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Oligonol (OLG), derived from lychee fruit, is a novel compound produced from the oligomerization of polyphenols. In this study, the acute effect of OLG treatment was investigated on heart, liver and kidney in rats. OLG treatment at two different doses (15 or 30 mg/kg body weight) and two different time points (1 day or 7 days of treatment) demonstrated that no toxic effects were observed on heart, liver and renal functions. Moreover, OLG did not induce any DNA damage or oxidative stress as measured by 8-hydroxy-2'-deoxyguanosine levels in plasma. OLG supplementation increased the phosphorylation of myocardial endothelial nitric oxide (NO) level (p-eNOS) in both the treatment groups. Even the low dose OLG treatment (15mg/kg b.w) demonstrated an increase in p-eNOS/eNOS ratio after normalization of p-eNOS values with eNOS on day 1 (1.5-fold) and day 7 (2.2-fold) groups as compared to control. The above results suggest that OLG treatment increases endothelial NO levels and may play a role in NO-mediated vasodilatory effects without adverse side effects on cardiovascular function. This endothelial NO production may underlie the beneficial effect of OLG in cardiovascular health.

Oligonol was orally administered at 10 or 20 mg/kg body weight per d for 8 weeks to db/db mice with type 2 diabetes, and its effects were compared with those of the vehicle in db/db and m/m (misty, non-diabetic) mice. Serum and renal biochemical factors, protein expressions related to lipid metabolism and inflammation, and advanced glycation endproducts were measured. There were significant reductions in the serum lipid concentration, reactive oxygen species (ROS) and lipid peroxidation, as well as improvements in renal function parameters. In addition, oligonol treatment significantly decreased ROS levels and lipid peroxidation in the kidney. In particular, the renal lipid contents such as TAG and total cholesterol were significantly reduced in the oligonol-administered groups through the up-regulation of PPARα and down-regulation of sterol regulatory element-binding protein-1 in db/db mice. Moreover, oligonol inhibited non-fluorescent AGE formation and their receptor expression, suggesting that it could effectively inhibit AGE development caused by oxidative stress and/or dyslipidaemia in the kidney of db/db mice. Furthermore, augmented expressions of NF-κBp65, cyclo-oxygenase-2 and inducible NO synthase were down-regulated to the levels of m/m mice in the group given oligonol at 20 mg/kg. This means that oligonol would act as a regulator in the inflammatory response of type 2 diabetes. The present results suggest that oligonol could have renoprotective effects against abnormal lipid metabolism and ROS-related AGE formation in type 2 diabetes.

Macrophage infiltration of white adipose tissue (WAT) is implicated in the metabolic complications of obesity. In addition, inflammatory changes through dysregulated expression of inflammation-related adipokines such as tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) in WAT are considered to be one of the causes of insulin resistance. Recently, enhanced oxidative stress in adipocytes has been reported to be implicated in dysregulated expression of inflammation-related adipokines. Polyphenols are well known as potent natural antioxidants in the diet. In the present study, we investigated the antioxidative effects of an oligomerized grape seed polyphenol (OGSP) on inflammatory changes in coculture of adipocytes and macrophages. Coculture of HW mouse white adipocytes and RAW264 mouse macrophages markedly increased the production of TNF-alpha, MCP-1 and plasminogen activator inhibitor-1 compared with control culture. Treatment of HW cells with OGSP significantly attenuated the dysregulated production of adipokines. Moreover, OGSP significantly suppressed coculture-induced production of reactive oxygen species (ROS). Although enhanced release of free fatty acids (FFAs) by coculture was not altered by OGSP, FFA-induced ROS production in HW cells was significantly attenuated by OGSP. Furthermore, OGSP significantly reduced increases in the transcriptional activity of nuclear factor-kappaB and activation of extracellular signal-regulated kinase by coculture. Thus, these results suggest that the antioxidative properties of OGSP attenuate inflammatory changes induced by the coculture of adipocytes and macrophages.

In this study we investigated the antioxidative effects of Oligonol (Amino Up Chemical Co., Ltd., Sapporo, Japan), a new polyphenol, in adipocytes. The levels of reactive oxygen species (ROS) and the expression of adipokine genes decreased in HW mouse white adipocytes upon treatment with Oligonol as compared to control cells. The transcriptional activity of nuclear factor-kappaB (NF-kappaB) and the activation of extracellular signal-regulated kinase (ERK) 1/2 were also down-regulated by Oligonol. In addition, when C57BL/6J mice were fed a high fat diet (HFD) for 5 weeks, the levels of epididymal white adipose tissue (WAT) mass and lipid peroxidation in WAT both increased, but Oligonol intake clearly inhibited such HFD-induced increases. Furthermore, dysregulated expression of genes for adipokines in WAT of mice fed solely a HFD was attenuated by Oligonol intake. These results suggest that Oligonol has antioxidative effects and that it attenuates HFD-induced dysregulated expression of genes for adipokines in adipocytes.

Controlled acid-catalyzed degradation of proanthocyanidin polymers in grape seeds together with L-cysteine led to oligomeric proanthocyanidin-L-cysteine complexes along with monomeric flavan-3-ol derivatives being isolated, and their structures were confirmed on the basis of spectroscopic data and by chemical means. In addition, comparative studies on the antioxidative and survival effects of oligomeric proanthocyanidin-L-cysteine complexes and proanthocyanidin polymers were performed. The oligomeric proanthocyanidin-L-cysteine complexes showed higher bioavailability and antioxidant capacity and enhanced survival time in the animal test groups. In addition, it is suggested that the oligomeric complexes may help to prevent oxidative stress and may reduce free radical production.

Abstract: Potassium bromate (KBrO3) is a by-product from ozonation of high-bromide surface water for production of drinking water and is a rodent carcinogen. Oligonol is a product emanating from the oligomerization of polyphenols, typically proanthocyanidin from a variety of fruits (grapes, apples, persimmons, etc.) and contains catechin-type monomers and proanthocyanidin oligomers. In this study, the ability of oligonol derived from grape seeds, grape seeds extracts (Product A, containing biologically active flavonoids and the oligomeric proanthocyanidin) and pine bark extracts (Product B, composed of flavan-3-ol derivatives) to modulate the KBrO3-induced renal toxicity was compared with (+) catechin and (−)-epigallocatechin 3-O-gallate (EGCG). In the Trolox equivalent antioxidant capacity (TEAC) assay, the order of the antioxidant activity was EGCG>catechin>oligonol>Product A>Product B. However, oligonol elicits the strongest antioxidant capacity following in vivo supplementation to rats, with the order of efficacy of oligonol>Product A≥Product B>EGCG>catechin. Blood levels of lipid peroxidation products (LPO), urea nitrogen (BUN) and creatinine were elevated by KBrO3 treatment. Oligonol significantly restored LPO to the level in the untreated rats and had the strongest potency when compared with the effects of Products A and B. The five materials lowered KBrO3-induced BUN level, but this was not statistically significant. Oligonol significantly reduced the increased level of the creatinine, seconded by Product A, Product B and EGCG. Catechin had the lowest effect in both the BUN and creatinine levels. That oligonol was able to modulate KBrO3-induced lipid peroxidation and the levels of blood urea nitrogen and creatinine suggests potential chemopreventive function and application in mitigating toxicity due to long-term exposure to KBrO3 in public drinking water. [Copyright &y& Elsevier]

Abstract: Plant polyphenols possess anti-oxidant and anti-inflammatory activities and are hence potential candidates for preventing cancer. The present study was aimed at evaluating the anti-inflammatory and anti-tumor promoting activity of oligonol, a formulation of catechin-type oligomers, in mouse skin stimulated with a proto-type tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Pretreatment of mouse skin with oligonol significantly inhibited TPA-induced expression of cyclooxygenase-2 (COX-2). Oligonol diminished nuclear translocation and DNA binding of nuclear factor-kappaB (NF-κB) via blockade of phosphorylation and subsequent degradation of IκBα in TPA-treated mouse skin. Moreover, oligonol suppressed TPA-induced DNA binding of CCAAT/enhancer-binding protein (C/EBP) in mouse skin. Oligonol pretreatment also attenuated the phosphorylation and/or catalytic activities of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and p38 mitogen-activated protein (MAP) kinase. Moreover, p38 MAP kinase inhibitor SB203580, but not the MEK inhibitor U0126, negated TPA-induced DNA binding of C/EBP. In addition, oligonol reduced the incidence and the multiplicity of papillomas and squamous cell carcinomas in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and TPA-promoted mouse skin, and prolonged the survival of tumor-bearing mice. Pretreatment with oligonol diminished the levels of proliferating cell nuclear antigen and expression of COX-2 in papillomas and carcinomas, respectively, as compared to DMBA plus TPA treatment alone. Taken together, the above findings suggest that oligonol inhibits TPA-induced COX-2 expression by blocking the activation of NF-κB and C/EBP via modulation of MAP kinases and suppresses chemically induced mouse skin tumorigenesis. [Copyright &y& Elsevier]