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Lipoic Acid Supplementation Decreases Biomarkers of Inflammation and Lipid Peroxidation in Overweight or Obese Adults: Results of a Randomized, Double-Blind, Placebo-Controlled Study
Diabetes mellitus is one of the most significant public health problems in the world and WHO projects that diabetes will be the 7th leading cause of death in 2030. Healthy diet, regular physical exercise, maintaining a normal body weight and avoiding tobacco are possible approaches to prevent type 2 diabetes. A healthy diet can help to prevent the development of diabetes and can retard the complication of diabetes. Significant evidence suggests that polyphenol-rich diets have the ability to protect against diabetes. Since several previous reviews focused on the nutrition and health effects including type 2 diabetes of polyphenols in 2007-2008, a number of related original publications have been published in this field. This review summarizes important advances related to influence of dietary polyphenols and polyphenol-rich diets on preventing and managing type 2 diabetes, as well as diabetes-mediated changes in bioactivities of dietary polyphenols. It appears that anthocyanins or anthocyanin-rich food intake are related to the risk of type 2 diabetes, but there is no association for other polyphenol subclasses. It is discussed that procyanidins are more active when administered individually than when mixed with food. The benefits of dietary polyphenols for type 2 diabetes can be summarized as: protection of pancreatic β-cells against glucose toxicity, anti-inflammatory and antioxidant effects, inhibition of ĮDP\ODVHV RU Į-glucosidases and thus decrease of starch digestion, and inhibition of advanced glycation end products formation. Moreover, type 2 diabetes also significantly influences the benefits of dietary polyphenols, although there are very limited studies have been conducted so far. How type 2 diabetes impacts the pharmacology of dietary polyphenols is not well understood. Comprehension of type 2 diabetes-mediated changes in pharmacokinetics and bioactivity of dietary polyphenols might lead to improve the benefits of these phytochemicals and subsequent clinical outcomes for type 2 diabetics. doi: 10.1016/j.freeradbiomed.2014.10.333
228 High Selective and High Sensitive Detection Method for Ascorbic Acid Using a Profluorescent Nitroxide Ken-ichi Yamada1,2, Yuta Matsuoka1, Mayumi Yamato1, Toshihide Yamasaki1, and Fumiya Mito1 1 Kyushu University, Japan, 2JST, PRESTO, Japan Ascorbic acid is a small molecule reductant with multiple functions in vivo. Reducing ascorbic acid intake leads to a lack of hydroxylation of prolines and lysines, causing a looser triple helix and resulting in scurvy. Ascorbic acid also acts as an antioxidant to prevent oxidative stress. Because ascorbic acid is related to disease states, rapid and convenient detection of ascorbic acid should be useful in diagnosis. Nitroxide is reduced to the corresponding hydroxylamine by ascorbic acid and a sensitive and novel approach to its detection employs covalent coupling of nitroxide with a fluorophore, leading to intramolecular quenching of fluorescence emission by electron exchange interactions. Here, we developed a new fluorophore-nitroxide probe, Naph-DiPy nitroxide, for ascorbic acid. Naph-DiPy nitroxide rapidly reacted with ascorbic acid and showed fluorescence enhancement but not in response to other reductants or reactive oxygen species. To confirm the practical usefulness of the fluorophore-nitroxide probe, we demonstrated the use of Naph-DiPy nitroxide for the measurement of ascorbic acid in an rat plasma. The results suggest that this novel fluorophore-nitroxide probe could sensitively and easily detect ascorbic acid. doi: 10.1016/j.freeradbiomed.2014.10.334
229 Mitigation of Radiation-Mediated Suppression of Hippocampal Neurogenesis Phillip Yang1,2, David Leu1,3, Hsun Yang1,3, Melody Khosrav1,3, Artak Tovmasyan4, Ivan Spasojevic4, Ines Batinic-Haberle4, and Ting-Ting Huang1,2 1 Stanford University, USA, 2VA Palo Alto Health Care System, USA, 3Palo Alto Veterans Institute for Research, USA, 4Duke University, USA Adult hippocampal neurogenesis is important for learning and memory. However, the process is sensitive to irradiation, resulting in altered dendritic structures, reduced production of newborn neurons, and impaired cognitive functions. Reactive oxygen species (ROS) is produced by radiation and plays an important role in irradiation-mediated damages. Down-regulation of brain derived neurotrophic factor (BDNF) signaling has been suggested to be one of the molecular mechanisms responsible for neuronal dysregulation following radiation-induced oxidative stress. Thus therapeutic strategies targeted at reducing oxidative stress or enhancing BDNF signaling could be beneficial following radiation therapy. The class of Mn-containing porphyrins (MnPs) is designed to mimic the kinetics and thermodynamics of superoxide dismutases and have been shown to be effective in mitigating oxidative stress. Among this class of compounds, MnTnBuOE-2PyP5+ (MnBuOE) is able to cross the blood brain barrier and accumulate in hippocampus with high efficiency. 7,8dihydroxyflavone (7,8-DHF) is a small molecule agonist for the high affinity BDNF receptor TrkB, and acts as a neuroprotective compound by mimicking the action of BDNF in vivo and in vitro. To investigate the efficacy of MnBuOE and DHF in radiation protection of hippocampal neurogenesis, consecutive daily treatment with MnBuOE or DHF for 2 to 3 weeks was initiated before or after a single dose of cranial irradiation. Whereas MnBuOE was effective in reducing the loss of immature neurons following irradiation without a significant impact on progenitor cell proliferation, DHF appeared to be effective in preserving progenitor cell proliferation but not in immature neuron loss. Consistent with this finding, long-term survival of newborn neurons was also significantly improved in irradiated mice treated with MnBuOE. No overt side effects from long-term treatment of MnBuOE and DHF were observed. Further understanding of the effects of MnBuOE and DHF on BDNF/TrkB signaling, dendritic structures, and cognitive functions will be helpful in designing an effective therapeutic approach targeting different aspects of neurogenesis for radiation protection. doi: 10.1016/j.freeradbiomed.2014.10.335
230 Lipoic Acid Supplementation Decreases Biomarkers of Inflammation and Lipid Peroxidation in Overweight or Obese Adults: Results of a Randomized, DoubleBlind, Placebo-Controlled Study Weijian Zhang1, Jonathan Purnell2, Clive Woffendin3, Cliff Pereira4, Alexander J Michels1, Joseph A Vita5, Maret G Traber1, Tory M Hagen1, Gerd Bobe1, and Balz Frei1 1 Linus Pauling Institute, Oregon State University, USA, 2 Department of Medicine, Oregon Health & Science University, USA, 3Oregon Clinical & Translational Research Institute, Oregon Health & Science University, USA, 4Department of Statistics, Oregon State University, USA, 5Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, USA :H KDYH VKRZQ SUHYLRXVO\ WKDW Į-lipoic acid inhibits
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atherosclerosis, body weight gain, and vascular inflammation in apoE-/- and apoE-/- LDLR-/- mice. Further, Į-lipoic acid induces Nrf2-mediated gene expression of antioxidant enzymes and inhibits the age-related increase in lipid peroxidation in rats. We, therefore, hypothesized that oral (R)- Į-lipoic acid (R-LA) supplementation of overweight or obese adults decreases biomarkers of inflammation and lipid peroxidation. Eighty adults (46 women, 34 men; 21-60 years; BMI 25.6-52.0 kg/m2; plasma triglycerides 100-401 mg/dL) were enrolled in a 24-week randomized, double-blind, placebo-controlled trial and assigned to either R-LA (600 mg/day) or matching placebo. The study was completed by 64 participants (31 receiving R-LA). Using an intention-to-treat analysis, 24-week R-LA supplementation compared to placebo decreased plasma concentrations of sICAM-1 (- 3 EXW LQFUHDVHG 71)Į 3 and had no effect on hs-CRP (P=0.78). Specifically in women (n=35), R-LA treatment compared to placebo decreased plasma sE-selectin (-17%; P=0.01). In both males and females, mRNA levels of antioxidant enzymes in PBMCs tended to be higher in RLA supplemented subjects (+13%; P=0.10). Furthermore, lipid peroxidation was decreased by R-LA treatment, as assessed by urinary concentrations of total F2-isoprostanes (-25%; P=0.02), as well as 5- and 15-series PGFĮ (-26%; P=0.05 and -29%; P=0.002, respectively), 8-iso-PGFĮ metabolites (-29%; P=0.002), and 2,3-dinor-5,6-dihydro-8-iso-PGFĮ (-20%; P=0.03). We conclude that R-LA supplementation of overweight or obese adults decreases plasma and urinary markers of inflammation and oxidative stress. In the same study, we also found that R-LA supplementation decreases body weight and body fat mass in women. Based on these observations and our preclinical studies, R-LA supplementation may decrease the risk of cardiovascular disease in overweight or obese adults. ± This study was supported by NIH grants P01 AT002034 and UL1TR000128. doi: 10.1016/j.freeradbiomed.2014.10.336
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228 High Selective and High Sensitive Detection Method for Ascorbic Acid Using a Profluorescent Nitroxide Ken-ichi Yamada1,2, Yuta Matsuoka1, Mayumi Yamato1, Toshihide Yamasaki1, and Fumiya Mito1 1 Kyushu University, Japan, 2JST, PRESTO, Japan Ascorbic acid is a small molecule reductant with multiple functions in vivo. Reducing ascorbic acid intake leads to a lack of hydroxylation of prolines and lysines, causing a looser triple helix and resulting in scurvy. Ascorbic acid also acts as an antioxidant to prevent oxidative stress. Because ascorbic acid is related to disease states, rapid and convenient detection of ascorbic acid should be useful in diagnosis. Nitroxide is reduced to the corresponding hydroxylamine by ascorbic acid and a sensitive and novel approach to its detection employs covalent coupling of nitroxide with a fluorophore, leading to intramolecular quenching of fluorescence emission by electron exchange interactions. Here, we developed a new fluorophore-nitroxide probe, Naph-DiPy nitroxide, for ascorbic acid. Naph-DiPy nitroxide rapidly reacted with ascorbic acid and showed fluorescence enhancement but not in response to other reductants or reactive oxygen species. To confirm the practical usefulness of the fluorophore-nitroxide probe, we demonstrated the use of Naph-DiPy nitroxide for the measurement of ascorbic acid in an rat plasma. The results suggest that this novel fluorophore-nitroxide probe could sensitively and easily detect ascorbic acid. doi: 10.1016/j.freeradbiomed.2014.10.334
229 Mitigation of Radiation-Mediated Suppression of Hippocampal Neurogenesis Phillip Yang1,2, David Leu1,3, Hsun Yang1,3, Melody Khosrav1,3, Artak Tovmasyan4, Ivan Spasojevic4, Ines Batinic-Haberle4, and Ting-Ting Huang1,2 1 Stanford University, USA, 2VA Palo Alto Health Care System, USA, 3Palo Alto Veterans Institute for Research, USA, 4Duke University, USA Adult hippocampal neurogenesis is important for learning and memory. However, the process is sensitive to irradiation, resulting in altered dendritic structures, reduced production of newborn neurons, and impaired cognitive functions. Reactive oxygen species (ROS) is produced by radiation and plays an important role in irradiation-mediated damages. Down-regulation of brain derived neurotrophic factor (BDNF) signaling has been suggested to be one of the molecular mechanisms responsible for neuronal dysregulation following radiation-induced oxidative stress. Thus therapeutic strategies targeted at reducing oxidative stress or enhancing BDNF signaling could be beneficial following radiation therapy. The class of Mn-containing porphyrins (MnPs) is designed to mimic the kinetics and thermodynamics of superoxide dismutases and have been shown to be effective in mitigating oxidative stress. Among this class of compounds, MnTnBuOE-2PyP5+ (MnBuOE) is able to cross the blood brain barrier and accumulate in hippocampus with high efficiency. 7,8dihydroxyflavone (7,8-DHF) is a small molecule agonist for the high affinity BDNF receptor TrkB, and acts as a neuroprotective compound by mimicking the action of BDNF in vivo and in vitro. To investigate the efficacy of MnBuOE and DHF in radiation protection of hippocampal neurogenesis, consecutive daily treatment with MnBuOE or DHF for 2 to 3 weeks was initiated before or after a single dose of cranial irradiation. Whereas MnBuOE was effective in reducing the loss of immature neurons following irradiation without a significant impact on progenitor cell proliferation, DHF appeared to be effective in preserving progenitor cell proliferation but not in immature neuron loss. Consistent with this finding, long-term survival of newborn neurons was also significantly improved in irradiated mice treated with MnBuOE. No overt side effects from long-term treatment of MnBuOE and DHF were observed. Further understanding of the effects of MnBuOE and DHF on BDNF/TrkB signaling, dendritic structures, and cognitive functions will be helpful in designing an effective therapeutic approach targeting different aspects of neurogenesis for radiation protection. doi: 10.1016/j.freeradbiomed.2014.10.335
230 Lipoic Acid Supplementation Decreases Biomarkers of Inflammation and Lipid Peroxidation in Overweight or Obese Adults: Results of a Randomized, DoubleBlind, Placebo-Controlled Study Weijian Zhang1, Jonathan Purnell2, Clive Woffendin3, Cliff Pereira4, Alexander J Michels1, Joseph A Vita5, Maret G Traber1, Tory M Hagen1, Gerd Bobe1, and Balz Frei1 1 Linus Pauling Institute, Oregon State University, USA, 2 Department of Medicine, Oregon Health & Science University, USA, 3Oregon Clinical & Translational Research Institute, Oregon Health & Science University, USA, 4Department of Statistics, Oregon State University, USA, 5Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, USA :H KDYH VKRZQ SUHYLRXVO\ WKDW Į-lipoic acid inhibits
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atherosclerosis, body weight gain, and vascular inflammation in apoE-/- and apoE-/- LDLR-/- mice. Further, Į-lipoic acid induces Nrf2-mediated gene expression of antioxidant enzymes and inhibits the age-related increase in lipid peroxidation in rats. We, therefore, hypothesized that oral (R)- Į-lipoic acid (R-LA) supplementation of overweight or obese adults decreases biomarkers of inflammation and lipid peroxidation. Eighty adults (46 women, 34 men; 21-60 years; BMI 25.6-52.0 kg/m2; plasma triglycerides 100-401 mg/dL) were enrolled in a 24-week randomized, double-blind, placebo-controlled trial and assigned to either R-LA (600 mg/day) or matching placebo. The study was completed by 64 participants (31 receiving R-LA). Using an intention-to-treat analysis, 24-week R-LA supplementation compared to placebo decreased plasma concentrations of sICAM-1 (- 3 EXW LQFUHDVHG 71)Į 3 and had no effect on hs-CRP (P=0.78). Specifically in women (n=35), R-LA treatment compared to placebo decreased plasma sE-selectin (-17%; P=0.01). In both males and females, mRNA levels of antioxidant enzymes in PBMCs tended to be higher in RLA supplemented subjects (+13%; P=0.10). Furthermore, lipid peroxidation was decreased by R-LA treatment, as assessed by urinary concentrations of total F2-isoprostanes (-25%; P=0.02), as well as 5- and 15-series PGFĮ (-26%; P=0.05 and -29%; P=0.002, respectively), 8-iso-PGFĮ metabolites (-29%; P=0.002), and 2,3-dinor-5,6-dihydro-8-iso-PGFĮ (-20%; P=0.03). We conclude that R-LA supplementation of overweight or obese adults decreases plasma and urinary markers of inflammation and oxidative stress. In the same study, we also found that R-LA supplementation decreases body weight and body fat mass in women. Based on these observations and our preclinical studies, R-LA supplementation may decrease the risk of cardiovascular disease in overweight or obese adults. ± This study was supported by NIH grants P01 AT002034 and UL1TR000128. doi: 10.1016/j.freeradbiomed.2014.10.336
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