Many polyphenols that contain more than two phenolic hydroxyl groups are natural antioxidants and can provide health benefits to humans. These polyphenols include, for example, oleuropein, hydroxytyrosol, catechin, chlorogenic acids, hesperidin, nobiletin, and isoflavones. These have been studied widely because of their strong radical-scavenging and antioxidative effects. These effects may contribute to the prevention of diseases, such as diabetes. Insulin secretion, insulin resistance, and homeostasis are important factors in the onset of diabetes, a disease that is associated with dysfunction of pancreatic β-cells. Oxidative stress is thought to contribute to this dysfunction and the effects of antioxidants on the pathogenesis of diabetes have, therefore, been investigated. Here, we summarize the antioxidative effects of polyphenols from the perspective of their radical-scavenging activities as well as their effects on signal transduction pathways. We also describe the preventative effects of polyphenols on diabetes by referring to recent studies including those reported by us. Appropriate analytical approaches for evaluating antioxidants in studies on the prevention of diabetes are comprehensively reviewed.

Recently, the biological roles of lipid peroxidation products have received a great deal of attention not only for elucidating pathological mechanisms but also for practical clinical applications as biomarkers. In the last 50 years, lipid peroxidation has been the subject of extensive studies from the viewpoints of mechanisms, dynamics, product analysis, involvement in diseases, inhibition, and biological signaling. Lipid hydroperoxides are formed as major primary products, but they are substrates for various enzymes and they also undergo various secondary reactions. During this decade, hydroxyoctadecadienoic acid from linoleates, F2-isoprostanes from arachidonates, and neuroprostanes from docosahexanoates have been proposed as biomarkers for evaluating oxidative stress in vivo and its related diseases. The implications of lipid peroxidation products in vivo will be briefly reviewed and their practical applications will be discussed.

Breakthroughs in biochemistry have furthered our understanding of the onset and progression of various diseases, and have advanced the development of new therapeutics. Oxidative stress and reactive oxygen species (ROS) are ubiquitous in biological systems. ROS can be formed non-enzymatically by chemical, photochemical and electron transfer reactions, or as the byproducts of endogenous enzymatic reactions, phagocytosis, and inflammation. Imbalances in ROS homeostasis, caused by impairments in antioxidant enzymes or non-enzymatic antioxidant networks, increase oxidative stress, leading to the deleterious oxidation and chemical modification of biomacromolecules such as lipids, DNA, and proteins. While many ROS are intracellular signaling messengers and most products of oxidative metabolisms are beneficial for normal cellular function, the elevation of ROS levels by light, hyperglycemia, peroxisomes, and certain enzymes causes oxidative stress-sensitive signaling, toxicity, oncogenesis, neurodegenerative diseases, and diabetes. Although the underlying mechanisms of these diseases are manifold, oxidative stress caused by ROS is a major contributing factor in their onset. This review summarizes the relationship between ROS and oxidative stress, with special reference to recent advancements in the detection of biomarkers related to oxidative stress. Further, we will introduce biomarkers for the early detection of neurodegenerative diseases and diabetes, with a focus on our recent work.

Current diagnostic tests such as glycemic indicators have limitations for early detection of impaired glucose tolerance (IGT), which leads to diabetes. Oxidative stress induced by various oxidants in a random and destructive manner is considered to play an important role in the pathophysiology of a number of human disorders and diseases such as impaired glucose tolerance. We have developed an improved method for the measurement of in vivo lipid peroxidation, where the presence of 8-iso-prostaglandin F2α (8-iso-PGF2α), hydroxyoctadecadienoic acids (HODEs), hydroxyeicosatetraenoic acids (HETEs), and 7-hydroxycholesterol (7-OHCh), as well as their parent molecules, linoleic acid (LA) and cholesterol (Ch), was determined by performing LC-MS/MS (for 8-iso-PGF2α, HODE, and HETE) and GC-MS (for 7-OHCh, LA, and Ch) after reduction with triphenyl phosphine and saponification by potassium hydroxide. We then applied this method to volunteers (n = 57), including normal type (n = 43), “high-normal” (fasting plasma glucose, 100–109 mg/dL, n = 7), pre-diabetic type (IGT, n = 5), and diabetic type (n = 2) subjects who are diagnosed by performing oral glucose tolerance tests (OGTTs). Several biomarkers in plasma, such as insulin, leptin, adiponectin, interleukin-6, tumor necrosis factor-α, high sensitivity-C-reactive protein, HbA1c, and glucose levels were measured during OGTT. We found that the fasting levels of (10- and 12-(Z,E)- HODE)/LA increased significantly with increasing levels of HbA1c and glucose during OGTT and with insulin secretion and resistance index. In conclusion, 10- and 12-(Z,E)-HODE may be prominent biomarkers for the early detection of IGT and “high-normal” type without OGTT.

A relationship between type 2 diabetes mellitus (T2DM) and intestinal flora has been suggested since development of analysis technology for intestinal flora. An animal model of T2DM is important for investigation of T2DM. Although there are some animal models of T2DM, a comparison of the intestinal flora of healthy animals with that of T2DM animals has not yet been reported. The intestinal flora of Tsumura Suzuki Obese Diabetes (TSOD) mice was compared with that of Tsumura, Suzuki, Non Obesity (TSNO) mice in the present study. The TSOD mice showed typical type 2 diabetes symptoms, which were high-fat diet-independent. The TSOD and the TSNO mouse models were derived from the same strain, ddY. In this study, we compared the intestinal flora of TSOD mice with that if TSNO mice at 5 and 12 weeks of age. We determined that that the number of operational taxonomic units (OTUs) was significantly higher in the cecum of TSOD mice than in that of TSNO mice. The intestinal flora of the cecum and that of the feces were similar between the TSNO and the TSOD strains. The dominant bacteria in the cecum and feces were of the phyla Firmicutes and Bacteroidetes. However, the content of some bacterial species varied between the two strains. The percentage of Lactobacillus spp. within the general intestinal flora was higher in TSOD mice than in TSNO mice. In contrast, the percentages of order Bacteroidales and family Lachnospiraceae were higher in TSNO mice than in TSOD mice. Some species were observed only in TSOD mice, such as genera Turicibacter and SMB53 (family Clostridiaceae), the percentage of which were 3.8% and 2.0%, respectively. Although further analysis of the metabolism of the individual bacteria in the intestinal flora is essential, genera Turicibacter and SMB53 may be important for the abnormal metabolism of type 2 diabetes.

A membrane-type adsorbent of spinel-type manganese oxide was prepared by a solvent exchange method using poly(vinyl chloride) (PVC) as a binder. PVC was dissolved in N,N-dimethylformamide (DMF) solution, after which spinel-type lithium manganese oxide was mixed with the DMF solution. The suspension was spread into a thin film and immersed in water to solidify the PVC. The membrane was treated with an HCl solution to extract lithium, resulting in a membrane-type adsorbent. The preparation conditions were studied by changing the initial PVC concentration versus DMF and lithium manganese oxide content. The membrane thickness, manganese oxide content, and tensile and abrasion strengths were measured for each membrane. A new type of adsorption cell was designed for obtaining a parallel seawater flow along the membrane-type adsorbents. The lithium adsorption experiment was carried out using natural seawater at a linear velocity of 1.25 cm/min. Placing the membrane between spacers was found to be effective in raising the lithium adsorption rate. The adsorption rate depended on the preparation conditions. The membrane prepared from an initial PVC concentration of 8%, and a PVC additive content of 20% is optimum for the adsorption of lithium in seawater. The adsorbed lithium could be easily eluted by treating with an HCl solution.

1Oleuropein, a phenolic compound found in abundance in olive leaves, has 2 beneficial effects on various diseases. However, it is unknown whether an oleuropein-rich 3 diet is efficacious against type 2 diabetic phenotypes. In this study, we investigated the 4 effects of the oleuropein-containing supplement OPIACE, whose oleuropein content 5 exceeds 35% (w/w), on the diabetic phenotypes in type 2 diabetes model Tsumura Suzuki 6 Obese Diabetes (TSOD) mouse. TSOD mice were fed OPIACE at 4 weeks of age, i.e., 7 before the TSOD mice exhibited diabetic phenotypes. We revealed that OPIACE attenuated 8 hyperglycemia and impaired glucose tolerance in TSOD mice over the long term (from 10 9 to 24 weeks of age), but had no effect on obesity. Furthermore, we demonstrated that 10 OPIACE mildly reduced oxidative stress in TSOD mice by 26.2%, and attenuated 11 anxiety-like behavioral abnormality in aged TSOD mice. The results suggest that 12 oleuropein suppresses the progression of type 2 diabetes and diabetes-related behavioral 13 abnormality over the long term. 14 15 ACS Paragon Plus Environment Journal of Agricultural and Food Chemistry mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes 328 to Alzheimer disease. Diabetes 2014, 63, 2262-2272.329 8. Santiago, J. A.; Potashkin, J. A., System-based approaches to decode the 330 molecular links in Parkinson's disease and diabetes. Neurobiol. Dis. 2014, 72PA, 84-91. 331 9 Siddiqui, S., Depression in type 2 diabetes mellitus--a brief review. Diabetes 332 Metab. Syndr. 2014, 8, 62-65. 333 10. Collins, M. M.; Corcoran, P.; Perry, I. J., Anxiety and depression symptoms in 334 patients with diabetes. Diabet. Med. 2009, 26, 153-161. 335 Page 17 of 32 ACS Paragon Plus Environment Journal of Agricultural and Food Chemistry Hodgkinson, S. C.; Hofman, P. L.; Cutfield, W. S., Olive (Olea europaea L.) leaf 392 polyphenols improve insulin sensitivity in middle-aged overweight men: a randomized, 393 placebo-controlled, crossover trial. PLoS One 2013, 8, e57622. Lyoo, K. S.; 395 You, C. R.; Jung, E. S.; Jung, C. K.; Park, T.; Um, S. J.; Yoon, S. K., Oleuropein prevents 396 the progression of steatohepatitis to hepatic fibrosis induced by a high-fat diet in mice. Exp. 397 Mol. Med. 2014, 46, e92. 398 33. Kim, S.; Jin, Y.; Choi, Y.; Park, T., Resveratrol exerts anti-obesity effects via 399

We have previously found that fasting plasma levels of totally assessed 10- and 12-(Z,E)-hydroxyoctadecadienoic acid (HODE) correlated well with levels of glycated hemoglobin (HbA1c) and glucose during oral glucose tolerance tests (OGTT); these levels were determined via liquid chromatography—mass spectrometry after reduction and saponification. However, 10- and 12-(Z,E)-HODE alone cannot perfectly detect early impaired glucose tolerance (IGT) and/or insulin resistance, which ultimately lead to diabetes. In this study, we randomly recruited healthy volunteers (n = 57) who had no known history of any diseases, and who were evaluated using the OGTT, the HODE biomarkers, and several additional proposed biomarkers, including retinol binding protein 4 (RBP4), adiponectin, leptin, insulin, glycoalbumin, and high sensitivity-C-reactive protein. The OGTT revealed that our volunteers included normal individuals (n = 44; Group N), “high-normal” individuals (fasting plasma glucose 100–109 mg/dL) with IGT (n = 11; Group HN+IGT), and diabetic individuals (n = 2; Group D). We then used these groups to evaluate the potential biomarkers for the early detection of type 2 diabetes. Plasma levels of RBP4 and glycoalbumin were higher in Group HN+IGT, compared to those in Group N, and fasting levels of 10- and 12-(Z,E)-HODE/linoleic acids were significantly correlated with levels of RBP4 (p = 0.003, r = 0.380) and glycoalbumin (p = 0.006, r = 0.316). Furthermore, we developed a stepwise multiple linear regression models to predict the individuals’ insulin resistance index (the Matsuda Index 3). Fasting plasma levels of 10- and 12-(Z,E)-HODE/linoleic acids, glucose, insulin, and leptin/adiponectin were selected as the explanatory variables for the models. The risks of type 2 diabetes, early IGT, and insulin resistance were perfectly predicted by comparing fasting glucose levels to the estimated Matsuda Index 3 (fasting levels of 10- and 12-(Z,E)-HODE/linoleic acids, insulin, and leptin/adiponectin).