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

Stilbenes are naturally occurring phytoalexins that generally exist as their more stable E isomers. The most well known natural stilbene is resveratrol (Res), firstly isolated in 1939 from roots of Veratrum grandiflorum (white hellebore) (1) and since then found in various edible plants, notably in Vitis vinifera L. (Vitaceae) (2). The therapeutic potential of Res covers a wide range of diseases, and multiple beneficial effects on human health such as antioxidant, anti-inflammatory and anti-cancer activities have been suggested based on several in vitro and animal studies (3). In particular, Res has been reported to be an inhibitor of carcinogenesis at multiple stages via its ability to inhibit cyclooxygenase, and is an anticancer agent with a role in antiangiogenesis (4). Moreover, both in vitro and in vivo studies showed that Res induces cell cycle arrest and apoptosis in tumor cells (4). However, clinical studies in humans evidenced that Res is rapidly absorbed after oral intake, and that the low level observed in the blood stream is caused by a fast conversion into metabolites that are readily excreted from the body (5). Thus, considerable efforts have gone in the design and synthesis of Res analogues with enhanced metabolic stability. Considering that reduced Res (dihydro- resveratrol, D-Res) conjugates may account for as much as 50% of an oral Res dose (5), and that D-Res has a strong proliferative effect on hormone-sensitive cancer cell lines such as breast cancer cell line MCF7 (6), we recently devoted our synthetic efforts to the preparation of trans-restricted analogues of Res in which the E carbon-carbon double bond is embedded into an imidazole nucleus. To keep the trans geometry, the two aryl rings were linked to the heteroaromatic core in a 1,3 fashion. Based on this design, we successfully prepared a variety of 1,4-, 2,4- and 2,5-diaryl substituted imidazoles including Res analogues 1, 2 and 3, respectively, by procedures that involve transition metal-catalyzed Suzuki-Miyaura cross-coupling reactions and highly selective N-H or C-H direct arylation reactions as key synthetic steps. The anticancer activity of compounds 1–3 was evaluated against the 60 human cancer cell lines panel of the National Cancer Institute (NCI, USA). The obtained results, that will be showed and discussed along with the protocols developed for the preparation of imidazoles 1–3, confirmed that a structural optimization of Res may provide analogues with improved potency in inhibiting the growth of human cancer cell lines in vitro when compared to their natural lead. (1) Takaoka,M.J.Chem.Soc.Jpn.1939,60,1090-1100. (2) Langcake, P.; Pryce, R. J. Physiological. Plant Patology 1976, 9, 77-86. (3) Vang, O.; et al. PLoS ONE 2011, 6, e19881. doi:10.1371/journal.pone.0019881 (4) Kraft, T. E.; et al. Critical Reviews in Food Science and Nutrition 2009, 49, 782-799. (5) Walle, T. Ann. N.Y. Acad. Sci. 2011, 1215, 9-15. doi: 10.1111/j.1749-6632.2010.05842.x (6) Gakh,A.A.;etal.Bioorg.Med.Chem.Lett.2010,20,6149-6151

Differentiated Effects of Allyl Isothiocyanate in Diabetic Rats: From Toxic to Beneficial Action

Allyl isothiocyanate (AITC), a constituent of Brassica family plants, has been reported to possess a high bioactivity in animal and human cells, showing ambiguous properties from adverse to beneficial ones. It was reported its genotoxic, carcinogenic, goitrogenic effects. On the other side, AITC has shown anti-cancer, cardioprotective, neuroprotective, and lately anti-obesity abilities. So far, its anti-diabetic effects are poorly explored. We tried to assess AITC action on carbohydrate, lipid and hormonal disorders in high fat diet-fed/streptozotocin diabetic rats. In this report, diabetic rats were treated intragastrically at doses 2.5, 5 and 25 mg/kg b.w./day of AITC for 2 weeks. Irrespectively of doses, AITC considerably lowered thyroid hormones (fT4, fT3), increased liver TG content, and also caused robust LDL-cholesterol and direct bilirubin concentration enhancement. Moreover, AITC at the highest dose caused pancreatic amylase and lipase drops and thyroid gland hypertrophy. AITC at 2.5 and 5 mg significantly reduced blood glucose levels along with robust beta-hydroxybutyric acid drop. Additionally, AITC at 5 mg improved insulin sensitivity (HOMA-IR index) in spite of reduced blood insulin. To conclude, despite amelioration of diabetic hyperglycemia by AITC, the adverse lipids and hormonal effects may exclude its use as a health-promoting compound in terms of anti-diabetic properties

Effect of some phytoestrogens on metabolism of rat adipocytes

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Resveratrol Affects Insulin Signaling in Type 2 Diabetic Goto-Kakizaki Rats

Resveratrol is a biologically active diphenolic compound exerting multiple beneficial effects in the organism, including anti-diabetic properties. This action is, however, not fully elucidated. In the present study, we examined effects of resveratrol on some parameters related to insulin signaling, and also on diabetes-associated dysregulation in Goto-Kakizaki (GK) rats with congenital type 2 diabetes. Resveratrol was given at the dose of 20 mg/kg b.w. for 10 weeks. It was shown that the expression and phosphorylation levels of insulin receptor in the skeletal muscle of GK rats were significantly decreased, compared with control animals. However, these changes were totally prevented by resveratrol. Liver expression of the insulin receptor was also reduced, but in this case, resveratrol was ineffective. Resveratrol was also demonstrated to significantly influence parameters of insulin binding (dissociation constant and binding capacity) in the skeletal muscle and liver. Moreover, it was shown that the expression levels of proteins related to intracellular glucose transport (GLUT4 and TUG) in adipose tissue of GK rats were significantly decreased. However, treatment with resveratrol completely abolished these changes. Resveratrol was found to induce normalization of TUG expression in the skeletal muscle. Blood levels of insulin and GIP were elevated, whereas proinsulin and GLP-1 diminished in GK rats. However, concentrations of these hormones were not affected by resveratrol. These results indicate that resveratrol partially ameliorates diabetes-associated dysregulation in GK rats. The most relevant finding covers the normalization of the insulin receptor expression in the skeletal muscle and also GLUT4 and TUG in adipose tissue

Resveratrol Affects Insulin Signaling in Type 2 Diabetic Goto-Kakizaki Rats

Resveratrol is a biologically active diphenolic compound exerting multiple beneficial effects in the organism, including anti-diabetic properties. This action is, however, not fully elucidated. In the present study, we examined effects of resveratrol on some parameters related to insulin signaling, and also on diabetes-associated dysregulation in Goto-Kakizaki (GK) rats with congenital type 2 diabetes. Resveratrol was given at the dose of 20 mg/kg b.w. for 10 weeks. It was shown that the expression and phosphorylation levels of insulin receptor in the skeletal muscle of GK rats were significantly decreased, compared with control animals. However, these changes were totally prevented by resveratrol. Liver expression of the insulin receptor was also reduced, but in this case, resveratrol was ineffective. Resveratrol was also demonstrated to significantly influence parameters of insulin binding (dissociation constant and binding capacity) in the skeletal muscle and liver. Moreover, it was shown that the expression levels of proteins related to intracellular glucose transport (GLUT4 and TUG) in adipose tissue of GK rats were significantly decreased. However, treatment with resveratrol completely abolished these changes. Resveratrol was found to induce normalization of TUG expression in the skeletal muscle. Blood levels of insulin and GIP were elevated, whereas proinsulin and GLP-1 diminished in GK rats. However, concentrations of these hormones were not affected by resveratrol. These results indicate that resveratrol partially ameliorates diabetes-associated dysregulation in GK rats. The most relevant finding covers the normalization of the insulin receptor expression in the skeletal muscle and also GLUT4 and TUG in adipose tissue

Effects of Allyl Isothiocyanate on Oxidative and Inflammatory Stress in Type 2 Diabetic Rats

Oxidative stress and inflammation play a crucial role in the pathogenesis and progression of diabetes. Currently, there is a growing need to exploit plant-derived bioactive compounds to support conventional therapies. The purpose of this study was to explore allyl isothiocyanate (AITC) potency in reducing oxidative and inflammatory stress along with its profitable modulation trace element status in pathological conditions such as diabetes. Two weeks of oral AITC treatments (2.5, 5, and 25 mg/kg body weight per day) were evaluated in Wistar rats with diabetes induced by a high-fat diet and streptozotocin. The study included AITC influence on antioxidant factors (SOD, CAT, GST, Nrf2), stress and inflammatory markers (cortisol, CRP, IL-1β, IL-6, TNFα, NF-κB), lipid peroxidation indices (TBARS, -SH groups), and trace element status (Fe, Zn, and Cu) in the detoxification and lymphoid organs. Independently of dose, AITC increased cortisol levels in rat blood serum and decreased total thiol groups (T-SH) and protein-bound thiol groups (PB-SH) collaterally with raised thiobarbituric acid reactive substances (TBARS) in diabetic rat liver. The inflammation and oxidative effects were enhanced by an AITC dose increase. The highest dose of AITC, 25 mg/kg b.w., strongly affected the inflammation process by increasing IL-6, IL-1β, and TNFα in the blood serum, and it upregulated Nrf2 transcription factor with increased SOD, GPx, and GST activities in the liver. AITC showed an equivocal effect on profitable modulation of disturbances in mineral homeostasis in the liver, kidney, and spleen. Our findings revealed that two-week AITC treatment exacerbated oxidative and inflammation status in diabetic rats

Dietary polyphenols and type 2 diabetes: Human study and clinical trials

IF 6.015 (2017)International audienceSignificant evidence from epidemiological investigations showed that dietary polyphenols might manage and prevent type 2 diabetes (T2D). This review summarizes human studies and clinical trials of polyphenols as anti-diabetic agents. Polyphenols from coffee, guava tea, whortleberry, olive oil, propolis, chocolate, red wine, grape seed, and cocoa have been reported to show anti-diabetic effects in T2D patients through increasing glucose metabolism, improving vascular function as well as reducing insulin resistance and HbA1c level. However, individual flavonoid or isoflavonoid compounds appear to have no therapeutic effect on diabetes, based on the limited clinical data. Preliminary clinical trials provided evidence that resveratrol had anti-diabetic activity in humans by improving glycemic control in subjects with insulin resistance. Besides, anthocyanins exhibited anti-diabetic properties by reducing blood glucose and HbA1c levels or the improvement of insulin secretion and resistance. The structure-activity relationship of polyphenols as anti-diabetic agents in humans has been rarely reported