BBA - Molecular Basis of Disease (v.1852, #6)

The pharmacology of resveratrol in animals and humans by Eun-Jung Park; John M. Pezzuto (1071-1113).
In addition to thousands of research papers related to resveratrol (RSV), approximately 300 review articles have been published. Earlier research tended to focus on pharmacological activities of RSV related to cardiovascular systems, inflammation, and carcinogenesis/cancer development. More recently, the horizon has been broadened by exploring the potential effect of RSV on the aging process, diabetes, neurological dysfunction, etc. Herein, we primarily focus on the in vivo pharmacological effects of RSV reported over the past 5 years (2009–2014). In addition, recent clinical intervention studies performed with resveratrol are summarized. Some discrepancies exist between in vivo studies with animals and clinical studies, or between clinical studies, which are likely due to disparate doses of RSV, experimental settings, and subject variation. Nevertheless, many positive indications have been reported with mammals, so it is reasonable to advocate for the conduct of more definitive clinical studies. Since the safety profile is pristine, an added advantage is the use of RSV as a dietary supplement. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Keywords: Resveratrol; Animal study; Clinical trial; Pharmacological activity;

The molecular targets of resveratrol by Sameer S. Kulkarni; Carles Cantó (1114-1123).
Resveratrol has emerged in recent years as a compound conferring strong protection against metabolic, cardiovascular and other age-related complications, including neurodegeneration and cancer. This has generated the notion that resveratrol treatment acts as a calorie-restriction mimetic, based on the many overlapping health benefits observed upon both interventions in diverse organisms, including yeast, worms, flies and rodents. Though studied for over a decade, the molecular mechanisms governing the therapeutic properties of resveratrol still remain elusive. Elucidating how resveratrol exerts its effects would provide not only new insights in its fundamental biological actions but also new avenues for the design and development of more potent drugs to efficiently manage metabolic disorders. In this review we will cover the most recent advances in the field, with special focus on the metabolic actions of resveratrol and the potential role of SIRT1 and AMPK. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Keywords: Resveratrol; SIRT1; AMPK; Metabolism; Mitochondria;

Resveratrol and inflammation: Challenges in translating pre-clinical findings to improved patient outcomes by Morten Møller Poulsen; Karen Fjeldborg; Marie Juul Ornstrup; Thomas Nordstrøm Kjær; Mark Klitgaard Nøhr; Steen Bønløkke Pedersen (1124-1136).
Throughout the Western world obesity prevalence is steadily increasing, and associated metabolic co-morbidities are projected to rise during the years to come. As weight loss and weight maintenance remains a major problem, new strategies to protect against obesity-related morbidity are needed. There is a clear association between obesity, low-grade inflammation and obesity-associated diseases, thus, the development of new anti-inflammatory substances is urgently needed as these may ultimately pave the way for novel treatments of obesity and lifestyle-related diseases. A candidate molecule is the polyphenolic compound resveratrol, and in the present review, we provide an overview of the field, and discuss the future scientific perspectives. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Keywords: Resveratrol; Inflammation; Metabolism; In vitro; In vivo; Clinical trial;

Resveratrol and obesity: Can resveratrol relieve metabolic disturbances? by Marlies de Ligt; Silvie Timmers; Patrick Schrauwen (1137-1144).
There is an increasing need for novel preventive and therapeutic strategies to combat obesity and related metabolic disorders. In this respect, the natural polyphenol resveratrol has attracted significant interest. Animal studies indicate that resveratrol mimics the effects of calorie restriction via activation of sirtuin 1 (SIRT1). SIRT1 is an important player in the regulation of cellular energy homeostasis and mitochondrial biogenesis. Rodent studies have shown beneficial effects of resveratrol supplementation on mitochondrial function, glucose metabolism, body composition and liver fat accumulation. However, confirmation of these beneficial effects in humans by placebo-controlled clinical trials remains relatively limited. This review will give an overview of pre-clinical and clinical studies examining the effects of resveratrol on obesity-induced negative health outcomes. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Keywords: Resveratrol; Sirtuin; Obesity; Type 2 diabetes; Mitochondria;

Resveratrol and diabetes: from animal to human studies by Tomasz Szkudelski; Katarzyna Szkudelska (1145-1154).
Diabetes mellitus is a serious disease affecting about 5% of people worldwide. Diabetes is characterized by hyperglycemia and impairment in insulin secretion and/or action. Moreover, diabetes is associated with metabolic abnormalities and serious complications. Resveratrol is a natural, biologically active polyphenol present in different plant species and known to have numerous health-promoting effects in both animals and humans. Anti-diabetic action of resveratrol has been extensively studied in animal models and in diabetic humans. In animals with experimental diabetes, resveratrol has been demonstrated to induce beneficial effects that ameliorate diabetes. Resveratrol, among others, improves glucose homeostasis, decreases insulin resistance, protects pancreatic β-cells, improves insulin secretion and ameliorates metabolic disorders. Effects induced by resveratrol are strongly related to the capability of this compound to increase expression/activity of AMPK and SIRT1 in various tissues of diabetic subjects. Moreover, anti-oxidant and anti-inflammatory effects of resveratrol were shown to be also involved in its action in diabetic animals.Preliminary clinical trials show that resveratrol is also effective in type 2 diabetic patients. Resveratrol may, among others, improve glycemic control and decrease insulin resistance. These results show that resveratrol holds great potential to treat diabetes and would be useful to support conventional therapy. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clincial findigns to improved patient outcomes.
Keywords: Resveratrol; Diabetes; Insulin; Metabolism;

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases by Beshay N.M. Zordoky; Ian M. Robertson; Jason R.B. Dyck (1155-1177).
Cardiovascular disease is the leading cause of death worldwide. Despite advancements in diagnosis and treatment of cardiovascular disease, the incidence of cardiovascular disease is still rising. Therefore, new lines of medications are needed to treat the growing population of patients with cardiovascular disease. Although the majority of the existing pharmacotherapies for cardiovascular disease are synthesized molecules, natural compounds, such as resveratrol, are also being tested. Resveratrol is a non-flavonoid polyphenolic compound, which has several biological effects. Preclinical studies have provided convincing evidence that resveratrol has beneficial effects in animal models of hypertension, atherosclerosis, stroke, ischemic heart disease, arrhythmia, chemotherapy-induced cardiotoxicity, diabetic cardiomyopathy, and heart failure. Although not fully delineated, some of the beneficial cardiovascular effects of resveratrol are mediated through activation of silent information regulator 1 (SIRT1), AMP-activated protein kinase (AMPK), and endogenous anti-oxidant enzymes. In addition to these pathways, the anti-inflammatory, anti-platelet, insulin-sensitizing, and lipid-lowering properties of resveratrol contribute to its beneficial cardiovascular effects. Despite the promise of resveratrol as a treatment for numerous cardiovascular diseases, the clinical studies for resveratrol are still limited. In addition, several conflicting results from trials have been reported, which demonstrates the challenges that face the translation of the exciting preclinical findings to humans. Herein, we will review much of the preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular disease and provide information about the physiological and molecular signaling mechanisms involved. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Keywords: Resveratrol; Cardiovascular disease;

Resveratrol and cancer: Challenges for clinical translation by Chandra K. Singh; Mary A. Ndiaye; Nihal Ahmad (1178-1185).
Significant work has been done towards identifying the health-beneficial effects of the grape antioxidant resveratrol in a variety of bioassay- and disease- models, with much research being focused on its possible application to cancer management. Despite the large number of preclinical studies dealing with different aspects of the biological effects of resveratrol, its translation to clinics is far from reality due to a variety of challenges. In this review, we discuss the issues and questions associated with resveratrol becoming an effective in vivo anticancer drug, from basic metabolic issues to the problems faced by incomplete understanding of the mechanism(s) of action in the body. We also explore efforts taken by researchers, both public and private, to contend with some of these issues. By examining the published data and previous clinical trials, we have attempted to identify the problems and issues that hinder the clinical translation of resveratrol for cancer management. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Keywords: Resveratrol; Cancer; Clinical trial;

Osteoporosis is a major public health issue that is expected to rise as the global population ages. Resveratrol (RES) is a plant polyphenol with various anti-aging properties. RES treatment of bone cells results in protective effects, but dose translation from in vitro studies to clinically relevant doses is limited since bioavailability is not taken into account. The aims of this review is to evaluate in vivo evidence for a role of RES supplementation in promoting bone health to reduced osteoporosis risk and potential mechanisms of action. Due to multiple actions on both osteoblasts and osteoclasts, RES has potential to attenuate bone loss resulting from different etiologies and pathologies. Several animal models have investigated the bone protective effects of RES supplementation. Ovariectomized rodent models of rapid bone loss due to estrogen-deficiency reported that RES supplementation improved bone mass and trabecular bone without stimulating other estrogen-sensitive tissues. RES supplementation prior to age-related bone loss was beneficial. The hindlimb unloaded rat model used to investigate bone loss due to mechanical unloading showed RES supplementation attenuated bone loss in old rats, but had inconsistent bone effects in mature rats. In growing rodents, RES increased longitudinal bone growth, but had no other effects on bone. In the absence of human clinical trials, evidence for a role of RES on bone heath relies on evidence generated by animal studies. A better understanding of efficacy, safety, and molecular mechanisms of RES on bone will contribute to the determination of dietary recommendations and therapies to reduce osteoporosis. This article is part of a Special Issue entitled: Resveratol: Challenges in translating pre-clinical findings to improved patient outcomes.Display Omitted
Keywords: Resveratrol; Bone mass; Ovariectomized; Mechanical unloading; Osteoblast; Osteoclast;

Neuroprotective action of resveratrol by Stéphane Bastianetto; Caroline Ménard; Rémi Quirion (1195-1201).
Low-to-moderate red wine consumption appeared to reduce age-related neurological disorders including macular degeneration, stroke, and cognitive deficits with or without dementia. Resveratrol has been considered as one of the key ingredients responsible for the preventive action of red wine since the stilbene displays a neuroprotective action in various models of toxicity. Besides its well documented free radical scavenging and anti-inflammatory properties, resveratrol has been shown to increase the clearance of beta-amyloid, a key feature of Alzheimer's disease, and to modulate intracellular effectors associated with oxidative stress (e.g. heme oxygenase), neuronal energy homeostasis (e.g. AMP kinase), program cell death (i.e. AIF) and longevity (i.e. sirtuins). This article summarizes the most recent findings on mechanisms of action involved in the protective effects of this multi target polyphenol, and discusses its possible roles in the prevention of various age-related neurological disorders. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.Display Omitted
Keywords: Polyphenol; Alzheimer's disease; Amyloid; Ischemia; SIRT-1; Kinase;

Roles of resveratrol and other grape-derived polyphenols in Alzheimer's disease prevention and treatment by Giulio Maria Pasinetti; Jun Wang; Lap Ho; Wei Zhao; Lauren Dubner (1202-1208).
Alzheimer's disease (AD) is a devastating disorder that strikes 1 in 10 Americans over the age of 65, and almost half of all Americans over 85 years old. The odds of an individual developing AD double every five years after the age of 65. While it has become increasingly common to meet heart attack or cancer survivors, there are no AD survivors. There is mounting evidence that dietary polyphenols, including resveratrol, may beneficially influence AD. Based on this consideration, several studies reported in the last few years were designed to validate sensitive and reliable translational tools to mechanistically characterize brain bioavailable polyphenols as disease-modifying agents to help prevent the onset of AD dementia and other neurodegenerative disorders. Several research groups worldwide with expertise in AD, plant biology, nutritional sciences, and botanical sciences have reported very high quality studies that ultimately provided the necessary information showing that polyphenols and their metabolites, which come from several dietary sources, including grapes, cocoa etc., are capable of preventing AD. The ultimate goal of these studies was to provide novel strategies to prevent the disease even before the onset of clinical symptoms. The studies discussed in this review article provide support that the information gathered in the last few years of research will have a major impact on AD prevention by providing vital knowledge on the protective roles of polyphenols, including resveratrol. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Keywords: Resveratrol; Alzheimer's disease; Polyphenol; SIRT1;

Lifespan and healthspan extension by resveratrol by Khushwant S. Bhullar; Basil P. Hubbard (1209-1218).
A number of small molecules with the ability to extend the lifespan of multiple organisms have recently been discovered. Resveratrol, amongst the most prominent of these, has gained widespread attention due to its ability to extend the lifespan of yeast, worms, and flies, and its ability to protect against age-related diseases such as cancer, Alzheimer's, and diabetes in mammals. In this review, we discuss the origins and molecular targets of resveratrol and provide an overview of its effects on the lifespan of simple model organisms and mammals. We also examine the unique ability of resveratrol to extend the healthy years, or healthspan, of mammals and its potential to counteract the symptoms of age-related disease. Finally, we explore the many scientific, medical, and economic challenges faced when translating these findings to the clinic, and examine potential approaches for realizing the possibility of human lifespan extension. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Keywords: Lifespan extension; Healthspan extension; Disease prevention; Resveratrol; Sirtuin activating compounds; Clinical trials;