International Journal of Molecular Sciences

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15 pages, 1549 KiB

Open AccessArticle

Separation and Identification of Resveratrol Butyrate Ester Complexes and Their Bioactivity in HepG2 Cell Models

by Ming-Kuei Shih, You-Lin Tain, Chiu-Min Cheng, Chien-Ning Hsu, Yu-Wei Chen, Hung-Tse Huang, Chi-I Chang and Chih-Yao Hou

Int. J. Mol. Sci. 2021, 22(24), 13539; https://doi.org/10.3390/ijms222413539 - 17 Dec 2021

Cited by 12 | Viewed by 3659

Abstract

Resveratrol butyrate ester (RBE) complexes have demonstrated higher antioxidant capacity and anti-fat accumulation activity in previous studies. In this study, silica gel, high-performance liquid chromatography, and 1H nuclear magnetic resonance were used for separation and identification of RBE complex components. With the exception [...] Read more.

Resveratrol butyrate ester (RBE) complexes have demonstrated higher antioxidant capacity and anti-fat accumulation activity in previous studies. In this study, silica gel, high-performance liquid chromatography, and 1H nuclear magnetic resonance were used for separation and identification of RBE complex components. With the exception of resveratrol, five different structures of ester derivatives were separated from silica gel: 3,4′-di-O-butanoylresveratrol (ED2, 18.8%), 3-O-butanoylresveratrol (ED4, 35.7%), 4′-O-butanoylresveratrol (ED5, 4.4%), 3,5,4′-tri-O-butanoylresveratrol (ED6, 1.5%), and 3,5-di-O-butanoylresveratrol (ED7, 0.7%). Among the ester derivatives obtained, ED2 and ED4 were the main ester derivatives in the RBE complex. Thus, the cellular antioxidant activities of the RBE mixture, ED2, and ED4 were evaluated. Results showed that the antioxidant capacity of ED2 and ED4 was higher than that of the RBE mixture, demonstrating that the number and position of butyrate esterification sites are related to cell survival rate and antioxidant capacity. This study is the first to report the successful isolation, structural identification, and cellular biological antioxidant activity of RBE complex derivatives, which are key characteristics for the potential practical application of RBE complexes. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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12 pages, 1781 KiB

Open AccessArticle

Bare Metal Stents on Resveratrol-Coated Balloons in Porcine Coronary and Peripheral Arteries

by Stefanie Kamann, Tobias Haase, Nicola Stolzenburg, Melanie Löchel, Daniel Peters-Berg, Denise Schütt and Jörg Schnorr

Int. J. Mol. Sci. 2021, 22(23), 13099; https://doi.org/10.3390/ijms222313099 - 3 Dec 2021

Cited by 1 | Viewed by 2127

Abstract

Balloon angioplasty and stent implantation are standard techniques to reopen stenotic vessels. Often, balloons or stents coated with cytostatic drugs are used to prevent re-occlusion of the arteries. Resveratrol, which is known for its numerous beneficial effects on cardiovascular health, is used as [...] Read more.

Balloon angioplasty and stent implantation are standard techniques to reopen stenotic vessels. Often, balloons or stents coated with cytostatic drugs are used to prevent re-occlusion of the arteries. Resveratrol, which is known for its numerous beneficial effects on cardiovascular health, is used as an antioxidant additive on paclitaxel-coated balloon catheters. What is still unclear is whether resveratrol-only balloon coating in combination with a bare metal stent (BMS) also has positive effects on vascular healing. Here, we analyzed neointimal thickening, fibrin deposition, inflammation, vasa vasorum density, and reendothelialization after implantation of BMS via a resveratrol coated balloon approach in a porcine model. In general, resveratrol treatment did not result in significantly altered responses compared to the control group in peripheral arteries. In coronary arteries, an increase in vasa vasorum density became evident three days after resveratrol treatment compared to the control group and abolished up to day 7. Significant effects of the resveratrol treatment on the fibrin score or intima-media area were transient and restricted to either peripheral or coronary arteries. In conclusion, local single-dose resveratrol treatment via a resveratrol-only coated balloon and BMS approach did not lead to adverse systemic or local effects, but also no significant beneficial effects on vascular healing were detected in the current study. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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12 pages, 4833 KiB

Open AccessArticle

Resveratrol-Coated Balloon Catheters in Porcine Coronary and Peripheral Arteries

by Stefanie Kamann, Tobias Haase, Nicola Stolzenburg, Melanie Löchel, Daniel Peters and Jörg Schnorr

Int. J. Mol. Sci. 2019, 20(9), 2285; https://doi.org/10.3390/ijms20092285 - 9 May 2019

Cited by 10 | Viewed by 3755

Abstract

Angioplasty aiming at vascular dilatation causes endothelial denudation and induces complex inflammatory responses that affect vascular healing, including delayed reendothelialization and excessive neointima proliferation. Resveratrol is known for multiple beneficial effects on the vessel wall after systemic treatment or sustained release from a [...] Read more.

Angioplasty aiming at vascular dilatation causes endothelial denudation and induces complex inflammatory responses that affect vascular healing, including delayed reendothelialization and excessive neointima proliferation. Resveratrol is known for multiple beneficial effects on the vessel wall after systemic treatment or sustained release from a stent. It is also used as an additive on drug-coated balloon catheters (DCB). In this study, the effect of a single dose of resveratrol, three days to four weeks after administration as a balloon coating during angioplasty, was investigated. Sixteen pigs underwent angioplasty with resveratrol-coated or uncoated balloon catheters in coronary and peripheral arteries. Vessels were overstretched by approximately 20% to enhance vessel wall injury and to produce persistent vessel wall irritation. A significantly reduced number of micro vessels and macrophages in the adventitia, as well as an improved reendothelialization of the vessel lumen, were observed in resveratrol-treated peripheral arteries. The coronaries had a much higher injury score compared to peripheral vessels. Resveratrol-dependent reduction of macrophages, micro vessels or acceleration of reendothelialization was not evident in the coronary vessels. Additionally, no significant effect on neointima proliferation and inflammation score in either vessel territory was observed as a result of resveratrol treatment. In conclusion, the results suggest that resveratrol diminishes the inflammatory response and promotes vascular healing in peripheral arteries. These same effects are absent in more severely injured coronary arteries. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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12 pages, 2346 KiB

Open AccessArticle

Effect of Resveratrol-Enriched Rice on Skin Inflammation and Pruritus in the NC/Nga Mouse Model of Atopic Dermatitis

by Min Cheol Kang, Kyohee Cho, Jae Hyuk Lee, Lalita Subedi, Silvia Yumnam and Sun Yeou Kim

Int. J. Mol. Sci. 2019, 20(6), 1428; https://doi.org/10.3390/ijms20061428 - 21 Mar 2019

Cited by 33 | Viewed by 6367

Abstract

Resveratrol-enriched rice (RR) was developed using genetic engineering to combine the properties of resveratrol and rice. To evaluate the effect of RR on pruritic skin inflammation in atopic dermatitis (AD)-like skin lesions, we used dinitrochlorobenzene (DNCB)-induced NC/Nga mice and an in vitro 3D [...] Read more.

Resveratrol-enriched rice (RR) was developed using genetic engineering to combine the properties of resveratrol and rice. To evaluate the effect of RR on pruritic skin inflammation in atopic dermatitis (AD)-like skin lesions, we used dinitrochlorobenzene (DNCB)-induced NC/Nga mice and an in vitro 3D skin model. Normal rice (NR), resveratrol, and RR were topically applied to mice dorsal skin, following which the dermatitis index and scratching frequency were calculated. Histological examination was performed by hematoxylin and eosin and immunohistochemistry staining of IL-31 level. The level of immunoglobulin E (IgE) and IL-31 in the serum was determined by enzyme-linked immunosorbent assay (ELISA). The cytotoxicity of RR and the expression levels of pro-inflammatory cytokines were also determined in cultured human keratinocytes and a 3D skin model. RR significantly reduced scratching frequency, decreased the dermatitis severity and trans-epidermal water loss (TEWL) and improved skin hydration in DNCB-induced NC/Nga mice. RR also significantly decreased serum IL-31 and IgE levels and suppressed the production of IL-6 in human keratinocytes and the 3D skin model. Our study indicates that the synergistic effect of rice and resveratrol manifested by the topical application of RR can serve as a potential alternative therapy for chronic skin inflammatory diseases such as AD. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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17 pages, 3386 KiB

Open AccessArticle

Maternal Resveratrol Supplementation Prevents Cognitive Decline in Senescent Mice Offspring

by Vanesa Izquierdo, Verónica Palomera-Ávalos, Sergio López-Ruiz, Anna-Maria Canudas, Mercè Pallàs and Christian Griñán-Ferré

Int. J. Mol. Sci. 2019, 20(5), 1134; https://doi.org/10.3390/ijms20051134 - 6 Mar 2019

Cited by 37 | Viewed by 4813

Abstract

A variety of environmental factors contribute significantly to age-related cognitive decline and memory impairment in Alzheimer’s Disease (AD) and other neurodegenerative diseases. Nutrition can alter epigenetics, improving health outcomes, which can be transmitted across generations; this process is called epigenetic inheritance. We investigate [...] Read more.

A variety of environmental factors contribute significantly to age-related cognitive decline and memory impairment in Alzheimer’s Disease (AD) and other neurodegenerative diseases. Nutrition can alter epigenetics, improving health outcomes, which can be transmitted across generations; this process is called epigenetic inheritance. We investigate the beneficial effects of maternal resveratrol supplementation in the direct exposed F1 generation and the transgenerational F2 generation. The offspring was generated from females Senescence Accelerated Mouse-Prone (SAMP8) fed a resveratrol-enriched diet for two months prior to mating. Object novel recognition and Morris Water Maze (MWM) demonstrated improvements in cognition in the 6-month-old F1 and F2 generations from resveratrol fed mothers. A significant increase in global DNA methylation with a decrease in hydroxymethylation in F1 and F2 were found. Accordingly, Dnmt3a/b and Tet2 gene expression changed. Methylation levels of Nrf2 and NF-kβ genes promoters raised in offspring, inducing changes in target genes expression, as well as hydrogen peroxide levels. Offspring that resulted from a resveratrol fed mother showed increase AMPKα activation, mTOR inhibition, and an increase in Pgc-1α gene expression and Beclin-1 protein levels. Endoplasmic reticulum stress sensors were found changed both in F1 and F2 generations. Overall, our results demonstrated that maternal resveratrol supplementation could prevent cognitive impairment in the SAMP8 mice offspring through epigenetic changes and cell signaling pathways. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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16 pages, 2116 KiB

Open AccessArticle

Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure-Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC-1α Signaling Pathway

by Yao-Chung Chuang, Shang-Der Chen, Chung-Yao Hsu, Shu-Fang Chen, Nai-Ching Chen and Shuo-Bin Jou

Int. J. Mol. Sci. 2019, 20(4), 998; https://doi.org/10.3390/ijms20040998 - 25 Feb 2019

Cited by 51 | Viewed by 6239

Abstract

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of [...] Read more.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of cardiovascular and neurodegenerative diseases, stroke, and epilepsy. This study examined the neuroprotective effect of resveratrol on mitochondrial biogenesis in the hippocampus following experimental status epilepticus. Kainic acid was microinjected into left hippocampal CA3 in Sprague Dawley rats to induce bilateral prolonged seizure activity. PGC-1α expression and related mitochondrial biogenesis were investigated. Amounts of nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), cytochrome c oxidase 1 (COX1), and mitochondrial DNA (mtDNA) were measured to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis machinery after prolonged seizure were found in CA3. Resveratrol increased expression of PGC-1α, NRF1, and Tfam, NRF1 binding activity, COX1 level, and mtDNA amount. In addition, resveratrol reduced activated caspase-3 activity and attenuated neuronal cell damage in the hippocampus following status epilepticus. These results suggest that resveratrol plays a pivotal role in the mitochondrial biogenesis machinery that may provide a protective mechanism counteracting seizure-induced neuronal damage by activation of the PGC-1α signaling pathway. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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16 pages, 4788 KiB

Open AccessArticle

Differential Exosomic Proteomic Patterns and Their Influence in Resveratrol Sensitivities of Glioblastoma Cells

by Jun-Hua Nie, Hong Li, Mo-Li Wu, Xiao-Min Lin, Le Xiong and Jia Liu

Int. J. Mol. Sci. 2019, 20(1), 191; https://doi.org/10.3390/ijms20010191 - 7 Jan 2019

Cited by 9 | Viewed by 4341

Abstract

Glioblastoma multiforme (GBM) is the commonest primary brain malignancy with extremely poor prognosis. Resveratrol posseses anti-cancer effects, while GBM cells respond differently to it due to certain unknown reason(s). Because the tumor-derived exosomes are supposed to influence chemosensitivity, the exosomic proteins released from [...] Read more.

Glioblastoma multiforme (GBM) is the commonest primary brain malignancy with extremely poor prognosis. Resveratrol posseses anti-cancer effects, while GBM cells respond differently to it due to certain unknown reason(s). Because the tumor-derived exosomes are supposed to influence chemosensitivity, the exosomic proteins released from resveratrol-sensitive U251 and resveratrol-resistant glioblastoma LN428 cells are profiled before (N/Exo) and after drug treatment (Res/Exo) by label-free liquid chromatography-mass spectrometry (LC-MS). The therapeutic implications of the proteomic findings are estimated by gene ontology enrichment analysis (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG)-based bioinformatic analyses and further elucidated by exosome co-incubating. The results reveal that U251/N/Exo but not U251/Res/Exo enhances resveratrol sensitivity of resveratrol-resistant LN428 cells. The resveratrol sensitive properties of U251 cells are not altered by either LN428/N/Exo or LN428/Res/Exo. U251/N/Exo contains higher levels of chromatin silencing and epidermis development proteins, while U251/Res/Exo has more oxygen transport and G protein-coupled receptor. Both of LN428/N/Exo and LN428/Res/Exo are rich in the proteins related with nucleosome assembly, microtubule-based process and chromatin silencing. In conclusion, U251/N/Exo sensitizes LN428 cells to resveratrol via delivering drug sensitizing signals, suggesting the presence of additional factor(s) that may determine the resveratrol sensitivities of glioblastoma cells. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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16 pages, 4373 KiB

Open AccessArticle

Resveratrol Attenuates Staphylococcus Aureus-Induced Monocyte Adhesion through Downregulating PDGFR/AP-1 Activation in Human Lung Epithelial Cells

by I-Ta Lee, Chih-Chung Lin, Chien-Chung Yang, Li-Der Hsiao, Ming-Yen Wu and Chuen-Mao Yang

Int. J. Mol. Sci. 2018, 19(10), 3058; https://doi.org/10.3390/ijms19103058 - 7 Oct 2018

Cited by 15 | Viewed by 4326

Abstract

Staphylococcus aureus (S. aureus) is a very common Gram-positive bacterium. It is widely distributed in air, soil, and water. S. aureus often causes septicemia and pneumonia in patients. In addition, it is considered to play a key role in mediating cell [...] Read more.

Staphylococcus aureus (S. aureus) is a very common Gram-positive bacterium. It is widely distributed in air, soil, and water. S. aureus often causes septicemia and pneumonia in patients. In addition, it is considered to play a key role in mediating cell adhesion molecules upregulation. Resveratrol is a natural antioxidant with diverse biological effects, including the modulation of immune function, anti-inflammation, and cancer chemoprevention. In this study, we proved that S. aureus-upregulated vascular cell adhesion molecule-1 (VCAM-1) expression in human lung epithelial cells (HPAEpiCs) was inhibited by resveratrol. We also observed that resveratrol downregulated S. aureus-enhanced leukocyte count in bronchoalveolar lavage (BAL) fluid in mice. In HPAEpiCs, S. aureus stimulated c-Src, PDGFR, p38 MAPK, or JNK1/2 phosphorylation, which was inhibited by resveratrol. S. aureus induced the adhesion of THP-1 cells (a human monocytic cell line) to HPAEpiCs, which was also reduced by resveratrol. Finally, we found that S. aureus induced c-Src/PDGFR/p38 MAPK and JNK1/2-dependent c-Jun and ATF2 activation and in vivo binding of c-Jun and ATF2 to the VCAM-1 promoter, which were inhibited by resveratrol. Thus, resveratrol functions as a suppressor of S. aureus-induced inflammatory signaling, not only by inhibiting VCAM-1 expression but also by diminishing c-Src, PDGFR, JNK1/2, p38 MAPK, and AP-1 activation in HPAEpiCs. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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Review

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35 pages, 2328 KiB

Open AccessReview

Benefits and Implications of Resveratrol Supplementation on Microbiota Modulations: A Systematic Review of the Literature

by Alessio Danilo Inchingolo, Giuseppina Malcangi, Angelo Michele Inchingolo, Fabio Piras, Vito Settanni, Grazia Garofoli, Giulia Palmieri, Sabino Ceci, Assunta Patano, Nicole De Leonardis, Chiara Di Pede, Valentina Montenegro, Daniela Azzollini, Maria Grazia Garibaldi, Zamira Kruti, Antonella Tarullo, Giovanni Coloccia, Antonio Mancini, Biagio Rapone, Alexandra Semjonova, Denisa Hazballa, Maria Teresa D’Oria, Megan Jones, Luigi Macchia, Ioana Roxana Bordea, Antonio Scarano, Felice Lorusso, Gianluca Martino Tartaglia, Cinzia Maspero, Massimo Del Fabbro, Ludovica Nucci, Kenan Ferati, Arberesha Bexheti Ferati, Nicola Brienza, Alberto Corriero, Francesco Inchingolo and Gianna Dipalma Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(7), 4027; https://doi.org/10.3390/ijms23074027 - 5 Apr 2022

Cited by 81 | Viewed by 8355

Abstract

Resveratrol is a polyphenol that has been shown to possess many applications in different fields of medicine. This systematic review has drawn attention to the axis between resveratrol and human microbiota, which plays a key role in maintaining an adequate immune response that [...] Read more.

Resveratrol is a polyphenol that has been shown to possess many applications in different fields of medicine. This systematic review has drawn attention to the axis between resveratrol and human microbiota, which plays a key role in maintaining an adequate immune response that can lead to different diseases when compromised. Resveratrol can also be an asset in new technologies, such as gene therapy. PubMed, Cochrane Library, Scopus, Web of Science, and Google Scholar were searched to find papers that matched our topic dating from 1 January 2017 up to 18 January 2022, with English-language restriction using the following Boolean keywords: (“resveratrol” AND “microbio*”). Eighteen studies were included as relevant papers matching the purpose of our investigation. Immune response, prevention of thrombotic complications, microbiota, gene therapy, and bone regeneration were retrieved as the main topics. The analyzed studies mostly involved resveratrol supplementation and its effects on human microbiota by trials in vitro, in vivo, and ex vivo. The beneficial activity of resveratrol is evident by analyzing the changes in the host’s genetic expression and the gastrointestinal microbial community with its administration. The possibility of identifying individual microbial families may allow to tailor therapeutic plans with targeted polyphenolic diets when associated with microbial dysbiosis, such as inflammatory diseases of the gastrointestinal tract, degenerative diseases, tumors, obesity, diabetes, bone tissue regeneration, and metabolic syndrome. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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16 pages, 657 KiB

Open AccessReview

Effect of Resveratrol on In Vitro and In Vivo Models of Diabetic Retinophathy: A Systematic Review

by Mario D. Toro, Katarzyna Nowomiejska, Teresio Avitabile, Robert Rejdak, Sarah Tripodi, Alessandro Porta, Michele Reibaldi, Michele Figus, Chiara Posarelli and Michal Fiedorowicz

Int. J. Mol. Sci. 2019, 20(14), 3503; https://doi.org/10.3390/ijms20143503 - 17 Jul 2019

Cited by 29 | Viewed by 4663

Abstract

A large number of preclinical studies suggest the involvement of resveratrol in the prevention and treatment of eye diseases induced by oxidative stress and inflammation. We tested the hypothesis that resveratrol influences many pathways of in vitro and in vivo models of diabetic [...] Read more.

A large number of preclinical studies suggest the involvement of resveratrol in the prevention and treatment of eye diseases induced by oxidative stress and inflammation. We tested the hypothesis that resveratrol influences many pathways of in vitro and in vivo models of diabetic retinopathy through a systematic literature review of original articles. The review was conducted in accordance with the PRISMA guidelines. A literature search of all original articles published until April 2019 was performed. The terms “resveratrol” in combination with “retina”, “retinal pathology”, “diabetic retinopathy” and “eye” were searched. Possible biases were identified with the adopted SYRCLE’s tool. Eighteen articles met inclusion/exclusion criteria for full-text review. Eleven of them included in vitro experiments, 11 studies reported in vivo data and 3 studies described both in vitro and in vivo experiments. Most of the in vivo studies did not include data that would allow exclusion of bias risks, according to SYRCLE’s risk of bias tool. Both in vitro and in vivo data suggest anti-apoptotic, anti-inflammatory and anti-oxidative actions of resveratrol in models of diabetic retinopathy. However, results on its anti-angiogenic effects are contradictory and need more rigorous studies. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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20 pages, 493 KiB

Open AccessReview

Glut 1 in Cancer Cells and the Inhibitory Action of Resveratrol as A Potential Therapeutic Strategy

by Angara Zambrano, Matías Molt, Elena Uribe and Mónica Salas

Int. J. Mol. Sci. 2019, 20(13), 3374; https://doi.org/10.3390/ijms20133374 - 9 Jul 2019

Cited by 151 | Viewed by 14464

Abstract

An important hallmark in cancer cells is the increase in glucose uptake. GLUT1 is an important target in cancer treatment because cancer cells upregulate GLUT1, a membrane protein that facilitates the basal uptake of glucose in most cell types, to ensure the flux [...] Read more.

An important hallmark in cancer cells is the increase in glucose uptake. GLUT1 is an important target in cancer treatment because cancer cells upregulate GLUT1, a membrane protein that facilitates the basal uptake of glucose in most cell types, to ensure the flux of sugar into metabolic pathways. The dysregulation of GLUT1 is associated with numerous disorders, including cancer and metabolic diseases. There are natural products emerging as a source for inhibitors of glucose uptake, and resveratrol is a molecule of natural origin with many properties that acts as antioxidant and antiproliferative in malignant cells. In the present review, we discuss how GLUT1 is involved in the general scheme of cancer cell metabolism, the mechanism of glucose transport, and the importance of GLUT1 structure to understand the inhibition process. Then, we review the current state-of-the-art of resveratrol and other natural products as GLUT1 inhibitors, focusing on those directed at treating different types of cancer. Targeting GLUT1 activity is a promising strategy for the development of drugs aimed at treating neoplastic growth. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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20 pages, 311 KiB

Open AccessReview

Resveratrol Action on Lipid Metabolism in Cancer

by Terézia Kisková and Monika Kassayová

Int. J. Mol. Sci. 2019, 20(11), 2704; https://doi.org/10.3390/ijms20112704 - 1 Jun 2019

Cited by 36 | Viewed by 5853

Abstract

Cancer diseases have the leading position in human mortality nowadays. The age of oncologic patients is still decreasing, and the entire scientific society is eager for new ways to fight against cancer. One of the most discussed issues is prevention by means of [...] Read more.

Cancer diseases have the leading position in human mortality nowadays. The age of oncologic patients is still decreasing, and the entire scientific society is eager for new ways to fight against cancer. One of the most discussed issues is prevention by means of natural substances. Resveratrol is a naturally occurring plant polyphenol with proven antioxidant, anti-inflammatory, and anticancer effects. Tumor cells display specific changes in the metabolism of various lipids. Resveratrol alters lipid metabolism in cancer, thereby affecting storage of energy, cell signaling, proliferation, progression, and invasiveness of cancer cells. At the whole organism level, it contributes to the optimal metabolism extent with respect to the demands of the organism. Thus, resveratrol could be used as a preventive and anticancer agent. In this review, we focus on some of the plethora of lipid pathways and signal molecules which are affected by resveratrol during carcinogenesis. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

16 pages, 1417 KiB

Open AccessReview

Resveratrol and Vascular Function

by Huige Li, Ning Xia, Solveig Hasselwander and Andreas Daiber

Int. J. Mol. Sci. 2019, 20(9), 2155; https://doi.org/10.3390/ijms20092155 - 30 Apr 2019

Cited by 157 | Viewed by 15014

Abstract

Resveratrol increases the production of nitric oxide (NO) in endothelial cells by upregulating the expression of endothelial NO synthase (eNOS), stimulating eNOS enzymatic activity, and preventing eNOS uncoupling. At the same time, resveratrol inhibits the synthesis of endothelin-1 and reduces oxidative stress in [...] Read more.

Resveratrol increases the production of nitric oxide (NO) in endothelial cells by upregulating the expression of endothelial NO synthase (eNOS), stimulating eNOS enzymatic activity, and preventing eNOS uncoupling. At the same time, resveratrol inhibits the synthesis of endothelin-1 and reduces oxidative stress in both endothelial cells and smooth muscle cells. Pathological stimuli-induced smooth muscle cell proliferation, vascular remodeling, and arterial stiffness can be ameliorated by resveratrol as well. In addition, resveratrol also modulates immune cell function, inhibition of immune cell infiltration into the vascular wall, and improves the function of perivascular adipose tissue. All these mechanisms contribute to the protective effects of resveratrol on vascular function and blood pressure in vivo. Sirtuin 1, AMP-activated protein kinase, and estrogen receptors represent the major molecules mediating the vascular effects of resveratrol. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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16 pages, 496 KiB

Open AccessReview

Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol for Autism Spectrum Disorder

by Rita Barone, Renata Rizzo, Giovanni Tabbì, Michele Malaguarnera, Richard E. Frye and Jean Bastin

Int. J. Mol. Sci. 2019, 20(8), 1878; https://doi.org/10.3390/ijms20081878 - 16 Apr 2019

Cited by 33 | Viewed by 7119

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by defective social communication and interaction and restricted, repetitive behavior with a complex, multifactorial etiology. Despite an increasing worldwide prevalence of ASD, there is currently no pharmacological cure to treat core symptoms of ASD. [...] Read more.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by defective social communication and interaction and restricted, repetitive behavior with a complex, multifactorial etiology. Despite an increasing worldwide prevalence of ASD, there is currently no pharmacological cure to treat core symptoms of ASD. Clinical evidence and molecular data support the role of impaired mitochondrial fatty acid oxidation (FAO) in ASD. The recognition of defects in energy metabolism in ASD may be important for better understanding ASD and developing therapeutic intervention. The nuclear peroxisome proliferator-activated receptors (PPAR) α, δ, and γ are ligand-activated receptors with distinct physiological functions in regulating lipid and glucose metabolism, as well as inflammatory response. PPAR activation allows a coordinated up-regulation of numerous FAO enzymes, resulting in significant PPAR-driven increases in mitochondrial FAO flux. Resveratrol (RSV) is a polyphenolic compound which exhibits metabolic, antioxidant, and anti-inflammatory properties, pointing to possible applications in ASD therapeutics. In this study, we review the evidence for the existing links between ASD and impaired mitochondrial FAO and review the potential implications for regulation of mitochondrial FAO in ASD by PPAR activators, including RSV. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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18 pages, 284 KiB

Open AccessReview

Resveratrol and Its Effects on the Vascular System

by Johannes M. Breuss, Atanas G. Atanasov and Pavel Uhrin

Int. J. Mol. Sci. 2019, 20(7), 1523; https://doi.org/10.3390/ijms20071523 - 27 Mar 2019

Cited by 206 | Viewed by 17595

Abstract

Resveratrol, the phenolic substance isolated initially from Veratrum grandiflorum and richly present in grapes, wine, peanuts, soy, and berries, has been attracting attention of scientists and medical doctors for many decades. Herein, we review its effects on the vascular system. Studies utilizing cell [...] Read more.

Resveratrol, the phenolic substance isolated initially from Veratrum grandiflorum and richly present in grapes, wine, peanuts, soy, and berries, has been attracting attention of scientists and medical doctors for many decades. Herein, we review its effects on the vascular system. Studies utilizing cell cultures and pre-clinical models showed that resveratrol alleviates oxidative stress and inflammation. Furthermore, resveratrol suppresses vascular smooth muscle cell proliferation, promotes autophagy, and has been investigated in the context of vascular senescence. Pre-clinical models unambiguously demonstrated numerous vasculoprotective effects of resveratrol. In clinical trials, resveratrol moderately diminished systolic blood pressure in hypertensive patients, as well as blood glucose in patients with diabetes mellitus. Yet, open questions remain, as exemplified by a recent report which states that the intake of resveratrol might blunt certain positive effects of exercise in older persons, and further research addressing the framework for long-term use of resveratrol as a food supplement, will stay in demand. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

27 pages, 3306 KiB

Open AccessReview

Progress to Improve Oral Bioavailability and Beneficial Effects of Resveratrol

by Adele Chimento, Francesca De Amicis, Rosa Sirianni, Maria Stefania Sinicropi, Francesco Puoci, Ivan Casaburi, Carmela Saturnino and Vincenzo Pezzi

Int. J. Mol. Sci. 2019, 20(6), 1381; https://doi.org/10.3390/ijms20061381 - 19 Mar 2019

Cited by 227 | Viewed by 10888

Abstract

Resveratrol (3,5,4′-trihydroxystilbene; RSV) is a natural nonflavonoid polyphenol present in many species of plants, particularly in grapes, blueberries, and peanuts. Several in vitro and in vivo studies have shown that in addition to antioxidant, anti-inflammatory, cardioprotective and neuroprotective actions, it exhibits antitumor properties. [...] Read more.

Resveratrol (3,5,4′-trihydroxystilbene; RSV) is a natural nonflavonoid polyphenol present in many species of plants, particularly in grapes, blueberries, and peanuts. Several in vitro and in vivo studies have shown that in addition to antioxidant, anti-inflammatory, cardioprotective and neuroprotective actions, it exhibits antitumor properties. In mammalian models, RSV is extensively metabolized and rapidly eliminated and therefore it shows a poor bioavailability, in spite it of its lipophilic nature. During the past decade, in order to improve RSV low aqueous solubility, absorption, membrane transport, and its poor bioavailability, various methodological approaches and different synthetic derivatives have been developed. In this review, we will describe the strategies used to improve pharmacokinetic characteristics and then beneficial effects of RSV. These methodological approaches include RSV nanoencapsulation in lipid nanocarriers or liposomes, nanoemulsions, micelles, insertion into polymeric particles, solid dispersions, and nanocrystals. Moreover, the biological results obtained on several synthetic derivatives containing different substituents, such as methoxylic, hydroxylic groups, or halogens on the RSV aromatic rings, will be described. Results reported in the literature are encouraging but require additional in vivo studies, to support clinical applications. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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17 pages, 833 KiB

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The Potential Beneficial Effects of Resveratrol on Cardiovascular Complications in Marfan Syndrome Patients–Insights from Rodent-Based Animal Studies

by Mitzi M. van Andel, Maarten Groenink, Aeilko H. Zwinderman, Barbara J.M. Mulder and Vivian de Waard

Int. J. Mol. Sci. 2019, 20(5), 1122; https://doi.org/10.3390/ijms20051122 - 5 Mar 2019

Cited by 22 | Viewed by 6192

Abstract

Marfan syndrome (MFS) patients are at risk for cardiovascular disease. In particular, for aortic aneurysm formation, which ultimately can result in a life-threatening aortic dissection or rupture. Over the years, research into a sufficient pharmacological treatment option against aortopathy has expanded, mostly due [...] Read more.

Marfan syndrome (MFS) patients are at risk for cardiovascular disease. In particular, for aortic aneurysm formation, which ultimately can result in a life-threatening aortic dissection or rupture. Over the years, research into a sufficient pharmacological treatment option against aortopathy has expanded, mostly due to the development of rodent disease models for aneurysm formation and dissections. Unfortunately, no optimal treatment strategy has yet been identified for MFS. The biologically-potent polyphenol resveratrol (RES), that occurs in nuts, plants, and the skin of grapes, was shown to have a positive effect on aortic repair in various rodent aneurysm models. RES demonstrated to affect aortic integrity and aortic dilatation. The beneficial processes relevant for MFS included the improvement of endothelial dysfunction, extracellular matrix degradation, and smooth muscle cell death. For the wide range of beneficial effects on these mechanisms, evidence was found for the following involved pathways; alleviating oxidative stress (change in eNOS/iNOS balance and decrease in NOX4), reducing protease activity to preserve the extracellular matrix (decrease in MMP2), and improving smooth muscle cell survival affecting aortic aging (changing the miR21/miR29 balance). Besides aortic features, MFS patients may also suffer from manifestations concerning the heart, such as mitral valve prolapse and left ventricular impairment, where evidence from rodent models shows that RES may aid in promoting cardiomyocyte survival directly (SIRT1 activation) or by reducing oxidative stress (increasing superoxide dismutase) and increasing autophagy (AMPK activation). This overview discusses recent RES studies in animal models of aortic aneurysm formation and heart failure, where different advantageous effects have been reported that may collectively improve the aortic and cardiac pathology in patients with MFS. Therefore, a clinical study with RES in MFS patients seems justified, to validate RES effectiveness, and to judge its suitability as potential new treatment strategy. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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14 pages, 1287 KiB

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Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

by Francesca De Amicis, Adele Chimento, Francesca Ida Montalto, Ivan Casaburi, Rosa Sirianni and Vincenzo Pezzi

Int. J. Mol. Sci. 2019, 20(5), 1087; https://doi.org/10.3390/ijms20051087 - 3 Mar 2019

Cited by 29 | Viewed by 6347

Abstract

Extensive research over the past 25 years in hormone-dependent cancers, such as breast cancer and prostate cancer, has identified the molecular mechanisms driven by steroid receptors, elucidating the interplay between genomic and non-genomic steroid receptors mechanism of action. Altogether, these mechanisms create the [...] Read more.

Extensive research over the past 25 years in hormone-dependent cancers, such as breast cancer and prostate cancer, has identified the molecular mechanisms driven by steroid receptors, elucidating the interplay between genomic and non-genomic steroid receptors mechanism of action. Altogether, these mechanisms create the specific gene expression programs that contribute to endocrine therapy resistance and cancer progression. These findings, on the bidirectional molecular crosstalk between steroid and growth factor receptors pathways in endocrine resistance, suggest the use of multi-target inhibitors together with endocrine therapies, for treating resistant disease. In this review we will discuss the novel understanding on the chemopreventive and anti-cancer activities of Resveratrol (3,5,4′-trihydroxy-stilbene) (RSV), a phytoalexin found in grapes acting on a plethora of targets. We will highlight Resveratrol effect on steroid receptors signalling and its potential use in the treatment of hormone-dependent cancer. Understanding the molecular mechanisms by which the bioactive compound influences cancer cell behaviour, by interfering with steroid receptors functional activity, will help to advance the design of combination strategies to increase the rate of complete and durable clinical response in patients. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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14 pages, 1179 KiB

Open AccessReview

Resveratrol as a Multifunctional Topical Hypopigmenting Agent

by Jung-Im Na, Jung-Won Shin, Hye-Ryung Choi, Soon-Hyo Kwon and Kyung-Chan Park

Int. J. Mol. Sci. 2019, 20(4), 956; https://doi.org/10.3390/ijms20040956 - 22 Feb 2019

Cited by 50 | Viewed by 8280

Abstract

Melanin is produced in melanocytes and stored in melanosomes, after which it is transferred to keratinocytes and, thus, determines skin color. Despite its beneficial sun-protective effects, abnormal accumulation of melanin results in esthetic problems. A range of topical hypopigmenting agents have been evaluated [...] Read more.

Melanin is produced in melanocytes and stored in melanosomes, after which it is transferred to keratinocytes and, thus, determines skin color. Despite its beneficial sun-protective effects, abnormal accumulation of melanin results in esthetic problems. A range of topical hypopigmenting agents have been evaluated for their use in the treatment of pigmentary disorders with varying degrees of success. Hydroquinone (HQ), which competes with tyrosine, is the main ingredient in topical pharmacological agents. However, frequent occurrence of adverse reactions is an important factor that limits its use. Thus, efforts to discover effective topical hypopigmenting agents with less adverse effects continue. Here, we describe the potential of resveratrol to function as an effective hypopigmenting agent based on its mechanism of action. Resveratrol is not only a direct tyrosinase inhibitor but an indirect inhibitor as well. Additionally, it can affect keratinocytes, which regulate the function of melanocytes. Resveratrol regulates the inflammatory process of keratinocytes and protects them from oxidative damage. In this way, it prevents keratinocyte-induced melanocyte stimulation. Furthermore, it has a rescuing effect on the stemness of interfollicular epidermal cells that can repair signs of photoaging in the melasma, a typical pigmentary skin disorder. Overall, resveratrol is a promising potent hypopigmenting agent. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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18 pages, 1564 KiB

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Resveratrol as a Tumor-Suppressive Nutraceutical Modulating Tumor Microenvironment and Malignant Behaviors of Cancer

by Youngjin Han, HyunA Jo, Jae Hyun Cho, Danny N. Dhanasekaran and Yong Sang Song

Int. J. Mol. Sci. 2019, 20(4), 925; https://doi.org/10.3390/ijms20040925 - 20 Feb 2019

Cited by 65 | Viewed by 6853

Abstract

Tumor-suppressive effects of resveratrol have been shown in various types of cancer. However, regulation of tumor microenvironment by resveratrol is still unclear. Recent findings suggest resveratrol can potentiate its tumor-suppressive effect through modulation of the signaling pathways of cellular components (fibroblasts, macrophages and [...] Read more.

Tumor-suppressive effects of resveratrol have been shown in various types of cancer. However, regulation of tumor microenvironment by resveratrol is still unclear. Recent findings suggest resveratrol can potentiate its tumor-suppressive effect through modulation of the signaling pathways of cellular components (fibroblasts, macrophages and T cells). Also, studies have shown that resveratrol can suppress malignant phenotypes of cancer cells acquired in response to stresses of the tumor microenvironment, such as hypoxia, oxidative stress and inflammation. We discuss the effects of resveratrol on cancer cells in stress environment of tumors as well as interactions between cancer cells and non-cancer cells in this review. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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28 pages, 1982 KiB

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The Effects of Resveratrol in Patients with Cardiovascular Disease and Heart Failure: A Narrative Review

by Garrison J. B. Dyck, Pema Raj, Shelley Zieroth, Jason R. B. Dyck and Justin A. Ezekowitz

Int. J. Mol. Sci. 2019, 20(4), 904; https://doi.org/10.3390/ijms20040904 - 19 Feb 2019

Cited by 138 | Viewed by 11943

Abstract

Cardiovascular disease (CVD) is the main cause of death globally and responsible for the second highest number of deaths in Canada. Medical advancements in the treatment of CVD have led to patients living longer with CVD but often progressing to another condition called [...] Read more.

Cardiovascular disease (CVD) is the main cause of death globally and responsible for the second highest number of deaths in Canada. Medical advancements in the treatment of CVD have led to patients living longer with CVD but often progressing to another condition called heart failure (HF). As a result, HF has emerged in the last decade as a major medical concern. Fortunately, various “traditional” pharmacotherapies for HF exist and have shown success in reducing HF-associated mortality. However, to augment the treatment of patients with CVD and/or HF, alternative pharmacotherapies using nutraceuticals have also shown promise in the prevention and treatment of these two conditions. One of these natural compounds considered to potentially help treat HF and CVD and prevent their development is resveratrol. Herein, we review the clinical findings of resveratrol’s ability to be used as an effective treatment to potentially help treat HF and CVD. This will allow us to gain a more fulsome appreciation for the effects of resveratrol in the health outcomes of specific patient populations who have various disorders that constitute CVD. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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15 pages, 652 KiB

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The Effects of Resveratrol in the Treatment of Metabolic Syndrome

by Chih-Yao Hou, You-Lin Tain, Hong-Ren Yu and Li-Tung Huang

Int. J. Mol. Sci. 2019, 20(3), 535; https://doi.org/10.3390/ijms20030535 - 28 Jan 2019

Cited by 103 | Viewed by 11544

Abstract

Resveratrol, also known as 3,5,4′-trihydroxystilbene, is a natural polyphenol that occurs as a phytoalexin. It is produced by plant sources such as grapes, apples, blueberries, plums, peanuts, and other oilseeds. This compound has a variety of effects on human health and diseases. This [...] Read more.

Resveratrol, also known as 3,5,4′-trihydroxystilbene, is a natural polyphenol that occurs as a phytoalexin. It is produced by plant sources such as grapes, apples, blueberries, plums, peanuts, and other oilseeds. This compound has a variety of effects on human health and diseases. This review summarizes the mounting evidence that resveratrol is helpful in treating metabolic syndrome and related disorders. Resveratrol can be provided either early as a reprogramming agent or later as part of treatment. A few of the main mechanisms underlying the beneficial effects of resveratrol on metabolic syndrome are outlined. This review also discusses the potential of resveratrol derivatives as a complementary or alternative medicine. In conclusion, resveratrol could be a useful regimen for the prevention and treatment of metabolic syndrome and its related conditions. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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12 pages, 534 KiB

Open AccessReview

Developmental Programming of the Metabolic Syndrome: Can We Reprogram with Resveratrol?

by You-Lin Tain and Chien-Ning Hsu

Int. J. Mol. Sci. 2018, 19(9), 2584; https://doi.org/10.3390/ijms19092584 - 31 Aug 2018

Cited by 35 | Viewed by 4268

Abstract

Metabolic syndrome (MetS) is a mounting epidemic worldwide. MetS can start in early life, in a microenvironment that is now known as the developmental origins of health and disease (DOHaD). The concept of DOHaD also offers opportunities for reprogramming strategies that aim to [...] Read more.

Metabolic syndrome (MetS) is a mounting epidemic worldwide. MetS can start in early life, in a microenvironment that is now known as the developmental origins of health and disease (DOHaD). The concept of DOHaD also offers opportunities for reprogramming strategies that aim to reverse programming processes in early life. Resveratrol, a polyphenolic compound has a wide spectrum of beneficial effects on human health. In this review, we first summarize the epidemiological and experimental evidence supporting the developmental programming of MetS. This review also presents an overview of the evidence linking different molecular targets of resveratrol to developmental programming of MetS-related disorders. This will be followed by studies documenting resveratrol as a reprogramming agent to protect against MetS-related disorders. Further clinical studies are required in order to bridge the gap between animal models and clinical trials in order to establish the effective dose and therapeutic duration for resveratrol as a reprogramming therapy on MetS disorders from developmental origins. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol)

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