O resveratrol (Res), um polifenol presente no vinho tinto, é conhecido por possuir potente atividade antioxidante. O efeito do resveratrol (Res) frente à nefrotoxicidade do antineoplásico cisplatina (cDDP) foi avaliado em ratos neste estudo. Os animais foram tratados com Res (25 mg/Kg de peso copóreo, ip., dose única) 30 minutos antes da administração de cisplatina (5 mg/Kg de peso copóreo, ip., dose única) e foram sacrificados depois de 2 ou 5 dias do tratamento. Após 5 dias, o aumento da creatinina sérica, volume urinário e proteinúria, que são marcadores de alterações renais, apresentaram significativa redução (p < 0,05) com a administração de resveratrol. Os ratos tratados com cisplatina apresentaram necrose tubular aguda e maior marcação imuno-histoquímica para células ED1 e linfócitos T no córtex e medula externa renal. Estas alterações foram menos intensas nos animais tratados com resveratrol. Após 2 dias, a administração de cisplatina aos ratos induziu aumento na concentração de malonaldeído (MDA) e reduziu nos níveis de glutationa (GSH) no tecido renal, que não foram amenizadas pelo resveratrol. Os resultados desse estudo indicam que o tratamento com resveratrol atenuou as alterações renais funcionais, histológicas e imuno-histoquímicas induzidas pela cisplatina. O efeito protetor provavelmente está relacionado à diminuição de infiltrado de células inflamatórias no tecido renal / Resveratrol (Res), a polyphenolic present in red wine, is known to possess potent antioxidant properties. The ability of resveratrol to protect against the nephrotoxicity of the antineoplastic agent cisplatin (cDDP) was evaluated in rats. The animals were treated with Res (25 mg/Kg body weight, ip., single dose) 30 minutes before administration of cDDP (5 mg/Kg body weight, ip., single dose) and then, sacrificed in 2 or 5 days followed by the treatment. After 5 days with resveratrol administration, the enhanced serum creatinine levels, urinary volume and urinary protein, which are indicative of renal injury, shown a significant reduction (p < 0.05). The cisplatintreated rats presented a tubular cell necrosis and increase immunostaining for ED1 and T-lymphocytes in the renal cortex and outer medulla. Those alterations were less intense in animals treated with resveratrol. After 2 days, administration of cisplatin to rats induced a higher malondialdehyde levels (MDA), and reduction in glutathione (GSH) concentrations in kidney tissue that were not prevented by resveratrol. In this study, the results indicate that resveratrol treatment attenuated the functional, histological and immunohistochemical renal alterations induced by cisplatin. The protect effect is relatated to the decrease of cells infiltrated at kidney tissue.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jakub Jeřábek Supervisors: Prof. PharmDr. Martin Doležal, Ph.D. Prof. Maria Laura Bolognesi Title of Thesis: Design and Synthesis of Hybrid Compounds Based on Tacrine/Resveratrol Derivatives Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder, in which a progressive dementia appears. The cause of AD is currently unknown, however, scientific research has revealed several pathological hallmarks - β-amyloid plaques and neurofibrillary tangles. These changes cause gradual disintegration of nerve cells and they change the metabolism in the brain. The current drugs are not able to treat the cause of the disease, being able only to delay the onset of severe symptoms. The basic drugs for AD treatment are acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitors and, more recently approved, N-methyl- D-aspartate (NMDA) receptor antagonist memantine. These drugs are able to increase cholinergic activity or preventing glutamate excitotoxicity in the patient's brain, thus improving cognitive functions and delaying severe stages of the disease. One of the emerging approaches in drug synthesis represents multi-target-directed ligands (MTDLs). Apart from the ability...

Research interest in resveratrol, a structurally simple plant metabolite, has increased exponentially in the last two decades. Since its isolation from red wine it has been hypothesized that this structure may account for the so-called "French Paradox," the notion that despite a diet high in cholesterol one can enjoy a relatively healthy lifestyle through moderate red wine consumption. The biological implications of these claims are presented. Concurrently isolated along with resveratrol are hundreds of oligomeric natural products with structures varying in both size and complexity. The discovery, biosynthesis, and previous synthetic studies towards these natural products will be presented to frame the landscape of the field and its current limitations. Heimiol A and hopeahainol D are oxidized, resveratrol dimers characterized by their [3.2.2] bicyclic framework with a bridging ether. The total synthesis of these epimeric natural products was accomplished by the development of a halolactonization/Friedel-Crafts cascade to construct the bicyclic core. Subsequently, a steric bias inherent in the molecule was doubly exploited to synthesize both targets with complete selectivity. During the course of these studies, a number of unexpected results were observed which have led, or may potentially lead, to alternate courses of investigation. These results and their potential impact are also presented. Well-established in the synthetic community are the challenges associated with medium-sized ring construction. Of particularly rarity are solutions addressing all carbon 9-membered rings. Seeing this motif present in a subclass of resveratrol oligomers, we sought to investigate this challenging substructure. Our efforts to achieve this end are detailed with the successful development of two unique methods to construct the requisite 9-membered ring core. One succeeded in the first ever reported 9-exo-dig cyclization while the other enabled the robust total synthesis of caraphenol A. [1.1.1]-orthocyclophanes have received considerable attention of late due to their numerous applications in the field of supramolecular chemistry. Owing to their rigid, bowl shape, these scaffolds are capable of engaging in numerous guest-host complexes. The previous syntheses of [1.1.1]-orthocyclophanes as well as a survey of their applications are presented. In the course of our synthetic studies toward caraphenol A, we accomplished the synthesis of a unique [1.1.1]-orthocyclophane as well as the successful oxidation to its corresponding triketone. These results are presented noting that despite many efforts, no other [1.1.1]-orthocyclophane triketone has ever been successfully synthesized with our work constituting the first such report.

Glioblastomas são os tumores mais agressivos do Sistema Nervoso Central (SNC). Caracterizam-se por sua alta invasibilidade, proliferação, altos índices de recorrência e morte, assim como quimio e radiorresistência. Tumores sólidos apresentam uma organização hierárquica, em que há uma pequena população de células tronco tumorais (CSCs) ou células iniciadoras de tumor (CICs). Essas células são capazes de repopular o tumor, que leva à recorrência. CSCs caracterizam-se por realizar também a mitose assimétrica, na qual parte das células continuam como CSCs e a outra parte sofre diferenciação. Essas células diferenciadas são incapazes de repopular o tumor, uma vez que perderam a sua capacidade tronco. CSCs mostraram ser relativamente resistentes as terapias anticâncer tradicionais como quimio e/ou radioterapia. Doxorrubicina (Doxo) é um agente anticâncer usado em diversos tipos de tumor e atua formando adutos no DNA e também inibindo a ação da topoisomerase II. Dependendo da concentração utilizada de Doxo, diferentes efeitos são observados; por exemplo, baixas doses (100 nM) levam à senescência celular, enquanto que altas doses (10 μM) levam à apoptose. Temozolomida (Tmz) é um anti-tumoral utilizado na terapia de diversos tumores, inclusive gliomas. Resveratrol (Rsv) é um polifenol encontrado em diversas plantas, como a uva, e possui efeitos como: neuroproteção, antiinflamatório, anti-oxidante, proteção cardíaca, entre outros. Nosso objetivo foi avaliar a influência do efeito dessas três drogas nas CSCs derivadas de glioblastoma humano. Realizou-se o ensaio de formação de esferas, um indicador da presença de CSCs, citometria de fluxo para Oct4 e Nanog e ensaio de senescência. Nossos ensaios utilizaram a linhagem U87 e dois tipos diferentes de meio de cultura. O primeiro continha DMEM Low Glucose com SFB e o segundo, um meio de cultura para células tronco (SCM), contendo DMEM F12 suplementado com FGF (fator de crescimento fibroblástico), EGF (fator de crescimento epidermal), LIF (fator inibidor de leucemia) e B27. Os tratamentos realizados utilizaram Doxo 1 e 10 nM; Tmz 5 μM e Rsv 1, 10 e 30 μM. O número de esferas formadas foi reduzido tanto em Doxo 1 quanto em 10 nM quando SFB foi utilizado. Doxo 1 não alterou o número de células Oct4 e Nanog positivas enquanto que Doxo 10 nM reduziu. Ambas as doses induziram senescência. Tmz reduziu o número de esferas formadas e também a porcentagem de células Oct4 e Nanog positivas. Usando SCM, observamos que Doxo e Tmz reduziram o número de esferas e a porcentagem de células Nanog e Oct4 positivas. Rsv 10 μM reduziu o número de esferas formadas enquanto que Rsv 30 μM reduziu o número de células positivas para CD133 e Oct4 com meio com SFB. Nossos resultados sugerem que Doxo 10 nM possui um melhor efeito nas CSCs do que Doxo 1 nM. Doxo 10 nM, além de reduzir o número de esferas, reduziu a porcentagem dos marcadores de CSCs e também induziu senescência celular na presença de SFB. Tmz e Rsv apresentaram resultados semelhantes à Doxo 10 nM. / Glioblastomas are the most aggressive tumors of the central nervous system (CNS). They are characterized by their high invasiveness, proliferation, high rates of recurrence and death, as well as chemo and radioresistance. Solid tumors have a hierarchical organization, in which there is a small tumor stem cell population (CSCs) or tumor initiator cells (CICs). These cells are able to repopulate the tumor, which leads to recurrence. CSCs are characterized by also performing asymmetric mitosis, in which the cells remain as CSCs and the other part undergoes differentiation. These differentiated cells are unable to repopulate the tumor, since they have lost their stem cell capacity. CSCs showed to be relatively resistant to traditional anti-cancer therapies such as chemo and / or radiotherapy. Doxorubicin (Doxo) is an anticancer agent used in several tumor types and acts by forming DNA adducts as well as inhibiting the action of topoisomerase II. Depending on the concentration of Doxo used, different effects was observed, for example, low doses (100 nM) lead to cellular senescence, whereas high doses (10 μM) lead to apoptosis. Temozolomide (Tmz) is an anti-tumor therapy used in many tumors, including gliomas. Resveratrol (Rsv) is a polyphenol found in various plants, such as grapes, and has effects such as neuroprotective, antiinflammatory, anti-oxidant, cardiac protection, among others. Our objective was to evaluate the effects of these three drugs on CSCs derived from human glioblastoma. We performed the sphere formation assay, an indicator of the presence of CSCs, flow cytometry for Oct4 and Nanog and senescence assay. Our experiments used the cell line U87 and two different types of culture medium. The first contained DMEM Low Glucose with FBS and the second, a culture medium for stem cells (SCM), containing DMEM F12 supplemented with FGF (fibroblastic growth factor), EGF (epidermal growth factor), LIF (leukemia inhibitor factor) and B27. The tests were performed using Doxo 1 and 10 nM, Tmz 5 μM and Rsv 10 and 30 μM. The number of spheres formed was reduced in both doses of Doxo when FBS was used. Doxo 1 nM did not alter the number of Oct4 and Nanog positive cells while Doxo 10 nM reduced. Both doses induced senescence. Tmz reduced the number of spheres formed and also the percentage of Nanog and Oct4 positive cells. Using SCM, we saw that Doxo and Tmz reduced the number of spheres and the percentage of Nanog and Oct4 positive cells. Rsv 10 μM reduced the number of spheres formed while Rsv 30 μM reduced the number of CD133 and Oct4 positive cells with medium supplemented with FBS. Our results suggest that Doxo 10 nM has a better effect in the CSCs than Doxo 1 nM. Doxo 10 nM besides reducing the number of spheres also decreased the percentage of CSCs markers, and induced cellular senescence in the presence of FBS. Tmz and Rsv had similar effects as Doxo 10 nM.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 169-186). Also available in print.

Hypertension is accompanied by structural and mechanical abnormalities in resistance arteries. The effects of resveratrol, a phenolic phytoalexin found naturally in various foods, on systolic blood pressure and resistance artery structure and stiffness were assessed in spontaneously hypertensive rats (SHRs). Vascular geometry and mechanical properties of pressurized mesenteric resistance arteries were calculated from media and lumen dimensions measured using pressure myography. Compared to normotensive Wistar-Kyoto (WKY) rats, resistance arteries from SHRs displayed remodeling with narrowed lumen diameters (246.2±21.0 vs. 308.1±14.3 μm, p<0.05), thickened media widths (39.8±4.6 vs. 28.5±2.7 μm, p<0.05) and augmented media-to-lumen ratios (17.7±2.6 vs. 9.3±1.0, p<0.05). Calculations of remodeling and growth indices revealed that SHR vessels underwent mostly eutrophic remodeling. Systolic blood pressure was elevated in 20-week-old SHR versus WKY rats (219±6 vs. 155±6 mmHg, p<0.01) and was unaffected by resveratrol (2.5 mg/Kg/d). In SHRs, resveratrol treatment attenuated eutrophic remodeling and normalized increased vessel compliance (p<0.01) as determined by a restorative leftward shift in the stress-strain curve of SHR arteries (p<0.01). Resveratrol treatment restored stiffness in SHRs (4.2±0.4 vs. 6.6±0.5, p<0.05) through the normalization of vessel geometry. Immunoblotting revealed that resveratrol negated typical pronounced ERK1/2 signaling in SHR arteries. Thus, the results of this study suggest that resveratrol restores vascular mechanical properties in SHRs and attenuates remodeling. Furthermore the attenuation of remodeling in SHR arteries with resveratrol treatment is associated with the inhibition of ERK1/2 activity.

Hypertension is accompanied by structural and mechanical abnormalities in resistance arteries. The effects of resveratrol, a phenolic phytoalexin found naturally in various foods, on systolic blood pressure and resistance artery structure and stiffness were assessed in spontaneously hypertensive rats (SHRs). Vascular geometry and mechanical properties of pressurized mesenteric resistance arteries were calculated from media and lumen dimensions measured using pressure myography. Compared to normotensive Wistar-Kyoto (WKY) rats, resistance arteries from SHRs displayed remodeling with narrowed lumen diameters (246.2±21.0 vs. 308.1±14.3 μm, p<0.05), thickened media widths (39.8±4.6 vs. 28.5±2.7 μm, p<0.05) and augmented media-to-lumen ratios (17.7±2.6 vs. 9.3±1.0, p<0.05). Calculations of remodeling and growth indices revealed that SHR vessels underwent mostly eutrophic remodeling. Systolic blood pressure was elevated in 20-week-old SHR versus WKY rats (219±6 vs. 155±6 mmHg, p<0.01) and was unaffected by resveratrol (2.5 mg/Kg/d). In SHRs, resveratrol treatment attenuated eutrophic remodeling and normalized increased vessel compliance (p<0.01) as determined by a restorative leftward shift in the stress-strain curve of SHR arteries (p<0.01). Resveratrol treatment restored stiffness in SHRs (4.2±0.4 vs. 6.6±0.5, p<0.05) through the normalization of vessel geometry. Immunoblotting revealed that resveratrol negated typical pronounced ERK1/2 signaling in SHR arteries. Thus, the results of this study suggest that resveratrol restores vascular mechanical properties in SHRs and attenuates remodeling. Furthermore the attenuation of remodeling in SHR arteries with resveratrol treatment is associated with the inhibition of ERK1/2 activity.

Thesis--Auburn University, 2007. / Abstract. Vita. Includes bibliographic references (p.61-68).

Thesis (M.S.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains xi, 56 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 51-56).

The theoretical part is focused on the preparation of the trans-resveratrol dimers, their occurrence in the plants and their isolation possibility with emphasis to trans-epsilon-viniferin. In the experimental part of master thesis the selected reagents, namely 2-hydroxy-1,4-naphthoquinone, tetrachloro-1,4-benzoquinone, laccase and ferric chloride, were studied with the aim of the trans-resveratrol dimer preparation. Furthermore, the Fenton reaction and its modification was also studied. Last part of this thesis is devoted to the trans-epsilon-viniferin isolation from grape cane by chromatographic methods.