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.

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.

Disruption of the blood-brain barrier (BBB) caused by cerebral ischemia can initiate the development and progression of brain injuries, which may lead to irreversible dysfunction of the central nervous system. It is likely that tyrosine phosphorylation of a membrane-associated tight junctional protein, occludin, is important for the interaction of occludin with intracellular proteins, ZO-1 to ZO-3, and it regulates vascular permeability. Little is known about the pathophysiological alterations of tight junctional proteins after transient focal cerebral ischemia. In this study, we examined the tyrosine phosphorylation of occludin in isolated brain capillaries after transient focal cerebral ischemia. We further examined the effects of the Src-family tyrosine kinase inhibitor, PP2, on the tyrosine phosphorylation of occludin and on vascular permeability and infarct volume. Transient focal ischemia increased the tyrosine phosphorylation of occludin in the isolated brain capillaries. The administration of PP2 attenuated this phosphorylation, which was coincident with an inhibition of BBB leakage and a decrease in infarct volume. These results suggest that the increase in the tyrosine phosphorylation of occludin in the brain capillaries may be linked to the disruption of tight junctions, whose disruption can cause dysfunction of the BBB and the consequent increase in infarct volume.

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

The contribution of metabotropic glutamate receptors to brain injury after in vivo cerebral ischemia remains to be determined. We investigated the effects of the metabotropic glutamate receptor 1 (mGluR1) antagonist LY367385 on brain injury after transient (90 min) middle cerebral artery occlusion in the rat and sought to explore their mechanisms. The intravenous administration of LY367385 (10 mg/kg) reduced the infarct volume at 24 h after the start of reperfusion. As the Gq‐coupled mGluR1 receptor is known to activate the PKC/Src family kinase cascade, we focused on changes in the activation and amount of these kinases. Transient focal ischemia increased the amount of activated tyrosine kinase Src and PKC in the post‐synaptic density (PSD) at 4 h of reperfusion. The administration of LY367385 attenuated the increases in the amounts of PSD‐associated PKCγ and Src after transient focal ischemia. We further investigated phosphorylation of the NMDA receptor, which is a major target of Src family kinases to modulate the function of the receptor. Transient focal ischemia increased the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B. Tyrosine phosphorylation of NR2A, but not that of NR2B, in the PSD at 4 h of reperfusion was inhibited by LY367385. These results suggest that the mGluR1 after transient focal ischemia is involved in the activation of Src, which may be linked to the modification of properties of the NMDA receptor and the development of cerebral infarction.