<i>Trans</i>‐resveratrol simultaneously increases cytoplasmic Ca<sup>2+</sup> levels and nitric oxide release in human endothelial cells

Elíes, Jacobo; Cuíñas, Andrea; García-Morales, Verónica; Orallo, Francisco; Campos‐Toimil, Manuel

doi:10.1002/mnfr.201100240

Cited by 36 publications

(30 citation statements)

References 51 publications

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“…Nevertheless, its capacity of inhibiting oxygen free radical formation may come from the inhibition of reactive oxygen species (ROS) production by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) [78,79] and by the induction of antioxidative enzymes or their substrates, such as superoxide dismutase (SOD) [78,80-83], thioredoxin [84], heme oxygenase-1 (HO-1) [84- 87], glutathione peroxidase-1 (GPx1) [78,80] and catalase [81]. According to the published evidence, RES has the capacity to improve endothelium function mainly by stimulating endothelial production of nitric oxide (NO) [88-91] through multiple mechanisms, particularly by enhancing endothelial nitric oxide synthase (eNOS) expression and/or activity [88,92-94] even at physiological concentrations [89,90,95] (Supplementary Table ). It has been suggested that RES enhances eNOS activity via 5’-adenosine monophosphate-activated protein kinase (AMPK) or extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated phosphorylation at Ser1177 [90,96].…”

Section: Preclinical Studiesmentioning

confidence: 99%

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Tomé‐Carneiro

Larrosa²,

González‐Sarrías

et al. 2013

CPD

397

294

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Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of food-stuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol-based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of ‘potential’ benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called ‘Resveratrol Paradox’, i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol’s effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.

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Section: Preclinical Studiesmentioning

confidence: 99%

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Tomé‐Carneiro

Larrosa²,

González‐Sarrías

et al. 2013

CPD

397

294

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“…These interesting properties confer the cardiovascular protective capacity and ability to protect endothelial function on resveratrol [19], [20]. In cancer patients, resveratrol exhibits anticancer properties, such as suppression of tumor cell proliferation, induction of tumor cell apoptosis, increase in chemosensitization of tumor cells, and exerts chemopreventive effects [21], [22].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Prevents Endothelial Cells Injury in High-Dose Interleukin-2 Therapy against Melanoma

Guan

Singh

et al. 2012

PLoS ONE

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Immunotherapy with high-dose interleukin-2 (HDIL-2) is an effective treatment for patients with metastatic melanoma and renal cell carcinoma. However, it is accompanied by severe toxicity involving endothelial cell injury and induction of vascular leak syndrome (VLS). In this study, we found that resveratrol, a plant polyphenol with anti-inflammatory and anti-cancer properties, was able to prevent the endothelial cell injury and inhibit the development of VLS while improving the efficacy of HDIL-2 therapy in the killing of metastasized melanoma. Specifically, C57BL/6 mice were injected with B16F10 cells followed by resveratrol by gavage the next day and continued treatment with resveratrol once a day. On day 9, mice received HDIL-2. On day 12, mice were evaluated for VLS and tumor metastasis. We found that resveratrol significantly inhibited the development of VLS in lung and liver by protecting endothelial cell integrity and preventing endothelial cells from undergoing apoptosis. The metastasis and growth of the tumor in lung were significantly inhibited by HDIL-2 and HDIL-2 + resveratrol treatment. Notably, HDIL-2 + resveratrol co-treatment was more effective in inhibiting tumor metastasis and growth than HDIL-2 treatment alone. We also analyzed the immune status of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC) and FoxP3+CD4+ regulatory T cells (Treg). We found that resveratrol induced expansion and suppressive function of MDSC which inhibited the development of VLS after adoptive transfer. However, resveratrol suppressed the HDIL-2-induced expansion of Treg cells. We also found that resveratrol enhanced the susceptibility of melanoma to the cytotoxicity of IL-2-activated killer cells, and induced the expression of the tumor suppressor gene FoxO1. Our results suggested the potential use of resveratrol in HDIL-2 treatment against melanoma. We also demonstrated, for the first time, that MDSC is the dominant suppressor cell than regulatory T cell in the development of VLS.

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“…They assume that if it would act in the same way in human blood vessels in vivo, the pharmacological properties observed might contribute to the beneficial cardiovascular effects of this polyphenol by improving endothelial function. 9 The polyphenolic natural product resveratrol is considered to have potential as a drug for prevention and treatment of cardiovascular diseases (CVDs). A review published in Biofactors summarizes the molecular effects of resveratrol on endothelial cells that play a key role in the development of those diseases: Resveratrol enhances endothelial NO production, improves endothelial redox balance, and inhibits endothelial activation in response to pro-inflammatory and metabolic factors.…”

Section: Resveratrol Enhances Nitric Oxide Biosynthesis Andmentioning

confidence: 99%

The Polyphenolic Antioxidant Resveratrol, the Carotinoid Lycopene, and the Proanthocyanidin Pycnogenol

Fried

2014

Erectile Dysfunction as a Cardiovascular Impairment

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Trans‐resveratrol simultaneously increases cytoplasmic Ca²⁺ levels and nitric oxide release in human endothelial cells

Cited by 36 publications

References 51 publications

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Resveratrol Prevents Endothelial Cells Injury in High-Dose Interleukin-2 Therapy against Melanoma

The Polyphenolic Antioxidant Resveratrol, the Carotinoid Lycopene, and the Proanthocyanidin Pycnogenol

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Trans‐resveratrol simultaneously increases cytoplasmic Ca2+ levels and nitric oxide release in human endothelial cells

Cited by 36 publications

References 51 publications

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Resveratrol Prevents Endothelial Cells Injury in High-Dose Interleukin-2 Therapy against Melanoma

The Polyphenolic Antioxidant Resveratrol, the Carotinoid Lycopene, and the Proanthocyanidin Pycnogenol

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Product

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Trans‐resveratrol simultaneously increases cytoplasmic Ca²⁺ levels and nitric oxide release in human endothelial cells