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1.
Food Chem ; 340: 127894, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32906059

RESUMO

A novel delivery system using micron-scale grape skin powder (GSP) was developed that enhanced loading, stability and bioaccessibility of trans-resveratrol (trans-Res). Vacuum assisted infusion of GSP results in a high yield (~1 mg/g) of trans-Res and improved photostability of infused trans-Res in GSP exposed to UV-A light. The release of trans-Res from GSP was ~ 45% during gastric digestion and the total release in the intestinal phase during sequential digestion processes using low and high bile salts was ~ 70% and ~ 90%, respectively. Moreover, the release of endogenous polyphenols in GSP during simulated gastrointestinal digestion was similar to the release profile of infused resveratrol, suggesting strong interactions of infused resveratrol with the GSP matrix. In summary, this research illustrates a novel approach to utilize food by-products to enhance stability and bioaccessibility of bioactive compounds.


Assuntos
Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Resveratrol/química , Resveratrol/farmacocinética , Vitis/química , Digestão , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Frutas/química , Fenóis/análise , Fotólise , Pós/química , Resveratrol/administração & dosagem , Raios Ultravioleta , Vácuo
2.
Environ Health Prev Med ; 25(1): 70, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33160329

RESUMO

BACKGROUND: Resveratrol has been shown to inhibit platelet aggregation. However, the mechanism for this action of resveratrol remains to be clarified. The purpose of this study was to elucidate the Ca2+-related mechanism for the inhibitory action of resveratrol on platelet aggregation. METHODS: Ca2+ entry and subsequent aggregation of human platelets induced by different stimulants including thrombin, thapsigargin, and 1-oleoyl-2-acetylglycerol (OAG) were measured by the fluorescence method and light transmittance method, respectively. Each stimulant was added to a nominally Ca2+-free medium containing platelets, and then CaCl2 was added to the medium to induce Ca2+ influx into platelets. RESULTS: Thapsigargin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 6.25 µM or higher concentrations, while OAG-induced Ca2+ entry and subsequent platelet aggregation were not affected by resveratrol at concentrations up to 50 µM. In the nominally Ca2+-free medium, thrombin induced a small transient increase in intracellular Ca2+ concentrations, which was attenuated in the presence of resveratrol at 12.5 µM or higher concentrations. Thrombin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 12.5 µM or higher concentrations. CONCLUSIONS: The results suggest that resveratrol inhibits thrombin-induced platelet aggregation through decreasing Ca2+ release from its stores and inhibiting store-operated Ca2+ influx into platelets.


Assuntos
Cálcio/fisiologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antioxidantes/administração & dosagem , Humanos , Inibidores da Agregação de Plaquetas/administração & dosagem , Resveratrol/administração & dosagem
3.
Life Sci ; 258: 118178, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739468

RESUMO

AIMS: Gentamicin (GEN) is one of the most valuable aminoglycoside antibiotics utilized against life-threatening bacterial infections. Unfortunately, GEN-induced nephrotoxicity limited its clinical utility. The pathologic process of nephrotoxicity caused by GEN may involve epithelial to mesenchymal transition (EMT). Resveratrol (RES) is a natural compound was revealed to inhibit EMT in kidney. The present work was conducted to explore the potential renoprotective role of RES on GEN-induced EMT. Moreover, the underlying signaling pathway of this inhibition was investigated. MAIN METHODS: Mice were treated with GEN by intraperitoneal (i.p.) route daily for 15 days to identify EMT onset with regard to GEN-induced nephrotoxicity. To assess the ameliorative role of RES against GEN-induced EMT, RES was i.p. administrated in high and low doses before and concurrently with GEN treatment. KEY FINDINGS: GEN administration significantly deteriorated kidney functions. In addition, reduced glutathione (GSH) content and catalase (CAT) activity were significantly decreased with a concomitant increase in the content of kidney malondialdehyde (MDA) after GEN treatment. Histological changes and deposition of collagen were extensive in renal corpuscles and tubules. Increased expression of alpha smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) and phosphorylated (p)-Smad2 were observed after GEN administration, while E-cadherin expression was decreased. On the contrary, pretreatment with both doses of RES reversed the modifications caused by GEN administration. SIGNIFICANCE: We concluded that EMT contributes to pathogenesis of GEN-induced nephrotoxicity. RES has a protective effect on GEN-induced EMT via suppressing oxidative stress and a possible involvement of TGF-ß/Smad signaling pathway.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Gentamicinas/efeitos adversos , Rim/metabolismo , Rim/patologia , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/farmacologia , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Biomarcadores/sangue , Fibrose , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Resveratrol/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
4.
AAPS PharmSciTech ; 21(5): 183, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632576

RESUMO

Pulmonary drug delivery is a noninvasive therapeutic approach that offers many advantages including localized drug delivery and higher patient compliance. As with all formulations, the low aqueous solubility of a drug often poses a challenge in the formulation development. Thus, strategies such as cyclodextrin (CD) complexation have been utilized to overcome this challenge. Resveratrol (RES), a natural stilbene, has shown abundant anti-cancer properties. Due to many drawbacks of conventional chemotherapeutics, RES has been proposed as an emerging alternative with promising pharmacological effects. However, RES has limited therapeutic applications due to low water solubility, chemical stability, and bioavailability. This study was aimed at developing an inhalable therapy that would increase the aqueous solubility and stability of RES by complexation with sulfobutylether-ß-cyclodextrin (SBECD). Phase solubility profiles indicated an optimal stoichiometric inclusion complex at 1:1 (SBECD:RES) ratio for formulation considerations. Physiochemical characterizations were performed to analyze CD-RES. Stability studies at pH 7.4 and in plasma indicated significant improvement in RES stability after complexation, with a much longer half-life. The mass median aerodynamic diameter (MMAD) of CD-RES was 2.6 ± 0.7 µm and fine particle fraction (FPF) of 83.4 ± 3.0% are suitable for pulmonary delivery and efficient deposition. Lung cancer was selected as the respiratory model disease, owing to its high relevance as the major cause of cancer deaths worldwide. Cell viability studies in 5 non-small-cell-lung-cancer (NSCLC) cell lines suggest CD-RES retained significant cytotoxic potential of RES. Taken together, CD-RES proves to be a promising inhalation treatment for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ciclodextrinas/química , Neoplasias Pulmonares/tratamento farmacológico , Resveratrol/administração & dosagem , Administração por Inalação , Disponibilidade Biológica , Portadores de Fármacos/metabolismo , Estabilidade de Medicamentos , Humanos , Pulmão/metabolismo , Solubilidade
5.
Am J Clin Nutr ; 112(4): 1029-1038, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32492138

RESUMO

BACKGROUND: Effects of resveratrol on metabolic health have been studied in several short-term human clinical trials, with conflicting results. Next to dose, the duration of the clinical trials may explain the lack of effect in some studies, but long-term studies are still limited. OBJECTIVES: The objective of this study was to investigate the effects of 6-mo resveratrol supplementation on metabolic health outcome parameters. METHODS: Forty-one overweight men and women (BMI: 27-35 kg/m2; aged 40-70 y) completed the study. In this parallel-group, double-blind clinical trial, participants were randomized to receive either 150 mg/d of resveratrol (n = 20) or placebo (n = 21) for 6 mo. The primary outcome of the study was insulin sensitivity, using the Matsuda index. Secondary outcome measures were intrahepatic lipid (IHL) content, body composition, resting energy metabolism, blood pressure, plasma markers, physical performance, quality of life, and quality of sleep. Postintervention differences between the resveratrol and placebo arms were evaluated by ANCOVA adjusting for corresponding preintervention variables. RESULTS: Preintervention, no differences were observed between the 2 treatment arms. Insulin sensitivity was not affected after 6 mo of resveratrol treatment (adjusted mean Matsuda index: 5.18 ± 0.35 in the resveratrol arm compared with 5.50 ± 0.34 in the placebo arm), although there was a significant difference in postintervention glycated hemoglobin (HbA1c) between the arms (P = 0.007). The adjusted means showed that postintervention HbA1c was lower on resveratrol (35.8 ± 0.43 mmol/mol) compared with placebo (37.6 ± 0.44 mmol/mol). No postintervention differences were found in IHL, body composition, blood pressure, energy metabolism, physical performance, or quality of life and sleep between treatment arms. CONCLUSIONS: After 6 mo of resveratrol supplementation, insulin sensitivity was unaffected in the resveratrol arm compared with the placebo arm. Nonetheless, HbA1c was lower in overweight men and women in the resveratrol arm. This trial was registered at Clinicaltrials.gov as NCT02565979.


Assuntos
Resistência à Insulina , Sobrepeso/metabolismo , Resveratrol/administração & dosagem , Adulto , Idoso , Composição Corporal , Suplementos Nutricionais , Metabolismo Energético , Feminino , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Desempenho Físico Funcional , Qualidade de Vida
6.
Life Sci ; 256: 117962, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534040

RESUMO

AIMS: The aim of the present study was to evaluate the oral resveratrol effects associated with diet and physical training changes on anthropometric and biochemical parameters. MAIN METHODS: 25 individuals aged from 30 to 60 years old; with Body Mass Index (BMI) ≥ 30 kg/m2 were included in the study. Following the primary evaluation (anthropometric and clinical), the patients were randomly divided into 2 groups: (1) Placebo: Physical activity program + Diet + Placebo; (2) Resveratrol: Physical activity program + Diet + Resveratrol (RVS) (250 mg/day) for three months. Anthropometric and biochemical parameters were evaluated at baseline and after the treatment period. KEY FINDINGS: The main findings showed that the resveratrol supplementation improved total cholesterol (TC), High-density Lipoprotein cholesterol (HDL-c), Very-low density Lipoprotein cholesterol (VLDL-c), urea, creatinine and albumin serum levels. SIGNIFICANCE: These findings indicate that this polyphenol may be an option to potentiate the beneficial effects induced by dietary and physical activity programs in the Metabolic Syndrome (MetS) treatment.


Assuntos
Suplementos Nutricionais , Estilo de Vida , Síndrome Metabólica/complicações , Síndrome Metabólica/tratamento farmacológico , Obesidade/complicações , Resveratrol/administração & dosagem , Resveratrol/uso terapêutico , Administração Oral , Adulto , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Obesidade/sangue , Placebos
7.
Int. j. morphol ; 38(3): 558-564, June 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1098287

RESUMO

Chronic hepatotoxicity is a debilitating and frequently life-threatening disease resulting in progressive liver failure. The toxic chemical, thioacetamide (TAA) is used to evaluate hepatoprotective agents, and the polyphenolic compound, resveratrol was proposed as a novel treatment for diseases with hyperactivation of the mammalian target of rapamycin (mTOR) cell signaling pathway. This analysis sought to investigate the potential protective effect of resveratrol against liver injury induced by TAA via the inhibition of hepatic mTOR. Model group rats received several injections of TAA (200 mg/kg; twice a week for 8 weeks) before being sacrificed at week 10 and the protective group was pretreated with resveratrol (20 mg/kg) daily for two weeks prior to TAA injections and continued receiving both agents until the end of the experiment. Harvested liver tissues were examined using light microscopy and liver homogenates were assayed for biomarkers of inflammation and assessed the levels of mTOR protein in all animal groups. In addition, blood samples were assayed for biomarkers of liver injury enzyme. TAA substantially damaged the hepatic tissue of the model group such as infiltration of inflammatory cells, vacuolated cytoplasm, dark pyknotic nuclei, and dilated congested blood vessel that were effectively protected by resveratrol. Resveratrol also significantly (p<0.05) inhibited TAA-induced mTOR, high sensitivity c-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in harvested liver homogenates and blood samples. Thus, we conclude that resveratrol effectively protects against TAA-induced hepatotoxicity in rats, possibly due to the inhibition of mTOR and inflammation.


La hepatotoxicidad crónica es una enfermedad debilitante y potencialmente mortal que produce insuficiencia hepática progresiva. La toxicidad del químico de la tioacetamida (TAA) se utiliza para evaluar los agentes hepatoprotectores y el compuesto polifenólico, resveratrol, se propuso como un nuevo tratamiento para enfermedades con hiperactivación de la vía de señalización celular mTOR (mammalian Target of Rapamycin). Aquí buscamos investigar el posible efecto protector del resveratrol contra la lesión hepática inducida por TAA a través de la inhibición de la vía de señalización mTOR en hepatocitos. Las ratas del grupo modelo recibieron varias inyecciones de TAA (200 mg / kg; dos veces por semana durante 8 semanas) antes de ser sacrificadas en la semana 10 y el grupo protector se trató previamente con resveratrol (20 mg / kg) diariamente durante dos semanas antes de las inyecciones de TAA y continuó recibiendo ambos agentes hasta el final del experimento. Se examinaron los tejidos hepáticos recolectados usando microscopía óptica y se analizaron los homogeneizados hepáticos para detectar biomarcadores de inflamación y se evaluaron los niveles de proteína mTOR en todos los grupos de animales. Además, se analizaron muestras de sangre para detectar biomarcadores de la enzima de lesión hepática. TAA dañó sustancialmente el tejido hepático del grupo modelo, con infiltración de células inflamatorias, citoplasma vacuolado, núcleos picnóticos oscuros y vasos sanguíneos congestionados dilatados que estaban efectivamente protegidos por el resveratrol. El resveratrol también inhibió significativamente (p <0.05) mTOR, proteína C-reactiva (hs-CRP), factor de necrosis tumoral alfa (TNF-α), interleucina-6 (IL-6), alanina aminotransferasa (ALT ) y aspartato aminotransferasa (AST) en las muestras de sangre y de hígados recolectados. En conclusión, el resveratrol protege eficazmente contra la hepatotoxicidad inducida por TAA en ratas, posiblemente debido a la inhibición de mTOR y de la inflamación.


Assuntos
Animais , Masculino , Camundongos , Tioacetamida/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resveratrol/administração & dosagem , Aspartato Aminotransferases/análise , Proteína C-Reativa/análise , Fator de Necrose Tumoral alfa/análise , Alanina Transaminase/análise , Modelos Animais de Doenças
8.
Int. j. morphol ; 38(3): 585-591, June 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1098291

RESUMO

Acetaminophen (also called paracetamol, or APAP) induced nephrotoxicity is reported after accidental or intentional ingestion of an overdose of the drug. Renal tubular ultrastructural alterations induced by APAP overdose associated with the induction of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic anti-inflammatory and antioxidants agents, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced acute kidney injury. The model group of rats received a single dose of APAP (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP. All rats were then sacrificed one day post APAP ingestion. Harvested kidney tissues were prepared for transmission electron microscopy (TEM) staining and blood samples were assayed for urea, creatinine, and biomarkers of inflammation and oxidative stress. TEM images and blood chemistry analysis showed that APAP overdose induced kidney damage as demonstrated by substantial alterations to the proximal convoluted tubule ultrastructure, and a significant (p<0.05) increase in urea, creatinine, tumor necrosis factor-alpha (TNF-a), and malondialdehyde (MDA) blood levels, which were protected by RES+QUR. These findings indicate that APAP induces alterations to the renal tubular ultrastructure, which is inhibited by resveratrol plus quercetin, which also decreases blood levels of kidney injury biomarkers.


El objetivo de este trabajo fue estudiar la nefrotoxicidad inducida por acetaminofeno (también llamado paracetamol o APAP) después de la ingestión accidental o intencional de una sobredosis de la droga. Las alteraciones ultraestructurales tubulares renales inducidas por sobredosis de APAP asociadas con la inducción de biomarcadores de daño renal no se han investigado. Además, estudiamos si los agentes combinados antiinflamatorios y antioxidantes polifenólicos, el resveratrol (RES) y la quercetina (QUR) pueden proteger contra la lesión renal aguda inducida por APAP. El grupo modelo de ratas recibió una dosis única de APAP (2 g / kg), mientras que el grupo protector de ratas se trató previamente durante 7 días con dosis combinadas de RES (30 mg / kg) y QUR (50 mg / kg) antes de recibir una dosis única de APAP. Todas las ratas se sacrificaron un día después de la ingestión de APAP. Los tejidos renales fueron preparados para el análisis a través de la microscopía electrónica de transmisión (MET). En las muestras de sangre se determinaron la urea, creatinina y los biomarcadores de inflamación y estrés oxidativo. Las imágenes MET y el análisis químico de la sangre mostraron que la sobredosis de APAP inducía daño renal, como lo demuestran las alteraciones sustanciales en la ultraestructura del túbulo contorneado proximal, y además, de un aumento significativo (p <0,05) de la urea, creatinina, factor de necrosis tumoral alfa y niveles sanguíneos de malondialdehído, protegidos por RES + QUR. Estos hallazgos indican que APAP induce alteraciones en la ultraestructura tubular renal, inhibida por el resveratrol más quercetina, que también disminuye los niveles sanguíneos de biomarcadores de daño renal.


Assuntos
Animais , Ratos , Quercetina/administração & dosagem , Resveratrol/administração & dosagem , Túbulos Renais/efeitos dos fármacos , Acetaminofen/toxicidade , Quercetina/farmacologia , Ureia/sangue , Ratos Sprague-Dawley , Creatinina/sangue , Microscopia Eletrônica de Transmissão , Modelos Animais de Doenças , Overdose de Drogas , Resveratrol/farmacologia , Túbulos Renais/patologia , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem
9.
Artigo em Inglês | MEDLINE | ID: mdl-32316577

RESUMO

Obesity during pregnancy increases the risk of cardiovascular problems, diabetes, asthma, and cognitive impairments, affecting the offspring. It is important to reduce the negative effects of obesity and high-fat (HF) diet during pregnancy. We employed a rat model of maternal HF diet to evaluate the possible de-programming effects of resveratrol in rodent male offspring with maternal HF diet/obesity. Male rat offspring were randomized into four groups: maternal control diet/postnatal control diet, maternal HF diet/postnatal control diet, maternal control diet plus maternal resveratrol treatment/postnatal control diet, and maternal HF diet plus maternal resveratrol treatment/postnatal control diet. Maternal HF diet during pregnancy plus lactation resulted in retroperitoneal adiposity in the male offspring. Maternal resveratrol treatment re-programmed maternal HF exposure-induced visceral adiposity. Offspring that received prenatal HF diet showed higher leptin/soluble leptin receptor (sOB-R) ratio than offspring that received prenatal control diet. Maternal resveratrol treatment ameliorated maternal HF exposure-induced increase in leptin/sOB-R ratio and altered the expression of genes for crucial fatty acid synthesis enzymes in the offspring. Thus, maternal resveratrol administration reduces retroperitoneal adiposity in rat offspring exposed to prenatal HF diet/obesity and could be used to ameliorate negative effects of maternal HF diet in the offspring.


Assuntos
Adiposidade , Dieta Hiperlipídica , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal , Resveratrol/administração & dosagem , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Masculino , Gravidez , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
10.
J Helminthol ; 94: e140, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32238206

RESUMO

Trichinellosis is a serious food-borne zoonotic infection of cosmopolitan distribution. Currently, treatment for trichinellosis is far from ideal. Given the important role of oxidative stress and immune-mediated inflammation in the pathogenesis of trichinellosis, this study was designed to evaluate the possible protective effects of resveratrol (RSV) during the intestinal and muscular phases of Trichinella spiralis infection in mice. The oral administration of RSV at a dose of 20 mg/kg once daily for two weeks resulted in significant reductions in both adult and larval counts; significant improvements in the redox status of the small intestine and muscles; a significant reduction in interleukin 4, pentraxin 3 and vascular endothelial growth factor expression; and the mitigation of intestinal and muscular inflammation. In conclusion, this study identifies RSV as a promising agent for the treatment of experimental trichinellosis, and more studies in experimental animals and humans are worth consideration.


Assuntos
Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Resveratrol/uso terapêutico , Trichinella spiralis/efeitos dos fármacos , Triquinelose/tratamento farmacológico , Administração Oral , Animais , Intestino Delgado/parasitologia , Larva/efeitos dos fármacos , Masculino , Camundongos , Músculos/parasitologia , Resveratrol/administração & dosagem
11.
Toxicol Appl Pharmacol ; 394: 114962, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32205187

RESUMO

Trans-resveratrol (RES) is a naturally occurring stilbene found in numerous plants and foods. Due to its widespread human exposure and lack of toxicity and carcinogenicity data, RES was nominated to the National Toxicology Program for testing. To aid the toxicology studies, the dose, sex, and species differences in RES toxicokinetics was investigated in Harlan Sprague Dawley rats and B6C3F1/N mice following single intravenous (IV) (10 mg/kg) or oral gavage administration (312.5, 625, and 1250 mg/kg and 625, 1250, and 2500 mg/kg in rats and mice, respectively). Following IV and gavage administration, systemic exposure of RES based on AUC was trans-resveratrol-3-O-ß-D-glucuronide (R3G)> > trans-resveratrol-3-sulfate (R3S) > RES in both species. Following gavage administration Tmax_predicted values were ≤ 263 min for both species and sexes. RES elimination half-life was longer in rats than mice, and shortest in male mice. Clearance was slower in mice with no apparent sex difference in both species. In both rats and mice, following gavage administration AUC increased proportionally to the dose. After gavage administration, enterohepatic recirculation of RES was observed in both rats and mice with secondary peaks occurring around 640 min in the concentration-time profiles. RES was rapidly metabolized to R3S and R3G in both species. Extensive first pass conjugation and metabolism resulted in low levels of the parent compound RES which was confirmed by the low estimates for bioavailability. The bioavailability of RES was low, ~12-31% and ~2-6% for rats and mice, respectively, with no apparent difference between sexes.


Assuntos
Resveratrol/farmacocinética , Resveratrol/toxicidade , Administração Intravenosa , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Biotransformação , Circulação Êntero-Hepática , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Radiação , Ratos , Ratos Sprague-Dawley , Resveratrol/administração & dosagem , Caracteres Sexuais , Especificidade da Espécie , Distribuição Tecidual
12.
Invest Ophthalmol Vis Sci ; 61(3): 13, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32176263

RESUMO

Purpose: To investigate the efficacy of intravitreal administration of resveratrol (RSV) in a microbead-induced high intraocular pressure (IOP) murine model for glaucoma. Methods: Experiments were performed using adult C57BL/6JJcl mice. Polystyrene microbeads were injected into the anterior chamber to induce IOP elevation. Retinal flat-mounts and sections were assessed by immunohistochemistry to detect the expression of reactive oxygen species and acetyl-p53 in retinal ganglion cells (RGCs), brain-derived neurotrophic factor (BDNF) in Müller glial cells (MGCs), and the receptor tropomyosin receptor kinase B (TrkB) in RGCs. Light cycler real-time PCR was also used for confirming gene expression of BDNF in primary cultured MGCs exposed to RSV. Results: Microbeads induced high IOP followed by RGC death and axon loss. Administration of RSV rescued RGCs via decreased reactive oxygen species generation and acetyl-p53 expression in RGCs and upregulated BDNF in MGCs and TrkB expression in RGCs, which exhibited a strong cytoprotective action against cell death through multiple pathways under high IOP. Conclusions: Our data suggest that administration of RSV may delay the progress of visual dysfunction during glaucoma and may therefore have therapeutic potential.


Assuntos
Antioxidantes/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Resveratrol/uso terapêutico , Células Ganglionares da Retina/efeitos dos fármacos , Acetilação , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citoproteção/fisiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Pressão Intraocular/efeitos dos fármacos , Injeções Intravítreas , Masculino , Camundongos Endogâmicos C57BL , Microesferas , Hipertensão Ocular/etiologia , Hipertensão Ocular/metabolismo , Hipertensão Ocular/patologia , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/administração & dosagem , Resveratrol/farmacologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo
13.
PLoS One ; 15(3): e0229017, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130239

RESUMO

We have earlier reported that cell-free chromatin (cfCh) particles that are released from dying cells, or those that circulate blood, can readily enter into healthy cells, illegitimately integrate into their genomes and induce dsDNA breaks, apoptosis and intense activation of inflammatory cytokines. We hypothesized that sepsis is caused by cfCh released from dying host cells following microbial infection leading to bystander host cell apoptosis and inflammation which are perpetuated in a vicious cycle with release of more cfCh from dying host cells. To test this hypothesis we used three cfCh inactivating agents namely 1) anti-histone antibody complexed nanoparticles which inactivate cfCh by binding to histones; 2) DNase I which inactivates cfCh by degrading its DNA component, and 3) a novel pro-oxidant combination of Resveratrol and Copper which, like DNase I, inactivates cfCh by degrading its DNA component. Female C57 BL/6 mice, 6-8 weeks old, were administered a single i.p. injection of LPS at a dose of 10 mg/Kg or 20 mg/Kg with or without concurrent treatment with the above cfCh inactivating agents. Administration of cfCh inactivating agents concurrently with LPS resulted in prevention of following pathological parameters: 1) release of cfCh in extra-cellular spaces of brain, lung and heart and in circulation; 2) release of inflammatory cytokines in circulation; 3) activation of DNA damage, apoptosis and inflammation in cells of thymus, spleen and in PBMCs; 4) DNA damage, apoptosis and inflammation in cells of lung, liver, heart, brain, kidney and small intestine; 5) liver and kidney dysfunction and elevation of serum lactate; 6) coagulopathy, fibrinolysis and thrombocytopenia; 7) lethality. We conclude that cfCh that are released from dying host cells in response to bacterial endotoxin represents a global instigator of sepsis. cfCh inactivation may provide a novel approach to management of sepsis in humans.


Assuntos
Morte Celular , Ácidos Nucleicos Livres/metabolismo , Cromatina/metabolismo , Endotoxinas , Sepse/metabolismo , Sepse/patologia , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Cromatina/patologia , Cromatina/fisiologia , Cobre/administração & dosagem , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Desoxirribonuclease I/metabolismo , Desoxirribonuclease I/uso terapêutico , Feminino , Histonas/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/uso terapêutico , Resveratrol/administração & dosagem , Sepse/induzido quimicamente , Sepse/prevenção & controle
14.
Nutrients ; 12(2)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023928

RESUMO

The aim of the present critical review is to summarize the available clinical evidence supporting the use of some dietary supplements that have been shown to lower blood pressure in hypertensive pregnant women. A systematic search strategy was carried out to identify trials in MEDLINE (National Library of Medicine, Bethesda, Maryland, MD, USA; January 1980 to September 2019) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). The terms 'nutraceuticals', 'dietary supplements', 'pregnancy', 'pre-eclampsia', 'clinical trial', and 'human' were incorporated into an electronic search strategy. The references of the identified studies and review articles were reviewed to look for additional studies of interest. We preferably selected papers that reported recent comprehensive reviews or meta-analysis, or original clinical trials of substances with blood pressure-lowering or vascular protective effect in pregnancy. There is a relative body of evidence that supports the use of calcium, vitamin D, folic acid, and resveratrol in preventing the development of hypertensive disorders in pregnancy, and evidence supporting drug treatment too. Further clinical research is advisable to identify the dosage and timing of the supplementation, the group of women that might benefit the most from this approach, and the nutraceuticals with the best cost-effectiveness and risk-benefit ratio for widespread use in clinical practice.


Assuntos
Suplementos Nutricionais , Hipertensão Induzida pela Gravidez/prevenção & controle , Cuidado Pré-Natal/métodos , Pressão Sanguínea , Cálcio na Dieta/administração & dosagem , Feminino , Ácido Fólico/administração & dosagem , Humanos , Gravidez , Resveratrol/administração & dosagem , Resultado do Tratamento , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem
15.
Int J Nanomedicine ; 15: 301-313, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021181

RESUMO

Purpose: Multifunctional drug delivery systems (DDS) are emerging as a new strategy to highly treat malignant tumors. The aim of this study is to develop a drug dual-carriers delivery system (DDDS) using the natural protein ferritin (FRT) and a nanoscale graphene oxide (NGO) as dual-carriers. Methods: The FRT is a pH-sensitive hollow cage protein with disassembly and reassembly properties and the NGO has a large surface area and a photothermal effect by which it can load and release drugs under near-infrared irradiation (NIR). Due to these unique features, the NGO loaded the anticancer drug resveratrol (RSV) and the conjugated mitochondrion targeted molecule IR780 as IR780-NGO-RSV (INR), the first drug delivery platform. Next, the INR was capsulated by FRT to form the DDDS INR@FRT which was applied for synergistic photothermal-chemotherapy of ovarian cancer. Results: Through a series of characterizations, INR@FRT showed a uniform nanosphere structure and remarkable stability in physiological condition. Heat/pH 5.0 was confirmed to trigger RSV release from the INR@FRT. After taken up by cells, INR@FRT located to the lysosomes where the acidic environment triggered INR release. INR targeted the mitochondrion and released RSV to directly react with organelles, which in turn decreased the mitochondrion membrane potential and caused cell apoptosis. In-vivo experiments showed that INR@FRT combined with NIR irradiation displayed remarkable tumor suppression with a high survival rate after 60 days of treatment. Finally, the biocompatibility of INR@FRT was demonstrated in vitro and in vivo. Conclusion: These results highlight the immense potential of INR@FRT as a type of DDDS for the treatment of tumors.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Indóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Nanoestruturas/química , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Feminino , Ferritinas/química , Grafite/química , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Indóis/administração & dosagem , Indóis/química , Raios Infravermelhos , Camundongos Nus , Nanoestruturas/administração & dosagem , Resveratrol/administração & dosagem , Resveratrol/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Drug Dev Ind Pharm ; 46(3): 365-375, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32041433

RESUMO

Objectives: The objective of the present work to encapsulate the resveratrol (RES) inside the chitosan-based microsponges, employing the systematic optimization by 33 Box-Behnken design for the colonic targeting.Significance: Enhanced therapeutic efficacy of RES-loaded microsponges and matrix tablets, vis-a-vis pureRES for ulcerative colitis.Methods: RES-loaded microsponges were prepared employing the systematic optimization by 33 Box-Behnken design for the colonic targeting. The best-optimizedRES-loaded microsponge was compressed in the form of a tablet, employing pectin as a matrix-forming material. The encapsulation of RES inside microsponge was confirmed by XRD, DSC and FT-IR. Further, both RES-loaded microsponges and matrix tablets were evaluated for in vitro release kinetics and further evaluated for in vivo ulcerative colitis animal model.Results: Optimization experiments was obtained as the high value of r2 (particle size = 0.9999; %EE = 0.9652; %CDR = 0.9469) inferred excellent goodness of fit. SEM revealed nearly spherical and porous nature of RES-loaded microsponges. The in vitro release kinetic showed zero-order release for RES-loaded microsponges and Korsmeyer-Peppas model for matrix tablets. The pharmacodynamic studies, in ulcerative colitis rat model, indicated better therapeutic efficacy of drug-loaded microsponges and matrix tablets, vis-a-vis pure RES. Thus, the present study advocates the potential of RES based microsponges delivered by pectin based matrix tablet, in the treatment of various colonic disorders.Conclusion: The present study proved that RES-loaded microsponges and matrix tablets based on chitosan and pectin can be the ideal delivery system for colonic delivery of RES.


Assuntos
Antioxidantes/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Resveratrol/administração & dosagem , Ácido Acético , Animais , Antioxidantes/farmacologia , Química Farmacêutica , Quitosana/química , Colite Ulcerativa/fisiopatologia , Colo/metabolismo , Colo/fisiopatologia , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Tamanho da Partícula , Pectinas/química , Ratos , Ratos Wistar , Resveratrol/farmacologia , Comprimidos
17.
Int. j. morphol ; 38(1): 83-90, Feb. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1056402

RESUMO

We sought to determine whether the combined polyphenolic compounds, resveratrol and quercetin can substantially protect against modulation of hepatic biomarkers of apoptosis and survival, p53-Bax axis and B-cell lymphoma 2 (Bcl-2) in an animal model of acetaminophen-induced acute liver injury via the association of oxidative stress and interleukin-11 (IL-11). The model group of rats received a single dose of acetaminophen (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of resveratrol (30 mg/kg) and quercetin (50 mg/kg) before being given a single dose of acetaminophen. All rats were then sacrificed 24 hours post acetaminophen ingestion. Acetaminophen overdose induced acute liver injury as demonstrated by profound liver parenchymal damage and increased levels of the liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Acetaminophen significantly (p<0.05) modulated malondialdehyde (MDA), p53, apoptosis regulator Bax, Bcl-2, IL-11, interleukin-6 (IL-6), ALT, AST, superoxide dismutase (SOD), and glutathione peroxidase (GPx), which were significantly protected by resveratrol plus quercetin. We further demonstrated a significant (p<0.01) correlation between IL-11 scoring and the levels of p53, Bax, Bcl-2, and MDA. Thus, resveratrol plus quercetin effectively protect against acetaminophen-induced apoptosis, which is associated with the inhibition of oxidative stress and IL-11.


En el estudio se intentó determinar si los compuestos polifenólicos combinados, el resveratrol y la quercetina pueden proteger sustancialmente contra la modulación de los biomarcadores hepáticos de apoptosis y supervivencia, el eje p53-Bax y el linfoma de células B 2 (Bcl-2) en un modelo animal de lesión hepática aguda inducida por acetaminofén, a través de la asociación del estrés oxidativo y la interleucina-11 (IL-11). El grupo modelo de ratas recibió una dosis única de acetaminofén (2 g / kg), mientras que el grupo protector de ratas fue tratado durante 7 días con dosis combinadas de resveratrol (30 mg / kg) y quercetina (50 mg / kg) antes de recibir una dosis única de acetaminofén. Todas los animales fueron sacrificados 24 horas después de la ingestión de acetaminofén. La sobredosis de acetaminofén indujo una lesión hepática aguda, como se observó en el daño profundo del parénquima hepático y el aumento de los niveles de las enzimas en la lesión hepática, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). Acetaminofén moduló significativamente (p <0.05) malondialdehído (MDA), p53, regulador de apoptosis Bax, Bcl2, IL-11, interleucina-6 (IL-6), ALT, AST, superóxido dismutasa (SOD) y glutatión peroxidasa ( GPx), los que se encontraron significativamente protegidos por el resveratrol y quercetina. Además se determinó una correlación significativa (p <0.01) entre la puntuación de IL-11 y los niveles de p53, Bax, Bcl-2 y MDA. En conclusión, el resveratrol más la quercetina protegen de manera efectiva contra la apoptosis inducida por acetaminofén, asociada con la inhibición del estrés oxidativo y la IL-11.


Assuntos
Animais , Ratos , Quercetina/administração & dosagem , Apoptose/efeitos dos fármacos , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Resveratrol/administração & dosagem , Acetaminofen/toxicidade , Antioxidantes/administração & dosagem , Quercetina/farmacologia , Aspartato Aminotransferases/análise , Biomarcadores , Interleucina-1 , Estresse Oxidativo , Alanina Transaminase/análise , Modelos Animais de Doenças , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Resveratrol/farmacologia , Antioxidantes/farmacologia
18.
Drug Dev Ind Pharm ; 46(2): 227-235, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31928244

RESUMO

Objective: Aim of the present work was to optimize and formulate resveratrol loaded vesicular cream intended for dermal delivery of resveratrol with high skin deposition potential.Methods: Formulation was developed and optimized using Central Composite Design. Amount of phospholipid and sodium cholate were selected as critical material attributes and vesicle size and entrapment efficiency of resveratrol were taken as critical quality attributes. To increase the skin applicability and patient compliance, vesicles were further developed as vesicular cream which was then thoroughly characterized for physicochemical parameters, ex vivo skin permeation/deposition profile and antioxidant potential.Results: Vesicle size and entrapment efficiency of the optimized batch were found to be 178.9 ± 12.87 nm with 72.32 ± 3.45% respectively. Physicochemical properties and viscosity of cream formulation were also found to be favorable for skin applicability. Permeation flux at the end of 24 h was found to be 2.70 ± 0.73, 4.45 ± 0.56 and 4.95 ± 0.69 µg cm-2 h-1 for conventional cream, vesicular dispersion, and vesicular cream formulation respectively. Higher drug deposition in the skin via vesicular cream formulation was observed i.e. 335.2 ± 4.12 µg cm-2 (70.16 ± 0.87%) as compared to conventional cream i.e. 67.12 ± 19.63 µg cm-2 (14.05 ± 4.11%). Resveratrol encapsulated in vesicular cream has retained its inherent antioxidant activity suggesting the stability of resveratrol in vesicular cream.Conclusion: Thus, it can be concluded that deformable vesicular cream is capable of delivering encapsulated bioactive in deeper layers of skin, where it can be retained for achieving higher dermatological benefits.


Assuntos
Antioxidantes/administração & dosagem , Antioxidantes/química , Pomadas/administração & dosagem , Pomadas/química , Resveratrol/administração & dosagem , Resveratrol/química , Pele/efeitos dos fármacos , Administração Cutânea , Animais , Química Farmacêutica/métodos , Portadores de Fármacos/química , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Fosfolipídeos/química , Absorção Cutânea/efeitos dos fármacos , Suínos , Viscosidade/efeitos dos fármacos
19.
Drug Dev Ind Pharm ; 46(2): 236-245, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31928345

RESUMO

Nanoparticles based on gellan gum/pectin blends were designed for colon-targeted release of resveratrol (RES). Their impact on drug release rates and permeability were evaluated using Caco-2 cell model and mucus secreting triple co-culture model. Polymeric nanoparticles (PNP) were successfully prepared by nebulization/ionotropic gelation, achieving high drug loading (>80%). PNP were spherical with a low positive charge density (+5mV) and exhibited diameters of around 330 nm. Developed PNP were able to promote effective modulation of drug release rates, so that only 3% of RES was released in acidic media over 2 h, and, in pH 6.8, the drug was released in a sustained manner, reaching 85% in 30 h. The permeability of RES-loaded PNP in the Caco-2 model was 0.15%, while in the triple co-culture model, in the presence of mucus, it reached 5.5%. The everted gut sac experiment corroborated the low permeability of RES-loaded PNP in the presence or absence of mucus and highlighted their high ability to interact with the intestinal tissue. Results indicate that the novel PNP developed in this work are safe and promising carriers for controlled delivery of RES at the colon.


Assuntos
Colo/efeitos dos fármacos , Nanopartículas/administração & dosagem , Nanopartículas/química , Pectinas/química , Polissacarídeos Bacterianos/química , Resveratrol/administração & dosagem , Resveratrol/química , Administração Oral , Animais , Células CACO-2 , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Células HT29 , Humanos , Concentração de Íons de Hidrogênio , Mucosa Intestinal/metabolismo , Masculino , Muco/metabolismo , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Wistar
20.
Int J Biol Macromol ; 147: 150-159, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923496

RESUMO

The surfactant-free nature and higher stability of Pickering emulsions make them preferable solutions over conventional emulsions for skin applications. In this work, Pickering emulsions stabilized by chitosan/gum Arabic (CH/GA) nanoparticles were tested as vehicles for trans-resveratrol topical delivery. Skin absorption was examined ex vivo using Franz diffusion cells and porcine skin. Pickering emulsions allowed higher cutaneous retention and lower permeation of resveratrol, in comparison with a control solution based on a 20% v/v ethanol. The total amount of resveratrol retained in the skin, 24 h after the application, was 11.60% and 10.82% of the applied dose for the tested Pickering emulsion-based formulations prepared with 0.5% and 1.5% w/v CH/GA nanoparticles, respectively. In contrast, resveratrol skin retention from the control solution was only 2.86%. Confocal laser scanning microscopy revealed enhanced skin deposition of Nile Red to deeper layers from the Pickering emulsion-based formulations. Moreover, Pickering emulsions led to trans-resveratrol photostability increase, as measured after exposure to UV for 4 h. These results show that the CH/GA Pickering emulsions are promising solutions for the topical delivery of trans-resveratrol and have the potential to be used as green cosmetic products.


Assuntos
Quitosana/química , Emulsões/química , Goma Arábica/química , Luz , Resveratrol/administração & dosagem , Resveratrol/farmacologia , Administração Cutânea , Animais , Difusão , Liberação Controlada de Fármacos , Nanopartículas/química , Absorção Cutânea/efeitos dos fármacos , Suínos
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