Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

Background: Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingor, Denmark. Methodology: Literature search in databases as PubMed and ISI Web of Science in combination with manual search was used to answer the following five questions: 1 Can resveratrol be recommended in the prevention or treatment of human diseases?; 2 Are there observed ‘‘side effects’’ caused by the intake of resveratrol in humans?; 3 What is the relevant dose of resveratrol?; 4 What valid data are available regarding an effect in various species of experimental animals?; 5 Which relevant (overall) mechanisms of action of resveratrol have been documented? Conclusions/Significance: The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects.

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What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol

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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Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence.

Oxidative stress (OS) is considered as one of the etiologic factors involved in several signals and symptoms of inflammatory bowel diseases (IBD) that include diarrhea, toxic megacolon and abdominal pain. This systematic review discusses approaches, challenges and perspectives into the use of nontraditional antioxidant therapy on IBD, including natural and synthetic compounds in both human and animal models. One hundred and thirty four papers were identified, of which only four were evaluated in humans. Some of the challenges identified in this review can shed light on this fact: lack of standardization of OS biomarkers, absence of safety data and clinical trials for the chemicals and biological molecules, as well as the fact that most of the compounds were not repeatedly tested in several situations, including acute and chronic colitis. This review hopes to stimulate researchers to become more involved in this fruitful area, to warrant investigation of novel, alternative and efficacious antioxidant-based therapies.

Antioxidant therapy for treatment of inflammatory bowel disease: Does it work?

MicroRNAs (miRNAs) are an emerging class of gene expression modulators with relevant roles in several biological processes, including cell differentiation, development, apoptosis, and regulation of the cell cycle. Deregulation of those tiny RNA molecules has been described frequently as a major determinant for the initiation and progression of diseases, including cancer. Not only miRNAs but also the enzymes responsible for miRNA processing could be deregulated in cancer. In this review, we address the role of miRNAs in the pathogenesis of breast cancer, since there are oncogenic, tumor-suppressive, and metastatic-influencing miRNAs. Additionally, the different detection platforms and normalization strategies for miRNAs will be discussed. The major part of this review, however, will focus on the capability of miRNAs to act as diagnostic, predictive, or prognostic biomarkers. We will give an overview of their potential to correlate with response to or benefit from a given treatment and we will consider their ability to give information on prognosis in breast cancer. We will focus on miRNAs validated by more than one study or verified in independent cohorts or where results rely on preclinical as well as clinical evidence. As such, we will discuss their potential use in the personalized management of breast cancer.

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Dysregulation of microRNAs in breast cancer and their potential role as prognostic and predictive biomarkers in patient management.

Anti-oxidant effects of resveratrol on mice with DSS-induced ulcerative colitis.

Everolimus, an oral inhibitor of mammalian target of mTOR, has been recently shown to have antitumor effect in a phase III, double-blind, randomized trial (RADIANT-3) of 410 patients with advanced pancreatic neuroendocrine tumors (PNETs). The purpose of this study was to investigate the specific efficacy and safety of everolimus in the Chinese patient with PNETs. In this randomized phase II study, the analysis on Chinese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 44) and matching placebo (n = 35). The primary endpoint was progression-free survival (PFS). Adverse events were also examined. The median PFS was 15.47 months with everolimus [95 % confidence interval (CI) 10.52–26.37], as compared to 4.29 months with placebo (95 % CI 2.22–10.75), representing a 72 % reduction in the risk of progression or death (hazard ratio 0.27; 95 % CI 0.13–0.59; P < 0.001). Drug-associated adverse events (AEs) were mostly grade 1 or 2, observed in all 44 (100 %) patients receiving everolimus and in 29 (83 %) patients receiving placebo. The most common AEs (grade 1–4) associated with everolimus were rash (n = 38; 86 %), stomatitis (n = 30; 68 %), infections (n = 33; 75 %), epistaxis (n = 32; 73 %), pneumonitis (n = 27; 61 %) and anemia (n = 22; 50 %). Everolimus when compared with placebo is effectively in improving PFS in Chinese patients with PNETs.

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Retraction Note to: A randomized phase II study of everolimus for advanced pancreatic neuroendocrine tumors in Chinese patients

CONCLUSION: The therapeutic efficacy of resveratrol in UC is dose dependent and closely associated with the regulation of Treg/Th17 balance and the HIF-1α/mTOR signaling pathway

Effect of resveratrol on Treg/Th17 signaling and ulcerative colitis treatment in mice

Background: Baicalin is a bioactive ingredient extracted from the root of Scutellariae radix , which is used to treat ulcerative colitis (UC). Objective: We investigated the activity of baicalin on lipopolysaccharide-stimulated RAW264.7 cells and 2,4,6-trinitrobenzene sulfonic acid-induced rats, including the attenuation of oxidant stress and apoptosis. Materials and Methods: The severity of colitis was assessed by disease activity index. The activities of catalase (CAT), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), and the content of malondialdehyde (MDA) were determined by their corresponding kits. The terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was performed to study whether experimental colitis was associated with intestinal epithelial cell (IEC) apoptosis and the effect of baicalin on IEC apoptosis. Western blot analysis and immunocytochemistry assay were applied to determine the protein expressions. The reactive oxygen species (ROS) level in the colon of UC rats treated with baicalin was determined by ROS assay kit. Results: Baicalin remarkably upregulated the activities of CAT, GSH-PX, and SOD and decreased the content of MDA in a dose-dependent manner in vitro and in vivo . The TUNEL-positive cells in rats treated baicalin were remarkably reduced. Both Western blot analysis and immunocytochemistry assay indicated that baicalin significantly decreased the expressions of transforming growth factor beta-1, Bax protein and upregulated the expression of Bcl-2 protein. In addition, the expressions of total and cleaved caspase-3, total and cleaved caspase-9 protein, Fas, and FasL in vitro were downregulated by the treatment with baicalin. Baicalin of different doses reduced the generation of ROS in UC rats. Conclusion: Taken together, these evidences provide scientific basics for the application of baicalin in the treatment of UC and suggest that baicalin exerts its effect via suppression of oxidant stress and apoptosis. SUMMARY Baicalin remarkably upregulated the activities of catalase, glutathione peroxidase, and superoxide dismutase and decreased the content of MDA, both in vivo and in vitro The terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells in rats treated baicalin remarkably reduced in a concentration-dependent manner Western blot analysis and immunocytochemistry assay indicated that baicalin significantly decreased the expressions of transforming growth factor beta-1, Bax protein, and upregulated the expression of Bcl-2 protein The expressions of total and cleaved caspase-3, total and cleaved caspase-9 protein, Fas, and FasL in vitro were downregulated by the treatment with baicalin. Abbreviations used: UC: Ulcerative colitis, LPS: Lipopolysaccharide, TNBS: 2,4,6-trinitrobenzene sulfonic acid, DAI: Disease activity index, CAT: Catalase, GSH-PX: Glutathione peroxidase, SOD: Superoxide dismutase, MDA: Malondialdehyde, TUNEL: Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, ROS: Reactive oxygen species, IEC: Intestinal epithelial cell, SD: Sprague-Dawley, HE: H and E, DNTB: 5,5'-dithiobis-2-nitrobenzoic acid, TBA: Thiobarbituric acid, TBARS: Thiobarbituric acid-reactive substances, S.D: Standard deviation, and PBS: Phosphate-buffered saline.

Protective Effect of Baicalin Against Experimental Colitis via Suppression of Oxidant Stress and Apoptosis.

Nuclear factor- κB (NF- κB) plays a pivotal role in the regulation of immune and inflammatory responses. The real-time expression level of NF- κB reflects the development of ulcerative colitis (UC). Polydatin has vast pharmacological activities, including inhibiting the production of inflammatory mediators, inducing the production of antioxidants, regulating immune function, etc. The purpose of this study was to investigate the potential inhibitory effects of polydatin on NF- κB pathway activation in a mouse UC model. The results showed that polydatin treatment downregulated NF- κB p65 activity and expression, blocked the expression of TNF- α, IL-6 and IL-1 β at both mRNA and protein levels, decreased myeloperoxidase (MPO) activity, and alleviated inflammatory damage of colitis in mice with UC (p < 0.05), suggesting that the anti-inflammation effects of polydatin can be attributed, at least partially, to the blocking of the NF- κB pathway.

Jun Yao

Papers

Anti-oxidant effects of resveratrol on mice with DSS-induced ulcerative colitis.

Retraction Note to: A randomized phase II study of everolimus for advanced pancreatic neuroendocrine tumors in Chinese patients

Effect of resveratrol on Treg/Th17 signaling and ulcerative colitis treatment in mice

Protective Effect of Baicalin Against Experimental Colitis via Suppression of Oxidant Stress and Apoptosis.

Polydatin ameliorates DSS-induced colitis in mice through inhibition of nuclear factor-kappaB activation.