and rheumatism. He named this drug aspirin and introduced it to the mass market. The Aspirin as we know today was born. Due to a long history of aspirin use, it¡¦s confirmed that except high dosage uses on children or teenagers suffering from chicken-pox or the flu, aspirin is a safe drug for adults. Clinical tests in the medical field has proven using 100grams of aspirin daily can contain Thromboxane A2 It¡¦s concentration will not affect cyclo system Endothelin cell COX-1. It also does not have any anti-infection effect, so it is safe to take along with other anti-infection drugs, to safely prevent strokes and heart attacks. This research make use of the 4P analysis to do all-round analysis at Aspirin 100 primary prevention And use its framework to simulate the strategy Afterward it use new management though to simulate the strategy "the blue ocean strategy" the analysis tool and framework of Aspirin 100. This research hope the result can make.

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Thrombosis is the pathological formation of platelet aggregates that cause stroke and heart attack\textemdash the leading causes of death in developed nations. Determining effective dosages for platelet therapies (e.g. aspirin, Integrilin, and Plavix) to prevent thrombosis is a persistent medical challenge (studies estimate up to 45% of patients exhibit insufficient responses to these drugs) and recent studies have implicated pathological flow conditions of high shear rates and stenosis morphology as primary factors. However, there are currently no diagnostic instruments able to recapitulate a range of such pathological flow conditions for evaluating thrombosis with and without these drugs. In this work, a microfluidic device and associated optical system were designed and fabricated for simultaneous measurement of platelet aggregation at multiple initial wall shear rates within multiple stenotic channels in label-free whole blood and used to characterize thrombosis at varying dosages of two platelet therapies: acetyl-salicylic acid (aspirin) and eptifibatide (Integrilin). Results from our studies show the effects of pathologically high shear rates on enhancing platelet thrombosis and demonstrate the widely varied, shear-dependent efficacy of each therapy. This study lays the foundation for the future development of a medical diagnostic for optimizing the type and dosage of patient platelet therapy and to better understand their mechanisms of action.

Made available in DSpace on 2014-06-11T19:25:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-02-27Bitstream added on 2014-06-13T19:12:32Z : No. of bitstreams: 1 barretto_ab_me_botfm.pdf: 1068938 bytes, checksum: e95204fb445fad834353b39ef76acce2 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O objetivo do presente estudo foi estimar os efeitos da injeção local da solução de ácido acetilsalicílico a 20% em implantes de endométrio autólogo intraperitoneal. Foram utilizadas 30 coelhas adultas dividas em 3 grupos de 10 coelhas, com indução da endometriose peritoneal. Após 20 dias da indução da endometriose as coelhas foram randomizadas e de acordo com os grupos receberam os determinados tratamentos: solução fisiológica 0,9% por 20 dias (grupo 1, controle), solução bicarbonatada de ácido acetilsalicílico 20% durante 10 dias (grupo 2, tratamento) e solução bicarbonatada de ácido acetilsalicílico 20% durante 20 dias (grupo 3, tratamento). Os focos de endometriose foram removidos e preparados em lâminas para análise histológica. Foi utilizado um programa de computador para análise das lâminas e aferição da área total de endometriose remanescente. A área do grupo 2 (tratamento 10 dias) foi significativamente menor que a área de endometriose no grupo 1 (controle) e no grupo 3 (tratamento 20 dias), a área não foi aferida por não ter restado endometriose remanescente em nenhuma das 10 lâminas. O tratamento com ácido acetilsalicílico em um período de 20 dias destrói toda a área de endometrios... / The objective of the present study was to estimate the effects of local injection of acetylsalicylic acid solution into intraperitoneal implants of autologous endometrium. The 30 adult female rabbits utilized were divided into 3 groups of 10 each, in which peritoneal endometriosis was induced. Twenty days after endometriosis induction the rabbits were randomized and according to group received the following treatments: physiological solution 0.9% for 20 days (Group 1, control), bicarbonate solution of acetylsalicylic acid 20% for 10 days (Group 2, treatment) and bicarbonate solution of acetylsalicylic acid 20% for 20 days (Group 3, treatment). The endometriosis foci were removed and prepared on slides for histological analysis. A computer program was utilized to analyze the slides and measure the total area of remaining endometriosis. Group 2 (10- day treatment) presented a significantly smaller endometriosis area than Group 1 (control) and Group 3 (20-day treatment); the area was not measured on account of lack of endometriosis residue in any of the 10 slides. The 20-day treatment with acetylsalicylic acid destroys the entire endometriosis area... (Complete abstract, click electronic access below)

Orientador: Rogério Saad-Hossne / Banca: José Luis Chiaradia Gabriel / Banca: Juan Llanos / Resumo: O objetivo do presente estudo foi estimar os efeitos da injeção local da solução de ácido acetilsalicílico a 20% em implantes de endométrio autólogo intraperitoneal. Foram utilizadas 30 coelhas adultas dividas em 3 grupos de 10 coelhas, com indução da endometriose peritoneal. Após 20 dias da indução da endometriose as coelhas foram randomizadas e de acordo com os grupos receberam os determinados tratamentos: solução fisiológica 0,9% por 20 dias (grupo 1, controle), solução bicarbonatada de ácido acetilsalicílico 20% durante 10 dias (grupo 2, tratamento) e solução bicarbonatada de ácido acetilsalicílico 20% durante 20 dias (grupo 3, tratamento). Os focos de endometriose foram removidos e preparados em lâminas para análise histológica. Foi utilizado um programa de computador para análise das lâminas e aferição da área total de endometriose remanescente. A área do grupo 2 (tratamento 10 dias) foi significativamente menor que a área de endometriose no grupo 1 (controle) e no grupo 3 (tratamento 20 dias), a área não foi aferida por não ter restado endometriose remanescente em nenhuma das 10 lâminas. O tratamento com ácido acetilsalicílico em um período de 20 dias destrói toda a área de endometrios... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The objective of the present study was to estimate the effects of local injection of acetylsalicylic acid solution into intraperitoneal implants of autologous endometrium. The 30 adult female rabbits utilized were divided into 3 groups of 10 each, in which peritoneal endometriosis was induced. Twenty days after endometriosis induction the rabbits were randomized and according to group received the following treatments: physiological solution 0.9% for 20 days (Group 1, control), bicarbonate solution of acetylsalicylic acid 20% for 10 days (Group 2, treatment) and bicarbonate solution of acetylsalicylic acid 20% for 20 days (Group 3, treatment). The endometriosis foci were removed and prepared on slides for histological analysis. A computer program was utilized to analyze the slides and measure the total area of remaining endometriosis. Group 2 (10- day treatment) presented a significantly smaller endometriosis area than Group 1 (control) and Group 3 (20-day treatment); the area was not measured on account of lack of endometriosis residue in any of the 10 slides. The 20-day treatment with acetylsalicylic acid destroys the entire endometriosis area... (Complete abstract, click electronic access below) / Mestre

Introduction: The recurrence of the cerebral ischemic stroke after a history of TIA or ischemic stroke is 3-4% per year. One way of reducing the risk of reccurence is using antiplatelet therapy. The aim of our study was to investigate the effect of aspirin. Even though, newer antiplatelet drugs were developed, their risk/benefit profile has not been proved to be better than aspirin. Reasons for using aspirin in secondary prevention are: the longest experience, clearly proven effect in many studies and low price. On the other hand, aspirin prevents only 25% of strokes, thus there is wide space for searching for causes of failed therapy and alternative therapeutic ways. Noncompliance of aspirin use and embolic events are usually indicated as the most common causes of an ineffective therapy. The goal of our study was to find the antiplatelet therapy effectivity in patients with history of stroke treated with aspirin in daily dose of 100mg. We assured 100% compliance among these patients and as much as possible minimalized a likelihood of embolic causes of strokes. What is more, we tried to find out whether an insuffient suppression of 11-dehydrotromboxane B2 correlates with comorbidities, other used medication or laboratory parameters. Furthermore, whether by administrating an increased dose of...

Orientador: Jose Barreto Campello Carvalheira / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-10T01:08:04Z (GMT). No. of bitstreams: 1 Souza_KellenKettyde_M.pdf: 1724833 bytes, checksum: 44f766e2043af515b2f3f9462dc5c5e3 (MD5) Previous issue date: 2007 / Resumo: A resistência dos tumores aos quimioterápicos é um problema clínico comum. Recentemente, foi demonstrado que o bloqueio. da via de sinalização da PI3-quinase aumenta a apoptose induzida pelo SN-38, um metabólito ativo do irinotecano. Entretanto, os mecanismos moleculares destas mudanças ainda não são esclarecidos. Para investigar os eventos moleculares envolvidos no aumento da sinalização na via da PI3-quinase associada ao irinotecano, aspirina e rapamicina foram utilizadas para modular esta via de sinalização. Nós observamos que a aspirina é capaz de inibir a fosforilação do IRS-l, através de seus alvos JNK e IKK, e aumentar o crescimento dos tumores em camundongos Scid previamente injetados com linhagem de adenocarcinoma de cólon (HT29). Adicionalmente, demonstramos que o bloqueio da mTOR reduz a proliferação celular induzida pelo irinotecano. Assim, a ativação da via PI3-quinase/ Akt/mTOR pode contribuir para a quimiorresistência induzi da pelo irinoteco / Abstract: Resistance of tumors to chemotherapeutic agents is a common clinical problem in human cancer. Recently, the blocking of PI3-kinase signaling pathway was shown to enhance apoptosis induced by SN-38, an active form of irinotecan. To gain further insight into the molecular events of irinotecan-associated increase in PI3-kinase signaling pathway, aspirin and rapamycin were used to modulate this signaling pathway. We describe here that aspirin is able to further inhibit IRS-l serine phosphorylation induced by irinotecan through targeting JNK and IKK, thus agonist activation of IRS-l/PI3-kinase pathway blocked the growth-inhibitory effect of irinotecan in HT -29 colon cancer xenografts; our data also demonstrate a synergistic effect of mTOR inhibition and irinotecan on tumor growth. Activation of PI3-kinase/ Akt/mTOR pathway may thus contribute to refTactoriness to treatment with irinotecan / Mestrado / Ciencias Basicas / Mestre em Clinica Medica

Abstract Primary intracerebral hemorrhage (ICH) comprises 10–15% of all strokes. Arterial hypertension and warfarin use are well documented risk factors for ICH, but aspirin use also seems to predispose to ICH. The annual incidence of primary ICH in western populations is 12–31 / 100,000. Mortality is high: 14–52% during the first month and 14–80% during the first year after ICH. The size and location of the hemorrhage, a midline shift in head computed tomography, intraventricular spread of the hemorrhage, level of consciousness on admission, and high blood glucose independently predict mortality. For a risk factor study, 98 consecutive patients admitted into the Department of Neurology, Oulu University Hospital, because of ICH between January 1993 and September 1995 were compared with 206 control subjects drawn from a population register. Thromboxane and prostacyclin biosynthesis were measured from serial urine samples of 43 patients. For outcome studies, all subjects (n = 208) with incident ICH during the study period in the population of Northern Ostrobothnia, Finland, were identified. Untreated hypertension was the main modifiable risk factor for ICH. Use of aspirin appeared to be a significant risk factor for ICH in the subjects with a history of epistaxis. Enhanced thromboxane and prostacyclin biosynthesis were observed in the acute phase and 3 months after ICH. Regular use of aspirin preceding ICH doubled the 3-month mortality rate compared with nonusers of aspirin/warfarin. Aspirin use also associated with early hematoma growth. Patients with ICH showed increased long-term mortality up to 7 years after ICH compared to controls. No excess mortality was observed among those with good recovery at 3 months, but those who were severely disabled at 3 months after ICH showed marked excess mortality.