Jer An Lin

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.

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.

Glycative stress from advanced glycation end products (AGEs) and dicarbonyls: An emerging biological factor in cancer onset and progression

In recent years, glycative stress from exogenous or endogenous advanced glycation end products (AGEs) and highly reactive dicarbonyls has gained great attention for its putative effects on cancer development. AGEs are a group of compounds formed from the complex chemical reaction of reducing sugars with compounds containing an amino group. AGEs bind to and activate the receptor for AGEs (RAGE), which is a predominant modulator of inflammation-associated cancer, and AGEs induce reactive oxygen species that are an important regulator of the hallmarks of cancer. Dicarbonyls, which are formed during glycolysis, lipid oxidation, or protein degradation, include glyoxal, methylglyoxal, and 3-deoxyglucosone and are regarded as major precursors of AGEs. These dicarbonyls not only fuel the AGE pool in living organisms but also evoke carbonyl stress, which may contribute to the carbonylative damage of carbohydrates, lipids, proteins, or DNA. Carbonylative damage then leads to many lesions, some of which are implicated in the pathogenesis of cancer. In this review, studies regarding the effects of AGEs and dicarbonyls on cancer onset or progression are systematically discussed, and the utilization of AGE inhibitors and dicarbonyl scavengers in cancer therapy are noted.

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.

EGCG-rich green tea extract stimulates sRAGE secretion to inhibit S100A12-RAGE axis through ADAM10-mediated ectodomain shedding of extracellular RAGE in type 2 diabetes

The receptor for advanced glycation of end products (RAGE) plays a critical role in the progression of type 2 diabetes (T2D). Soluble RAGE (sRAGE) is one of the RAGE variants, which acts as a decoy domain receptor and competes with RAGE, thus contributing to prevention of T2D. In this study, we conducted clinical trials of (-)-epigallocatechin-3-gallate (EGCG) rich green tea extract (300-900 mg/day) to investigate the effect of EGCG on relationship between S100A12 RAGE ligand and diverse sRAGE in T2D. Moreover, mechanism of sRAGE production also confirmed in vitro. Our data indicated that EGCG could stimulate sRAGE circulation but inhibited RAGE ligand in T2D, and ADAM10-mediated ectodomain shedding of extracellular RAGE was mainly involved in EGCG-stimulated sRAGE circulation. The present evidence indicates that EGCG has a potential to block S100A12-RAGE axis by stimulating sRAGE production through ADAM10-mediated ectodomain shedding of extracellular RAGE. Therefore, EGCG contributes to nutritional strategies for diabetes, not only because of its efficient antioxidant activity to scavenge free radicals, but also because of its ability stimulating sRAGE release in the circulation. Additionally, ADAM10-induced ectodomain shedding of extracellular RAGE leading to sRAGE circulation should be a potential of passive mechanism of sRAGE production to block S100A12-RAGE axis-related pathogenesis of proinflammation and diabetes.

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.

Alternanthera paronychioides protects pancreatic β-cells from glucotoxicity by its antioxidant, antiapoptotic and insulin secretagogue actions

The antioxidant and antiglucotoxic effects of Alternanthera paronychioides on pancreatic β-cell were investigated. Antioxidant assays demonstrated that ethanol extracts of A. paronychioides (EEAP) exhibited the highest antioxidant activity, which also had the highest phenolic and flavonoid contents. Two major polyphenolics, ferulic acid and quercetin, were identified from EEAP by HPLC-DAD. Effects of EEAP, ferulic acid and quercetin on high glucose (25 mmol/L)-induced pancreatic β-cell apoptosis and dysfunction were further evaluated. Results showed that EEAP and quercetin but not ferulic acid protected β-cells from glucotoxicity through several mechanisms, including: (1) maintaining β-cell viability; (2) suppressing reactive oxygen species production; (3) reducing characteristic features of apoptosis; (4) inhibiting the activation of caspase-9 and caspase-3 and the cleavage of poly (ADP-ribose) polymerase; (5) upregulating pancreatic and duodenal homeobox 1 gene expression and the insulin secretagogue action of pancreatic β-cells. These findings may shed light on the preventive actions of A. paronychioides on diabetic glucotoxicity.

Methylglyoxal displays colorectal cancer-promoting properties in the murine models of azoxymethane and CT26 isografts

ABSTRACT Methylglyoxal (MG), a highly reactive carbonyl species (RCS) with pro‐oxidant and proinflammatory properties, may be a colon tumor‐promoting factor in food and biological systems. In the present study, we found that consumption of MG significantly deteriorated azoxymethane (AOM)‐induced colonic preneoplastic lesions in ICR mice, in which biomarkers of oxidative stress and inflammation within the body and feces induced by MG‐fueled carbonyl stress may have played important roles. Interestingly, exposure to MG also led to increases in the serum low‐density lipoprotein (LDL)/high‐density lipoprotein (HDL) ratio and fecal bile acid levels in mice, which may be critical factors involved in MG‐induced colonic lesions. Additionally, MG treatment (50 mg/kg body weight (BW); intraperitoneally) promoted tumor growth of CT26 isografts in mice partly by carbonyl stress‐evoked protumorigenic responses, including low‐grade inflammation and oxidative stress. Furthermore, primary tumor cells isolated from mice with MG‐induced CT26 isografts had greater proliferative and migratory activities as well as stem‐like properties compared to those isolated from the vehicle controls. Excitingly, enhanced expression or activation of proteins that modulate cell survival, proliferation, or migration/invasion was also observed in those cells. In conclusion, it is conceivable that MG‐induced carbonyl stress may be the pivotal promoter involved in colon cancer progression. Graphical abstract The effect of MG‐induced carbonyl stress on colon cancer progression. Figure. No caption available. HighlightsOral or intraperitoneal administration of methylglyoxal leads to pathogenic carbonyl stress.Methylglyoxal‐induced carbonyl stress results in oxidative stress and inflammation in vivo.Methylglyoxal‐induced carbonyl stress deteriorates colonic preneoplastic lesions.Methylglyoxal‐induced carbonyl stress enhances malignancy of colon tumor.

Perspective of Advanced Glycation End Products on Human Health

In the last 20 years, the effects of advanced glycation end products (AGEs) on health have received increasing attention. High AGE levels in the body correlate with the progression of many diseases, such as diabetes, cardiovascular disease, and some cancers. However, whether AGEs are a cause of these diseases or represent accompanying symptoms of these diseases still needs to be elucidated by more comprehensive research. Recently, many researchers have begun to investigate the effects of AGE intake-induced variations of gut microbiota on disease progression, which will further explain the impact of AGEs on health and open a new chapter in AGE research.