Chi Hao Wu

Inhibition of advanced glycation endproduct formation by foodstuffs.

The Maillard reaction, which is generally termed nonenzymatic browning or glycation, has been implicated in accelerated aging and diabetic complications in vivo. Although the molecular basis of glycation-induced pathogenesis is not well understood, the following have been noted: (1) protein glycation leads to the formation and accumulation of toxic advanced glycation endproducts (AGEs); (2) AGEs can permanently alter the structure and function of body proteins; and (3) the interaction between AGE-modified proteins and AGE-specific receptors (RAGEs) on the cell surface induces the overproduction of reactive oxygen species (ROSs) and inflammatory mediators, which leads to cellular disorders in biological systems. To date, studies that have examined the contribution of protein glycation to disease-states have primarily focused on the deleterious effects and related mechanisms of these glycotoxins. However, it remains unknown whether phytochemicals exert protective effects against glycotoxin-induced damage. Thus, the development and investigation of AGE inhibitors, especially the natural anti-AGE agents without adverse effects, may provide a therapeutic approach for delaying and preventing premature aging and diabetic complications. In this review, we provide an outline of anti-glycation properties of foodstuffs and/or their active components, and discuss their mechanisms of action.

Catechin protects against ketoprofen-induced oxidative damage of the gastric mucosa by up-regulating Nrf2 in vitro and in vivo

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ketoprofen, are widely used in clinical medicine. However, these drugs may damage the gastrointestinal mucosa. Some reports have suggested that intestinal diseases, such as ulcers, are associated with lipid peroxidation and oxidative damage in the mucosa. Phytochemicals, such as polyphenols, are common dietary antioxidants that possess many beneficial characteristics, such as antioxidant and anti-inflammatory capabilities. The objective of this study was to investigate the protective effects of polyphenols on ketoprofen-induced oxidative damage in the gastrointestinal mucosa. We evaluated the effects of catechin, theaflavin, malvidin, cyanidin and apigenin on the activity of antioxidant enzymes in human intestinal-407 (Int-407) cells and rat primary gastric cells treated with ketoprofen. The results indicated that catechin significantly (P<.05) decreased the levels of lipid peroxidation (40.5%) and reactive oxygen species (30.0%), and increased the activity of intracellular antioxidant enzymes glutathione peroxidase, glutathione reductase and total sulfhydryl groups. More importantly, the treatment of Sprague-Dawley rats with catechin (35 mg/kg/day) prior to the administration of ketoprofen (50 mg/kg/day) successfully inhibited oxidative damage and reversed the impairment of the antioxidant system in the intestinal mucosa. Western blot analysis revealed that catechin stimulated a time-dependent increase in both the nuclear factor erythroid 2-related factor 2 and total heme oxygenase-1 protein expression in Int-407 cells. These results suggest that catechin may have a protective effect on gastrointestinal ulcers.

Cytoprotective effects of hesperetin and hesperidin against amyloid β-induced impairment of glucose transport through downregulation of neuronal autophagy.

SCOPE This study investigated whether flavonoids, such as hesperetin and hesperidin, inhibited amyloid β (Aβ)-impaired glucose utilization through regulating cellular autophagy in insulin-stimulated neuronal cells. METHODS AND RESULTS In this study, we used a toxic Aβ1-42 peptide to impair insulin-stimulated glucose utilization in Neuro-2A cells, and this study also hypothesized that Aβ-induced autophagy might be emerging as a key process regulating neuronal glucose uptake. Additionally, hesperetin and hesperidin were used to test the neuroprotective effect against Aβ-induced impairment of glucose utilization. Our data found that Aβ-stimulated autophagy activation promoted the phenomenon of impairment of neuronal energy metabolism, including glucose uptake, glucose transporters (GLUTs), and insulin signaling cascades. In this study, confocal images of autophagy punctate further confirmed that downregulation of Aβ-stimulated autophagy could increase insulin-stimulated neuronal glucose uptake. Moreover, treatment with hesperetin and hesperidin improved Aβ-impaired glucose utilization by inhibiting Aβ-induced autophagy in neuronal cells. CONCLUSION These findings suggest that downregulation of autophagy may be one of the approaches to control the impairment of energy metabolism leading to neuronal injury in the early development of Alzheimers disease, and hesperetin or hesperidin may be a potential agent in the preventing of Alzheimers disease progression.

Protective effects of anthocyanins against amyloid β-peptide-induced damage in neuro-2A cells.

Alzheimers disease is neuropathologically characterized by amyloid β-protein (Aβ) deposition, resulting in neurotoxicity. Herein, we focused on the prevention of anthocyanins from amyloid-mediated neurodysfunction. The data demonstrated that combined exposure of Aβ(1-40) and Aβ(25-35) to Neuro-2A cells resulted in reactive oxygen species (ROS) production and perturbation of calcium homeostasis. The expressions of LXRα, ApoE, ABCA1, and seladin-1 genes were significantly down-regulated upon Aβ challenge. β-Secretase, the rate-limiting enzyme that catalyzes amyloid precursor protein transform to Aβ, was up-regulated by Aβ treatment. For the duration of Aβ stimulation, malvidin (Mal) or oenin (Oen; malvidin-3-O-glucoside) was added, and the protective effects were observed. Mal and Oen showed protective effects against Aβ-induced neurotoxicity through blocking ROS formation, preserving Ca(2+) homeostasis, and preventing Aβ-mediated perturbation of certain genes involved in Aβ metabolism and cellular defense. The present study implicates anthocyanin as a potential therapeutic candidate for the prevention of amyloid-mediated neurodysfunction.

The proglycation effect of caffeic acid leads to the elevation of oxidative stress and inflammation in monocytes, macrophages and vascular endothelial cells

In this study, the effects of phenolic acids [caffeic acid (CA), ferulic acid, m-coumaric acid, and chlorogenic acid] on methylglyoxal (MG)-induced protein glycation were investigated in vitro. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and advanced glycation end products (AGEs)-specific fluorescence showed that MG-mediated protein modification was enhanced dose-dependently by CA (P<.05), whereas α-lipoic acid, glutathione and EDTA inhibited these changes. Electron paramagnetic resonance spectra showed that CA increased reactive oxygen species (ROS) production during glycation, suggesting the proglycation mechanism of CA is associated with its pro-oxidative properties. Additionally, fetal bovine serum (FBS) was utilized as the source of target proteins for evaluating the effects of CA in cells. Differential glycation of FBS samples was performed by incubating FBS with MG, CA or aminoguanidine (AG, an AGE inhibitor). FBS incubated with MG and CA (MG/CA-FBS) evoked the greatest deleterious responses, as follows: (1) inducing proinflammatory tumor necrosis factor (TNF)-α and interleukin-1β expression and ROS production in monocytic THP-1 cells, (2) stimulating TNF-α secretion in RAW 264.7 macrophages and (3) causing oxidative DNA damage and inducing the expression of receptor for AGEs (RAGE), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 in human umbilical vein endothelial cells. Furthermore, adhesion and transendothelial migration of monocytes were also significantly increased by MG/CA-FBS treatment compared to MG-FBS (P<.05). In conclusion, our data show that CA exhibits pro-oxidative and pro-glycative effects during the glycation process, suggesting a detrimental role for CA under high-glycotoxin conditions.

AGE-Induced Interference of Glucose Uptake and Transport as a Possible Cause of Insulin Resistance in Adipocytes

The purpose of this study was to investigate the distinct roles of advanced glycation end products (AGEs) on insulin-mediated glucose disposal in 3T3-L1 adipocytes and C2C12 skeletal muscle cells. AGE-modified proteins, namely, GO-AGEs, were prepared by incubating bovine serum albumin (BSA) with glyoxal (GO) for 7 days. Glucose utilization rates and the expression of insulin signaling-associated proteins, including Akt, insulin receptor substrate-1, and glucose transporter 4, were determined. GO-AGEs caused insulin resistance (IR) by suppressing insulin-stimulated glucose uptake both in 3T3-L1 adipocytes and C2C12 muscle cells. Interestingly, an unexpected finding was that insulin-stimulated glucose transport in adipocytes was affected by GO-AGEs in a biphasic manner, with an initial steep increase (168%) during the first 8 h of incubation followed by a significantly impaired uptake after extended culture times (24-48 h, p < 0.05). Treatment with GO-AGEs for 24 h markedly accelerated lipid droplet formation compared to the BSA control; however, it was blocked by incubation with an anti-RAGE antibody. Our study suggests that GO-AGEs induce an early dramatic elevation of glucose transport in adipocytes that may be related to the activation of insulin signaling; however, subsequent IR may result from increased oxidative stress and proinflammatory TNF-α production.