Experiments were conducted to investigate the role of free radicals in exercise induced cardiac adaptations and to determine if statin administration would adversely affect cardiac adaptations to exercise. In the first experiment myocardial antioxidant enzymes, cardiac function and cardiac hypertrophy were assessed following a chronic exercise protocol previously used by our lab. MPG effectively reduced myocardial oxidative stress and activation of the signaling proteins Akt and S6 following an exercise bout. Skeletal muscle mitochondria content increased to similar levels in E and E+MPG. Similar increases (P<0.05) in both exercised groups were observed for heart wt and heart wt to body wt ratio. Cardiac function at the high workload improved in E vs S as indicated by higher (P<0.05) peak systolic pressure (SP), cardiac output (CO), coronary flow, COxSP and mechanical efficiency (COxSP/VO2). MPG prevented these exercise-induced functional improvements. This study provides evidence that free radicals do not play a role in the development of exercise-induced cardiac hypertrophy, however, they are involved in functional cardiac adaptations, which may be mediated through the PI3K/Akt pathway. In the second experiment a similar exercise protocol was used to determine if statins which have been shown to prevent pathological forms of cardiac hypertrophy, would be detrimental to exercise induced cardiac adaptations. In addition to the sedentary and exercise groups sedentary+statin and exercise+statin groups were assessed. Hearts were isolated and perfused and assessed for function at low and high workloads. Exercise treatment resulted in cardiac hypertrophy in absolute and relative terms to a similar extent in statin-treated and untreated exercised rats. Additionally it resulted in significant functional increases for SP, CO, COxSP, VO₂, and EFF in both exercised groups. In conclusion, these studies provide evidence that exercise in the cold is a valid model for physiological cardiac hypertrophy and that pathological and physiological cardiac hypertrophy signal through different pathways due to the fact that two well established treatments (mpg and statins) that prevent pathological cardiac hypertrophy did not affect exercise induced cardiac hypertrophy. / text

Prostate cancer is one of the leading causes of death in men aged 40-55. Genistein isoflavone (4', 5', 7-trihydroxyisoflavone) is a dietary phytochemical with demonstrated anti-tumor activities in a variety of cancers. Topotecan Hydrochloride (Hycamtin) is an FDA-approved chemotherapy drug, primarily used for secondary treatment of ovarian,cervical and small cell lung cancers. This study was to demonstrate the potential anticancer activities and synergy of topotecan-genistein combination in LNCaP prostate cancer cells. The potential efficacy and mechanism of topotecan/genistein-induced cell death was investigated... Results: The overall data indicated that i) both genistein and topotecan induce cellular death in LNCaP cells, ii) topotecan-genistein combination was significantly more efficacious in reducing LNCaP cell viabiligy compared to either genistein or topotecan alone, iii) in all cases, cell death was primarily through apoptosis, via the activation of the intrinsic pathway, iv) ROS levels were increased and VEGF expression was diminished significantly with the topotecan-genistein combination treatment, v) genetic analysis of topotecan-genistein treatment groups showed changes in genetic expression levels in pathway specific apoptotic genes.... Conclusion: Treatments involving topotecan-genistein combination may prove to be an attractive alternative phytotherapy of adjuvant therapy for prostate cancer. / by Vanessa P. Hèormann. / Thesis (Ph.D.)--Florida Atlantic University, 2012. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

<p align="justify">The production of reactive oxygen species is strictly kept under control in the Human body. However, several conditions are characterized by the over-production or the uncontrolled production of these species, promoting damage to the host tissue. Among oxygen species producer, the myeloperoxidase/hydrogen peroxide/chloride system is a key element. This the consequence of the large quantity of myeloperoxidase found in neutrophils and that can be released rapidly during an inflammatory process. Moreover, hypochlorous acid, synthesized by this system, is a powerful oxidant.</p><p><p align="justify">We have studied the impact of non-steroidal anti-inflammatory drugs (oxicams, nimesulid and flufenamic acid) on three reactive oxygen species, namely, hydroxyl radical, hydrogen peroxide and hypochlorous acid. The first results showed the weak antioxidant properties of these molecules and the necessity to focus on the myeloperoxidase/hydrogen peroxide/chloride system. During the study of the myeloperoxidase inhibition, it appeared that flufenamic acid was an efficient inhibitor that modulated the hypochlorous acid production and was directly oxidized by the enzyme.</p><p><p align="justify">Due to the efficacy of flufenamic acid, this molecule was tested in a model of myeloperoxidase-dependent low-density lipoprotein (LDL) oxidation and compared to thiol-containing molecules like N-AcetylCystein and its lysinate salt, glutathione and captopril. The results showed that flufenamic acid lost part of its inhibiting effect while thiol-containing molecules demonstrated an interesting inhibiting activity in this model. A potential explanation could be the ability of myeloperoxidase to bind lipoproteins, masking the entry of its catalytic pocket. In these conditions, the inhibitor size becomes a key parameter in the inhibition of the MPO-dependent low-density lipoprotein oxidation and N-AcetylCystein appears as a powerful inhibitor in this context. These results render N-AcetylCystein an excellent candidate for studies that focus on the reduction of cardiovascular pathology risk.</p><p><p><br><p><p><p align="justify">Le corps humain est le siège constant de la synthèse d’espèces oxygénées réactives dont la production contrôlée est indispensable au bon fonctionnement de l’organisme. Cependant dans de nombreuses pathologies, il arrive qu’une production exagérée et/ou incontrôlée de ces espèces aboutisse à des dégâts oxydatifs. Parmi les mécanismes de production d’espèces oxydantes, le système myéloperoxydase / peroxyde d’hydrogène / chlorure détient une place importante. Ceci est notamment la conséquence de la grande quantité de MPO présente dans les neutrophiles, pouvant être libérée très rapidement lors de l’inflammation. De plus l’acide l’hypochloreux synthétisé par ce système est un très bon oxydant.</p><p><p align="justify">Nous avons étudié l’impact des anti-inflammatoires non-stéroïdiens (oxicams, nimésulide et acide flufénamique) sur trois espèces oxygénées réactives :le radical hydroxyle, le peroxyde d’hydrogène et l’acide hypochloreux. Les premiers résultats montrent le faible pouvoir anti-oxydant des molécules testées et la nécessité de concentrer notre recherche sur le système myéloperoxydase / peroxyde d’hydrogène / chlorure, responsable de la synthèse de l’acide hypochloreux. Lors de l’étude de l’inhibition de ce système, il est ressorti que l’acide flufénamique est un bon inhibiteur de la myéloperoxydase car il inhibe la synthèse de l’acide hypochloreux en étant directement oxydé par l’enzyme.</p><p><p align="justify">En raison de l’efficacité de l’acide flufénamique, cette molécule a été testée dans un modèle d’oxydation des lipoprotéines de basse densité (LDL) par le système myéloperoxydase / peroxyde d’hydrogène / chlorure en comparaison avec des thiols tels que la N-acétylcystéine et son sel de lysine, le glutathion et le captopril. Les résultats montrent une perte importante du pouvoir d’inhibition de l’acide flufénamique dans ce modèle alors que les thiols et la N-acétylcystéine en particulier, présentent une efficacité non négligeable. Ce phénomène pourrait être attribué à la capacité de la myéloperoxydase de se fixer sur les lipoprotéines, ce qui pourrait masquer l’entrée du site catalytique. Dans ces conditions, la taille de la molécule devient un facteur crucial dans l’inhibition de l’oxydation des lipoprotéines de basse densité et la N-acétylcystéine apparaît dès lors comme un inhibiteur puissant dont les résultats en font un excellent candidat dans des études d’intervention visant la diminution du risque de pathologies cardiovasculaires chez certains patients.</p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

Introduction: Dark spots appearing on the skin caused by hyperpigmentation results from the action of tyrosinase, an enzyme whose activity leads to the production of the skin pigment melanin. Extracts of the plant Glycyrrhiza glabra, also known as liquorice, are commonly used to treat a range of conditions including skin hyperpigmentation. This study aimed at isolating and identifying compounds in extracts from South African liquorice root and assaying these compounds as to their antioxidant activity, their ability to inhibit the tyrosinase enzyme and their level of cytotoxicity. Methods: The ability of plant extracts to scavenge free radicals was tested using the 2,2-diphenyl-1-picrylhydrazyl (DPPH), [2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonicacid)] (ABTS) and the ferric ion reducing power (FRAP) tests. The polyphenolic content of extract fractions was determined and extract compounds were identified using UHPLC-QToF-20 MS. In vitro anti-tyrosinase activity was also investigated as well as cytotoxicity in HepG2 liver and SK-MEL-1 melanoma cells using the MTT cell viability assay. Results: Of the four fractions prepared from the 70% methanolic extract of liquorice root, fraction 3 (F3) showed increased polyphenolic content and antioxidant properties with IC50 of 56.1 ± 6.32, 39.14 ± 1.1 and 66.34 ± 1.4 μg/ml against DPPH, ABTS and FRAP, respectively. The anti-tyrosinase activity of this fraction showed an IC50 of 358.54 μg/ml compared to Kojic acid (0.75 mM) used as the control. In addition, this fraction showed reduced liver toxicity as a higher percentage cell viability was noted in the HepG2 cells compared to the SK-MEL-1 skin melanoma cells. However, both cell types showed higher percentage viability compared to acetaminophen that was used as cytotoxic control. The LC-MS analysis revealed the presence of a wide variety of compounds including 4-azido-3-benzyl-coumarin, ferulic acid, glycyrrhizin, quercitrin, cirsilineol, gentioflavine and 4'',6,7-trihydroxyisoflavone. The literature indicates the use of these compounds regarding antioxidant and anti-tyrosinase activity. Significantly, cularidine was identified in this study, a compound not previously reported in studies involving liquorice root. Conclusion: The results from this study concur with previous reports as to the anti-tyrosinase and antioxidant activities associated with liquorice roots, activities perhaps due to the relatively high polyphenolic content in extracts from South African liquorice root. / Life and Consumer Sciences / M. Sc. (Life Sciences)

This review summarizes the principles of cancer chemoprevention and discusses the evidence from epidemiologic and experimental studies and preclinical and clinical trials of potential colorectal chemopreventive agents. The putative mechanisms of action of the drugs in chemoprevention and their potential to reduce the incidence and mortality rate of colorectal neoplasms are discussed. The future of colorectal chemoprevention will depend on important new insights into molecular carcinogenesis of colorectal cancer, application of molecular markers as surrogate endpoints, and ultimately on therapeutic targets of prevention in clinical trials.

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin is the protein product of NF1 and functions as a negative regulator of Ras activity in both hematopoietic and vascular wall cells, which are critical for maintaining blood vessel homeostasis. NF1 patients are predisposed to chronic inflammation and premature cardiovascular disease, including development of large arterial aneurysms, which may result in sudden death secondary to their rupture. However, the molecular pathogenesis of NF1 aneurysm formation is completely unknown. Utilizing a novel model of Nf1 murine aneurysm formation, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/-) results in enhanced aneurysm formation with myeloid cell infiltration and increased reactive oxygen species in the vessel wall. Using cell lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/- aneurysm phenotype in vivo. Additionally, oral administration of simvastatin, a statin with antioxidant and anti-inflammatory effects, significantly reduced aneurysm formation in Nf1+/- mice. Finally, the antioxidant apocynin was administered orally and also resulted in a significant reduction of Nf1+/- aneurysms. These data provide genetic and pharmacologic evidence that neurofibromin-deficient myeloid cells are the central cellular triggers for aneurysm formation in a novel model of NF1 vascular disease, implicated oxidative stress as the key biochemical mechanisms of NF1 aneurysm formation and provide a potential therapeutic target for NF1 vasculopathy.

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