Obesity is a major epidemic and an independent risk factor for heart disease. Food derived compounds such as resveratrol has been reported to have strong medicinal properties and shown potential in preventing and reversing heart diseases. This study investigated the cardioprotective properties of resveratrol in an animal model of diet induced obesity and possible cellular mechanisms. Obese prone (OP) and obese resistant (OR) rats were fed with high fat diet while, sprague dawley (SD) rats that served as control were fed with normal lab chow for a total of 17 weeks. During the last 5 weeks of study, treatment group received resveratrol daily by oral gavage at a dosage of 2.5 mg/kg body weight. Treatment with resveratrol significantly improved cardiac isovolumic relaxation time (IVRT), thiobarbituric acid reactive substance (TBARS), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), triglycerides, glucose, low density lipoprotein and increased insulin in OP rats and TNF-α, glucose and leptin in OR rats. Cardiac calcium handling proteins such as sarcoendoplasmic reticulum Ca2+-ATPase2a (SERCA2a), phospholamban (PLB) and phosphorylated PLBthr17 and PLBser16 were unchanged in all the groups. Excess circulating lipids cause cellular dysfunction in major organs. Adult rat cardiomyocytes were incubated for 24 hours with different doses (10, 100 and 200µM) of palmitic acid (PA). One group cardiomyocytes were pretreated with resveratrol for 45minutes prior to addition of PA. Incubation with 200µM PA significantly increased the number of round shaped cardiomyocytes and apoptosis and resveratrol treatment prevented these changes. Cardiomyocytes contractility measurement showed 200µM PA resulted in reduced rate of relaxation and resveratrol prevented this reduction. Western blot analysis showed that the PA induced a 17% decrease in SERCA2a expression and SERCA2A:PLB ratio was preserved with resveratrol treatment. The change in SERCA2a with PA and resveratrol exposure was statistically not significant. In conclusion, resveratrol treatment reversed cardiac abnormalities in OP rats, but not in OR rats. Resveratrol treatment prevented PA induced contractile abnormality in adult cardiomyocytes. Importantly, this study showed that resveratrol can act directly on cardiomyocytes and protect against damage from exposure to high levels of lipids. / February 2015

Background: Cardiac hypertrophy is a compensatory enlargement of the heart in response to stress such as hypertension. It is beneficial in reducing stress placed on the heart. However, when the stress is of a chronic nature, it becomes pathological and leads to cardiac dysfunction and heart failure. Current treatments for hypertension and heart failure have proven beneficial but are not highly specific and associated with side effects. Accordingly, there is an important need for alternative strategies to provide safe and effective treatment. Methods: Ten-week-old male spontaneously hypertensive rats (SHRs) and Wistar–Kyoto (WKY) rats were treated with resveratrol (2.5mg/kg/day) for a period of 10 weeks. Systolic blood pressure, and cardiac structure and function were measured in all groups at different time points of resveratrol treatment. Oxidative stress was also determined in all groups after 10 weeks of resveratrol treatment. Results: SHRs were characterized with high blood pressure and concentric hypertrophy from 15 weeks of age. Cardiac functional abnormalities were also evident in SHR from 15 weeks onwards. Resveratrol treatment significantly prevented the development of concentric hypertrophy, and systolic and diastolic dysfunction in SHR without lowering blood pressure. Resveratrol also significantly reduced the oxidative stress levels of cardiac tissue in SHR. Conclusions: Resveratrol treatment was beneficial in preventing the development of concentric hypertrophy and cardiac dysfunction in SHR. The cardioprotective effect of resveratrol in SHR may be partially mediated by a reduction in oxidative stress. Thus, resveratrol may have potential in preventing cardiac impairment in patients with essential hypertension.

Background: Cardiac hypertrophy is a compensatory enlargement of the heart in response to stress such as hypertension. It is beneficial in reducing stress placed on the heart. However, when the stress is of a chronic nature, it becomes pathological and leads to cardiac dysfunction and heart failure. Current treatments for hypertension and heart failure have proven beneficial but are not highly specific and associated with side effects. Accordingly, there is an important need for alternative strategies to provide safe and effective treatment. Methods: Ten-week-old male spontaneously hypertensive rats (SHRs) and Wistar–Kyoto (WKY) rats were treated with resveratrol (2.5mg/kg/day) for a period of 10 weeks. Systolic blood pressure, and cardiac structure and function were measured in all groups at different time points of resveratrol treatment. Oxidative stress was also determined in all groups after 10 weeks of resveratrol treatment. Results: SHRs were characterized with high blood pressure and concentric hypertrophy from 15 weeks of age. Cardiac functional abnormalities were also evident in SHR from 15 weeks onwards. Resveratrol treatment significantly prevented the development of concentric hypertrophy, and systolic and diastolic dysfunction in SHR without lowering blood pressure. Resveratrol also significantly reduced the oxidative stress levels of cardiac tissue in SHR. Conclusions: Resveratrol treatment was beneficial in preventing the development of concentric hypertrophy and cardiac dysfunction in SHR. The cardioprotective effect of resveratrol in SHR may be partially mediated by a reduction in oxidative stress. Thus, resveratrol may have potential in preventing cardiac impairment in patients with essential hypertension.

Neuroinflammation is a common pathology found in patients with Parkinson's disease (PD). PD involves a loss of dopamine (DA) neurons and an increase in activated microglia with subsequent proinflammatory cytokine secretion in the substantia nigra (SN) and striatum. A loss of DA neurons is found in the offspring of animals exposed prenatally to the bacteriotoxin, lipopolysaccharide (LPS) (Ling et al., 2002). Activation of the extracellular regulated kinases, ERK1/2 and ERK5, the downstream targets in the mitogen-activated protein kinase (MAPK) pathway, has been shown to be involved in the dysregulation of the inflammatory process (Cuschieri and Maier, 2005). Consequently, LPS-induced activation of ERK1/2 and ERK5 may cause an increase in production and secretion of proinflammatory cytokines in activated microglia. LPS-mediated activation of ERK1/2 has been shown to be decreased by the phytochemical resveratrol (Zhang et al., 2010). However, the effect of LPS or resveratrol on ERK5 signaling has not been explored. The purpose of this study was to determine (1) the effect of resveratrol on LPS-induced dopaminergic deficits in pups exposed prenatally to LPS, (2) the impact of resveratrol on LPS-induced BV-2 microglial cell activation and (3) the roles of ERK1/2 and ERK5 in resveratrol mediated inhibition of LPS-induced BV-2 cell activation. To test our hypothesis, pregnant rats received an intraperitoneal (i.p.) injection 10,000 EU/kg LPS at gestational day 10.5 (E10.5) and were fed a resveratrol-enriched diet for 20 days (E3 - E22.5). LPS-induced dopaminergic deficits in pups exposed prenatally at postnatal day 21 (P21), but not at P10 or P40. These deficits were exhibited by a loss of striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and DA content and tyrosine hydroxylase (TH) expression in the P21 animals. However, dietary resveratrol supplementation increased TH expression, DA and DOPAC levels in the P21 pups following prenatal exposure to LPS. Thus, these data suggest that resveratrol treatment may restore the homeostasis of the DA neuronal system in vivo. However, contrary to previous reports it was determined in vitro that LPS-mediated BV-2 activation and ERK1/2 phosphorylation was not inhibited by resveratrol pretreatment. Interestingly, at 6 hours the MEK inhibitor U0126 decreased LPS-mediated ERK1/2 activation and TNF-α release. ERK5 was not activated by LPS, but preliminary data suggest that the MEK5 inhibitor BIX02189 inhibited LPS-induced TNF-α release. Therefore, BIX02189 may be inhibiting a distinct pathway in our model. Overall, these studies suggest that the use of dietary resveratrol supplementation may be protective against LPS-induced loss of striatal dopaminergic deficits in a time-dependent manner and inhibition of ERK signaling may reduce LPS-mediated microglial activation. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Pharmacology / MS / Thesis

Glioblastomas (GBMs) são os tumores primários (gliomas) mais comuns e agressivos do Sistema Nervosos Central, classificados pelos oncologistas como um dos maiores desafios da oncoterapia. O prognóstico dos pacientes é ruim mesmo após terapia cirúrgica seguida de radio e quimioterapia com Temozolomida (TMZ). Células de GBM apresentam resistência intrínseca à apoptose, porém, se mostram mais sensíveis à indução de senescência, autofagia e catástrofe mitótica. Resveratrol (Rsv) é um polifenol com ação neuroprotetora ao tecido neural sadio e, por outro lado, ação citotóxica em células de GBM. Porém, o mecanismo de ação do Rsv nestas células ainda não está esclarecido. O objetivo do presente trabalho é avaliar o mecanismo de ação do Rsv, bem como o efeito do co-tratamento de Rsv e TMZ, em células de GBM. Rsv reduziu o número de células em 3 linhagens de GBM humano, induzindo autofagia e acúmulo de células nas fases S-G2/M do ciclo celular, com aumento de pCdc2(Y15), das ciclinas E, A e B e redução de ciclina D1. A inibição da autofagia induzida pelo Rsv aumentou a toxicidade do composto, ativou a apoptose (acompanhado do aumento de Bax e de clivagem de caspase 3) e inibiu a parada no ciclo celular induzida pelo Rsv, reduzindo os níveis das ciclinas e de pCdc2 (Y15). Estes dados sugerem um papel citoprotetor da autofagia no efeito do Rsv. Por outro lado, Rsv potencializou o efeito citotóxico da TMZ através da inibição da parada em G2/M induzido pela TMZ, sem reduzir o dano ao DNA induzido pela TMZ ou a ativação da proteína de reconhecimento de dano ATM. Núcleos das células expostas ao co-tratamento apresentaram características típicas de catástrofe mitótica, acompanhado pelo acúmulo de ciclina B e redução de pCdc2(Y15). Através de uma ferramenta de análise morfométrica nuclear desenvolvida por nós, mostramos que o cotratamento de Rsv e TMZ induziu um aumento no número de núcleos em catástrofe mitótica. Em conclusão, Rsv apresentou potencial aplicação em GBM a ser testada em modelos in vivo deste tumor, tanto como terapia primária (especialmente se combinado a inibidores de autofagia) ou como adjuvante à TMZ. Uma vez que as células cancerosas são resistentes à morte celular e sabendo que um único composto geralmente modula mais de um mecanismo celular, é importante considerar estas interações para o desenvolvimento de alternativas para sensibilizar as células cancerosas e aumentar a eficácia terapêutica. / Glioblastomas (GBM) are the most common and aggressive primary tumors (gliomas) of the Central Nervous System, classified by oncologists as one of the biggest challenges of oncotherapy. The prognosis for patients is poor, even after surgical therapy followed by radiotherapy and chemotherapy with Temozolomide (TMZ). GBM cells are intrinsically resistance to apoptosis, but more sensitive to the induction of senescence, autophagy and mitotic catastrophe. Resveratrol (Rsv) is a polyphenol with a neuroprotective effect on healthy neural tissue but it has a a cytotoxic activity in GBM cells. Unfortunately, the mechanism of action of Rsv in these cells is still unclear. The aim of this study is to assess the mechanism of action of Rsv, as well as the effect of co-treatment of Rsv and TMZ in GBM cells. Rsv reduced the number of cells in three cell lines of human GBM, inducing autophagy and accumulation of cells in S-G2/M phase of cell cycle, increasing pCdc2 (Y15), pRb (S807/811), cyclins E, A and B, and reducing cyclin D1. Inhibition of Rsvinduced autophagy slightly increased the toxicity of the Rsv , accompained by triggering apoptosis (accompanied by an increase of Bax and cleavage of caspase 3) and inhibition of cell cycle arrest induced by Rsv, reducing the levels of cyclins and pCdc2 (Y15) in relation to Rsv alone, suggesting a cytoprotective role of autophagy in the effect of Rsv. Moreover, Rsv enhanced the cytotoxic effect of TMZ by abrogate the arrest in G2/M induced by TMZ, without reducing the DNA damage induced by TMZ or the activation of protein damage recognition ATM. Nuclei of cells exposed to co-treatment showed typical features of mitotic catastrophe, accompanied by the accumulation of cyclin B and reduced pCdc2 (Y15). Through a tool developed by us, we demonstrate that in fact the cotreatment induced an increase of nuclei with irregularities typical of mitotic catastrophe. In conclusion, Rsv has potential application in GBM, both as primary therapy (especially if combined with inhibitors of autophagy) or as adjuvant to TMZ. Since cancer cells are resistant to cell death and understanding that a single compound usually modulates more than one cellular mechanism, it is important to consider these interactions to the development of alternatives to sensitize cancer cells and increase therapeutic efficacy.

Glioblastomas (GBMs) são os tumores primários (gliomas) mais comuns e agressivos do Sistema Nervosos Central, classificados pelos oncologistas como um dos maiores desafios da oncoterapia. O prognóstico dos pacientes é ruim mesmo após terapia cirúrgica seguida de radio e quimioterapia com Temozolomida (TMZ). Células de GBM apresentam resistência intrínseca à apoptose, porém, se mostram mais sensíveis à indução de senescência, autofagia e catástrofe mitótica. Resveratrol (Rsv) é um polifenol com ação neuroprotetora ao tecido neural sadio e, por outro lado, ação citotóxica em células de GBM. Porém, o mecanismo de ação do Rsv nestas células ainda não está esclarecido. O objetivo do presente trabalho é avaliar o mecanismo de ação do Rsv, bem como o efeito do co-tratamento de Rsv e TMZ, em células de GBM. Rsv reduziu o número de células em 3 linhagens de GBM humano, induzindo autofagia e acúmulo de células nas fases S-G2/M do ciclo celular, com aumento de pCdc2(Y15), das ciclinas E, A e B e redução de ciclina D1. A inibição da autofagia induzida pelo Rsv aumentou a toxicidade do composto, ativou a apoptose (acompanhado do aumento de Bax e de clivagem de caspase 3) e inibiu a parada no ciclo celular induzida pelo Rsv, reduzindo os níveis das ciclinas e de pCdc2 (Y15). Estes dados sugerem um papel citoprotetor da autofagia no efeito do Rsv. Por outro lado, Rsv potencializou o efeito citotóxico da TMZ através da inibição da parada em G2/M induzido pela TMZ, sem reduzir o dano ao DNA induzido pela TMZ ou a ativação da proteína de reconhecimento de dano ATM. Núcleos das células expostas ao co-tratamento apresentaram características típicas de catástrofe mitótica, acompanhado pelo acúmulo de ciclina B e redução de pCdc2(Y15). Através de uma ferramenta de análise morfométrica nuclear desenvolvida por nós, mostramos que o cotratamento de Rsv e TMZ induziu um aumento no número de núcleos em catástrofe mitótica. Em conclusão, Rsv apresentou potencial aplicação em GBM a ser testada em modelos in vivo deste tumor, tanto como terapia primária (especialmente se combinado a inibidores de autofagia) ou como adjuvante à TMZ. Uma vez que as células cancerosas são resistentes à morte celular e sabendo que um único composto geralmente modula mais de um mecanismo celular, é importante considerar estas interações para o desenvolvimento de alternativas para sensibilizar as células cancerosas e aumentar a eficácia terapêutica. / Glioblastomas (GBM) are the most common and aggressive primary tumors (gliomas) of the Central Nervous System, classified by oncologists as one of the biggest challenges of oncotherapy. The prognosis for patients is poor, even after surgical therapy followed by radiotherapy and chemotherapy with Temozolomide (TMZ). GBM cells are intrinsically resistance to apoptosis, but more sensitive to the induction of senescence, autophagy and mitotic catastrophe. Resveratrol (Rsv) is a polyphenol with a neuroprotective effect on healthy neural tissue but it has a a cytotoxic activity in GBM cells. Unfortunately, the mechanism of action of Rsv in these cells is still unclear. The aim of this study is to assess the mechanism of action of Rsv, as well as the effect of co-treatment of Rsv and TMZ in GBM cells. Rsv reduced the number of cells in three cell lines of human GBM, inducing autophagy and accumulation of cells in S-G2/M phase of cell cycle, increasing pCdc2 (Y15), pRb (S807/811), cyclins E, A and B, and reducing cyclin D1. Inhibition of Rsvinduced autophagy slightly increased the toxicity of the Rsv , accompained by triggering apoptosis (accompanied by an increase of Bax and cleavage of caspase 3) and inhibition of cell cycle arrest induced by Rsv, reducing the levels of cyclins and pCdc2 (Y15) in relation to Rsv alone, suggesting a cytoprotective role of autophagy in the effect of Rsv. Moreover, Rsv enhanced the cytotoxic effect of TMZ by abrogate the arrest in G2/M induced by TMZ, without reducing the DNA damage induced by TMZ or the activation of protein damage recognition ATM. Nuclei of cells exposed to co-treatment showed typical features of mitotic catastrophe, accompanied by the accumulation of cyclin B and reduced pCdc2 (Y15). Through a tool developed by us, we demonstrate that in fact the cotreatment induced an increase of nuclei with irregularities typical of mitotic catastrophe. In conclusion, Rsv has potential application in GBM, both as primary therapy (especially if combined with inhibitors of autophagy) or as adjuvant to TMZ. Since cancer cells are resistant to cell death and understanding that a single compound usually modulates more than one cellular mechanism, it is important to consider these interactions to the development of alternatives to sensitize cancer cells and increase therapeutic efficacy.

Glioblastomas (GBMs) são os tumores primários (gliomas) mais comuns e agressivos do Sistema Nervosos Central, classificados pelos oncologistas como um dos maiores desafios da oncoterapia. O prognóstico dos pacientes é ruim mesmo após terapia cirúrgica seguida de radio e quimioterapia com Temozolomida (TMZ). Células de GBM apresentam resistência intrínseca à apoptose, porém, se mostram mais sensíveis à indução de senescência, autofagia e catástrofe mitótica. Resveratrol (Rsv) é um polifenol com ação neuroprotetora ao tecido neural sadio e, por outro lado, ação citotóxica em células de GBM. Porém, o mecanismo de ação do Rsv nestas células ainda não está esclarecido. O objetivo do presente trabalho é avaliar o mecanismo de ação do Rsv, bem como o efeito do co-tratamento de Rsv e TMZ, em células de GBM. Rsv reduziu o número de células em 3 linhagens de GBM humano, induzindo autofagia e acúmulo de células nas fases S-G2/M do ciclo celular, com aumento de pCdc2(Y15), das ciclinas E, A e B e redução de ciclina D1. A inibição da autofagia induzida pelo Rsv aumentou a toxicidade do composto, ativou a apoptose (acompanhado do aumento de Bax e de clivagem de caspase 3) e inibiu a parada no ciclo celular induzida pelo Rsv, reduzindo os níveis das ciclinas e de pCdc2 (Y15). Estes dados sugerem um papel citoprotetor da autofagia no efeito do Rsv. Por outro lado, Rsv potencializou o efeito citotóxico da TMZ através da inibição da parada em G2/M induzido pela TMZ, sem reduzir o dano ao DNA induzido pela TMZ ou a ativação da proteína de reconhecimento de dano ATM. Núcleos das células expostas ao co-tratamento apresentaram características típicas de catástrofe mitótica, acompanhado pelo acúmulo de ciclina B e redução de pCdc2(Y15). Através de uma ferramenta de análise morfométrica nuclear desenvolvida por nós, mostramos que o cotratamento de Rsv e TMZ induziu um aumento no número de núcleos em catástrofe mitótica. Em conclusão, Rsv apresentou potencial aplicação em GBM a ser testada em modelos in vivo deste tumor, tanto como terapia primária (especialmente se combinado a inibidores de autofagia) ou como adjuvante à TMZ. Uma vez que as células cancerosas são resistentes à morte celular e sabendo que um único composto geralmente modula mais de um mecanismo celular, é importante considerar estas interações para o desenvolvimento de alternativas para sensibilizar as células cancerosas e aumentar a eficácia terapêutica. / Glioblastomas (GBM) are the most common and aggressive primary tumors (gliomas) of the Central Nervous System, classified by oncologists as one of the biggest challenges of oncotherapy. The prognosis for patients is poor, even after surgical therapy followed by radiotherapy and chemotherapy with Temozolomide (TMZ). GBM cells are intrinsically resistance to apoptosis, but more sensitive to the induction of senescence, autophagy and mitotic catastrophe. Resveratrol (Rsv) is a polyphenol with a neuroprotective effect on healthy neural tissue but it has a a cytotoxic activity in GBM cells. Unfortunately, the mechanism of action of Rsv in these cells is still unclear. The aim of this study is to assess the mechanism of action of Rsv, as well as the effect of co-treatment of Rsv and TMZ in GBM cells. Rsv reduced the number of cells in three cell lines of human GBM, inducing autophagy and accumulation of cells in S-G2/M phase of cell cycle, increasing pCdc2 (Y15), pRb (S807/811), cyclins E, A and B, and reducing cyclin D1. Inhibition of Rsvinduced autophagy slightly increased the toxicity of the Rsv , accompained by triggering apoptosis (accompanied by an increase of Bax and cleavage of caspase 3) and inhibition of cell cycle arrest induced by Rsv, reducing the levels of cyclins and pCdc2 (Y15) in relation to Rsv alone, suggesting a cytoprotective role of autophagy in the effect of Rsv. Moreover, Rsv enhanced the cytotoxic effect of TMZ by abrogate the arrest in G2/M induced by TMZ, without reducing the DNA damage induced by TMZ or the activation of protein damage recognition ATM. Nuclei of cells exposed to co-treatment showed typical features of mitotic catastrophe, accompanied by the accumulation of cyclin B and reduced pCdc2 (Y15). Through a tool developed by us, we demonstrate that in fact the cotreatment induced an increase of nuclei with irregularities typical of mitotic catastrophe. In conclusion, Rsv has potential application in GBM, both as primary therapy (especially if combined with inhibitors of autophagy) or as adjuvant to TMZ. Since cancer cells are resistant to cell death and understanding that a single compound usually modulates more than one cellular mechanism, it is important to consider these interactions to the development of alternatives to sensitize cancer cells and increase therapeutic efficacy.

Resveratrol (3, 4, 5-trihidroxiestilbeno) é um polifenol produzido por uma grande variedade de plantas em resposta ao estresse e encontrado predominantemente em cascas de uvas. Este princípio ativo apresenta vários benefícios à saúde, como a capacidade antioxidante, relacionada à prevenção de diversos tipos de câncer e do envelhecimento precoce da pele. No entanto, apresenta baixa biodisponibilidade quando administrado por via oral, o que torna interessante sua aplicação tópica. O principal objetivo deste trabalho foi a incorporação de resveratrol em hidrogéis poliméricos para obtenção de um sistema de liberação utilizado topicamente contra o desenvolvimento de desordens cutâneas, como o envelhecimento cutâneo e o câncer de pele. As matrizes poliméricas compostas por poli(N-vinil-2-pirrolidona) (PVP), poli(etileno glicol) (PEG) e ágar ou PVP e propano-1,2,3-triol (glicerina) e irradiadas a 20 kGy foram caracterizadas pelos ensaios de fração gel e intumescimento; sua biocompatibilidade preliminar foi avaliada in vitro por meio do ensaio de citotoxicidade utilizando o método de incorporação do vermelho neutro. Devido à baixa solubilidade do resveratrol em água, verificou-se o efeito da adição de 2% de etanol às matrizes. Todas as matrizes estudadas, contendo ou não álcool, apresentaram alto grau de reticulação, capacidade de intumescimento e não apresentaram toxicidade em ensaio preliminar de biocompatibilidade. Os dispositivos foram obtidos pela incorporação de resveratrol nas matrizes poliméricas, realizada de forma direta e indireta, ou seja, antes e após irradiação, respectivamente. Os dispositivos obtidos pelo método direto foram submetidos aos ensaios de fração gel, intumescimento e citotoxicidade e apresentaram-se semelhantes às respectivas matrizes. Os dispositivos contendo 0,05% de resveratrol obtidos pelo método direto e os dispositivos contendo 0,1% de resveratrol obtidos pelo método indireto foram submetidos ao ensaio de cinética de liberação durante 24 h. A quantificação do resveratrol liberado foi realizada por cromatografia líquida de alta eficiência (HPLC). Apenas os dispositivos obtidos pelo método indireto apresentaram capacidade de liberar o resveratrol incorporado, que apresentou capacidade antioxidante após liberação. / Resveratrol (3, 4, 5-trihydroxystilbene) is a polyphenolic produced by a wide variety of plants in response to injury and found predominantly in grape skins. This active ingredient has been shown to possess benefits for the health, such as the antioxidant capacity which is related to the prevention of several types of cancer and skin aging. However, the oral bioavailability of resveratrol is poor and makes its topical application interesting. The purpose of this study was to immobilize resveratrol in polymeric hydrogels to obtain a release device for topical use. The polymeric matrices composed of poli(N-vinyl-2-pyrrolidone) (PVP), poly(ethyleneglycol) (PEG) and agar or PVP and glycerol irradiated at 20 kGy dose were physical-chemically characterized by gel fraction and swelling tests and its preliminary biocompatibility by in vitro test of cytotoxicity using the technique of neutral red uptake. Due to low solubility of resveratrol in water, the addition of 2% ethanol to the matrices was verified. All matrices showed a high crosslinking degree, capacity of swelling and the preliminary cytotoxicity test showed nontoxicity effect. The devices were obtained by resveratrol immobilizaton in polymeric matrices, carried out in a one-or-two-steps process, that is, before or after irradiation, respectively. The one step resveratrol devices were characterized by gel fraction, swelling tests and preliminary biocompatibility, and their properties were maintained even after the resveratrol incorporation. The devices containing 0,05% of resveratrol obtained by one-step process and 0,1% of resveratrol obtained by two-steps process were submitted to the release test during 24 h. Resveratrol quantification was done by high performance liquid chromatography (HPLC). The results obtained in the kinetics of release showed that only the devices obtained by two-step process release the resveratrol, which demonstrate antioxidant capacity after the release.

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.

Resveratrol (3, 4, 5-trihidroxiestilbeno) é um polifenol produzido por uma grande variedade de plantas em resposta ao estresse e encontrado predominantemente em cascas de uvas. Este princípio ativo apresenta vários benefícios à saúde, como a capacidade antioxidante, relacionada à prevenção de diversos tipos de câncer e do envelhecimento precoce da pele. No entanto, apresenta baixa biodisponibilidade quando administrado por via oral, o que torna interessante sua aplicação tópica. O principal objetivo deste trabalho foi a incorporação de resveratrol em hidrogéis poliméricos para obtenção de um sistema de liberação utilizado topicamente contra o desenvolvimento de desordens cutâneas, como o envelhecimento cutâneo e o câncer de pele. As matrizes poliméricas compostas por poli(N-vinil-2-pirrolidona) (PVP), poli(etileno glicol) (PEG) e ágar ou PVP e propano-1,2,3-triol (glicerina) e irradiadas a 20 kGy foram caracterizadas pelos ensaios de fração gel e intumescimento; sua biocompatibilidade preliminar foi avaliada in vitro por meio do ensaio de citotoxicidade utilizando o método de incorporação do vermelho neutro. Devido à baixa solubilidade do resveratrol em água, verificou-se o efeito da adição de 2% de etanol às matrizes. Todas as matrizes estudadas, contendo ou não álcool, apresentaram alto grau de reticulação, capacidade de intumescimento e não apresentaram toxicidade em ensaio preliminar de biocompatibilidade. Os dispositivos foram obtidos pela incorporação de resveratrol nas matrizes poliméricas, realizada de forma direta e indireta, ou seja, antes e após irradiação, respectivamente. Os dispositivos obtidos pelo método direto foram submetidos aos ensaios de fração gel, intumescimento e citotoxicidade e apresentaram-se semelhantes às respectivas matrizes. Os dispositivos contendo 0,05% de resveratrol obtidos pelo método direto e os dispositivos contendo 0,1% de resveratrol obtidos pelo método indireto foram submetidos ao ensaio de cinética de liberação durante 24 h. A quantificação do resveratrol liberado foi realizada por cromatografia líquida de alta eficiência (HPLC). Apenas os dispositivos obtidos pelo método indireto apresentaram capacidade de liberar o resveratrol incorporado, que apresentou capacidade antioxidante após liberação. / Resveratrol (3, 4, 5-trihydroxystilbene) is a polyphenolic produced by a wide variety of plants in response to injury and found predominantly in grape skins. This active ingredient has been shown to possess benefits for the health, such as the antioxidant capacity which is related to the prevention of several types of cancer and skin aging. However, the oral bioavailability of resveratrol is poor and makes its topical application interesting. The purpose of this study was to immobilize resveratrol in polymeric hydrogels to obtain a release device for topical use. The polymeric matrices composed of poli(N-vinyl-2-pyrrolidone) (PVP), poly(ethyleneglycol) (PEG) and agar or PVP and glycerol irradiated at 20 kGy dose were physical-chemically characterized by gel fraction and swelling tests and its preliminary biocompatibility by in vitro test of cytotoxicity using the technique of neutral red uptake. Due to low solubility of resveratrol in water, the addition of 2% ethanol to the matrices was verified. All matrices showed a high crosslinking degree, capacity of swelling and the preliminary cytotoxicity test showed nontoxicity effect. The devices were obtained by resveratrol immobilizaton in polymeric matrices, carried out in a one-or-two-steps process, that is, before or after irradiation, respectively. The one step resveratrol devices were characterized by gel fraction, swelling tests and preliminary biocompatibility, and their properties were maintained even after the resveratrol incorporation. The devices containing 0,05% of resveratrol obtained by one-step process and 0,1% of resveratrol obtained by two-steps process were submitted to the release test during 24 h. Resveratrol quantification was done by high performance liquid chromatography (HPLC). The results obtained in the kinetics of release showed that only the devices obtained by two-step process release the resveratrol, which demonstrate antioxidant capacity after the release.