Toxic Advanced Glycation End-Products Inhibit Axonal Elongation Mediated by ß-Tubulin Aggregation in Mice Optic Nerves.

Advanced glycation end-products (AGEs) form through non-enzymatic glycation of various proteins. Optic nerve degeneration is a frequent complication of diabetes, and retinal AGE accumulation is strongly linked to the development of diabetic retinopathy. Type 2 diabetes mellitus is a major risk factor for Alzheimer's disease (AD), with patients often exhibiting optic axon degeneration in the nerve fiber layer. Notably, a gap exists in our understanding of how AGEs contribute to neuronal degeneration in the optic nerve within the context of both diabetes and AD. Our previous work demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (TAGE) disrupt neurite outgrowth through TAGE-ß-tubulin aggregation and tau phosphorylation in neural cultures. In this study, we further illustrated GA-induced suppression of optic nerve axonal elongation via abnormal ß-tubulin aggregation in mouse retinas. Elucidating this optic nerve degeneration mechanism holds promise for bridging the knowledge gap regarding vision loss associated with diabetes mellitus and AD.

Structures of Toxic Advanced Glycation End-Products Derived from Glyceraldehyde, A Sugar Metabolite.

Advanced glycation end-products (AGEs) have recently been implicated in the onset/progression of lifestyle-related diseases (LSRDs); therefore, the suppression of AGE-induced effects may be used in both the prevention and treatment of these diseases. Various AGEs are produced by different biological pathways in the body. Glyceraldehyde (GA) is an intermediate of glucose and fructose metabolism, and GA-derived AGEs (GA-AGEs), cytotoxic compounds that accumulate and induce damage in mammalian cells, contribute to the onset/progression of LSRDs. The following GA-AGE structures have been detected to date: triosidines, GA-derived pyridinium compounds, GA-derived pyrrolopyridinium lysine dimers, methylglyoxal-derived hydroimidazolone 1, and argpyrimidine. GA-AGEs are a key contributor to the formation of toxic AGEs (TAGE) in many cells. The extracellular leakage of TAGE affects the surrounding cells via interactions with the receptor for AGEs. Elevated serum levels of TAGE, which trigger different types of cell damage, may be used as a novel biomarker for the prevention and early diagnosis of LSRDs as well as in evaluations of treatment efficacy. This review provides an overview of the structures of GA-AGEs.

Effect of Anagliptin on Vascular Injury in the Femoral Artery of Type 2 Diabetic Rats.

Patients with diabetes mellitus (DM) often experience complications such as peripheral arterial disease (PAD), which is thought to be caused by vascular damage resulting from increased oxidative stress. Dipeptidyl peptidase-4 inhibitors have been reported to reduce oxidative stress, although the exact mechanism remains unclear. This study aimed to investigate the impact of long-term (6 weeks) anagliptin treatment at a dose of 200 mg/kg/d against oxidative stress in the femoral artery of Otsuka Long-Evans Tokushima Fatty (OLETF) rats using a well-established animal model for type 2 DM. Serum toxic advanced glycation end-products concentrations and blood glucose levels after glucose loading were significantly elevated in OLETF rats compared to Long-Evans Tokushima Otsuka (LETO) rats but were significantly suppressed by anagliptin administration. Plasma glucagon-like peptide-1 concentrations after glucose loading were significantly increased in anagliptin-treated rats. Superoxide production and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in femoral arteries were significantly increased in OLETF rats compared to LETO rats but were significantly decreased by anagliptin administration. The expressions of NADPH oxidase components (p22phox in the intima region and p22phox and gp91phox in the media region) in the femoral artery were significantly increased in OLETF rats compared to LETO rats but were significantly suppressed by anagliptin administration. Furthermore, the femoral artery showed increased wall thickness in OLETF rats compared to LETO rats, but anagliptin administration reduced the thickening. This study suggests that long-term anagliptin administration can reduce oxidative stress in femoral arteries and improve vascular injury.

A Novel Approach: Investigating the Intracellular Clearance Mechanism of Glyceraldehyde-Derived Advanced Glycation End-Products Using the Artificial Checkpoint Kinase 1 d270KD Mutant as a Substrate Model.

Advanced glycation end-products (AGEs), formed through glyceraldehyde (GA) as an intermediate in non-enzymatic reactions with intracellular proteins, are cytotoxic and have been implicated in the pathogenesis of various diseases. Despite their significance, the mechanisms underlying the degradation of GA-derived AGEs (GA-AGEs) remain unclear. In the present study, we found that N-terminal checkpoint kinase 1 cleavage products (CHK1-CPs) and their mimic protein, d270WT, were degraded intracellularly post-GA exposure. Notably, a kinase-dead d270WT variant (d270KD) underwent rapid GA-induced degradation, primarily via the ubiquitin-proteasome pathway. The high-molecular-weight complexes formed by the GA stimulation of d270KD were abundant in the RIPA-insoluble fraction, which also contained high levels of GA-AGEs. Immunoprecipitation experiments indicated that the high-molecular-weight complexes of d270KD were modified by GA-AGEs and that p62/SQSTM1 was one of its components. The knockdown of p62 or treatment with chloroquine reduced the amount of high-molecular-weight complexes in the RIPA-insoluble fraction, indicating its involvement in the formation of GA-AGE aggregates. The present results suggest that the ubiquitin-proteasome pathway and p62 play a role in the degradation and aggregation of intracellular GA-AGEs. This study provides novel insights into the mechanisms underlying GA-AGE metabolism and may lead to the development of novel therapeutic strategies for diseases associated with the accumulation of GA-AGEs.

Involvement of Intracellular TAGE and the TAGE-RAGE-ROS Axis in the Onset and Progression of NAFLD/NASH.

The repeated excessive intake of sugar, a factor that contributes to the onset of nonalcoholic fatty liver disease (NAFLD) and its progression to the chronic form of nonalcoholic steatohepatitis (NASH), markedly increases the hepatocyte content of glyceraldehyde (GA), a glucose/fructose metabolic intermediate. Toxic advanced glycation end-products (toxic AGEs, TAGE) are synthesized by cross-linking reactions between the aldehyde group of GA and the amino group of proteins, and their accumulation has been implicated in the development of NAFLD/NASH and hepatocellular carcinoma (HCC). Our previous findings not only showed that hepatocyte disorders were induced by the intracellular accumulation of TAGE, but they also indicated that extracellular leakage resulted in elevated TAGE concentrations in circulating fluids. Interactions between extracellular TAGE and receptor for AGEs (RAGE) affect intracellular signaling and reactive oxygen species (ROS) production, which may, in turn, contribute to the pathological changes observed in NAFLD/NASH. RAGE plays a role in the effects of the extracellular leakage of TAGE on the surrounding cells, which ultimately promote the onset and progression of NAFLD/NASH. This review describes the relationships between intracellular TAGE levels and hepatocyte and hepatic stellate cell (HSC) damage as well as the TAGE-RAGE-ROS axis in hepatocytes, HSC, and HCC cells. The "TAGE theory" will provide novel insights for future research on NAFLD/NASH.

Prediagnostic serum glyceraldehyde-derived advanced glycation end products and mortality among colorectal cancer patients.

Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) could contribute to colorectal cancer development and progression due to their pro-oxidative and pro-inflammatory properties. However, the association of glycer-AGEs with mortality after colorectal cancer diagnosis has not been previously investigated. Circulating glycer-AGEs were measured by competitive ELISA. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for associations of circulating glycer-AGEs concentrations with CRC-specific and all-cause mortality among 1034 colorectal cancer (CRC) cases identified within the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1993 and 2013. During a mean of 48 months of follow-up, 529 participants died (409 from CRC). Glycer-AGEs were statistically significantly positively associated with CRC-specific (HRQ5 vs Q1  = 1.53, 95% CI: 1.04-2.25, Ptrend  = .002) and all-cause (HRQ5 vs Q1  = 1.62, 95% CI: 1.16-2.26, Ptrend  < .001) mortality among individuals with CRC. There was suggestion of a stronger association between glycer-AGEs and CRC-specific mortality among patients with distal colon cancer (per SD increment: HRproximal colon  = 1.02, 95% CI: 0.74-1.42; HRdistal colon  = 1.51, 95% CI: 1.20-1.91; Peffect modification  = .02). The highest HR was observed among CRC cases in the highest body mass index (BMI) and glycer-AGEs category relative to lowest BMI and glycer-AGEs category for both CRC-specific (HR = 1.78, 95% CI: 1.02-3.01) and all-cause mortality (HR = 2.15, 95% CI: 1.33-3.47), although no statistically significant effect modification was observed. Our study found that prediagnostic circulating glycer-AGEs are positively associated with CRC-specific and all-cause mortality among individuals with CRC. Further investigations in other populations and stratifying by tumor location and BMI are warranted.

Effects of Toxic AGEs (TAGE) on Human Health.

The habitual and excessive consumption of sugar (i.e., sucrose and high-fructose corn syrup, HFCS) is associated with the onset and progression of lifestyle-related diseases (LSRD). Advanced glycation end-products (AGEs) have recently been the focus of research on the factors contributing to LSRD. Approaches that inhibit the effects of AGEs may be used to prevent and/or treat LSRD; however, since the structures of AGEs vary depending on the type of reducing sugars or carbonyl compounds to which they respond, difficulties are associated with verifying that AGEs are an etiological factor. Cytotoxic AGEs derived from glyceraldehyde, a triose intermediate in the metabolism of glucose and fructose, have been implicated in LSRD and are called toxic AGEs (TAGE). A dietary imbalance (the habitual and excessive intake of sucrose, HFCS, or dietary AGEs) promotes the generation/accumulation of TAGE in vivo. Elevated circulating levels of TAGE have been detected in non-diabetics and diabetics, indicating a strong relationship between the generation/accumulation of TAGE in vivo and the onset and progression of LSRD. We herein outline current findings on "TAGE as a new target" for human health.

Intracellular Toxic Advanced Glycation End-Products May Induce Cell Death and Suppress Cardiac Fibroblasts.

Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) induced by the dysfunction and cell death of cardiomyocytes. Cardiac fibroblasts are activated and differentiate in response to specific signals, such as transforming growth factor-ß released from injured cardiomyocytes, and are crucial for the protection of cardiomyocytes, cardiac tissue repair, and remodeling. In contrast, cardiac fibroblasts have been shown to induce injury or death of cardiomyocytes and are implicated in the pathogenesis of diseases such as cardiac hypertrophy. We designated glyceraldehyde-derived advanced glycation end-products (AGEs) as toxic AGEs (TAGE) due to their cytotoxicity and association with LSRD. Intracellular TAGE in cardiomyocytes decreased their beating rate and induced cell death in the absence of myocardial ischemia. The TAGE levels in blood were elevated in patients with CVD and were associated with myocardial ischemia along with increased risk of atherosclerosis in vascular endothelial cells in vitro. The relationships between the dysfunction or cell death of cardiac fibroblasts and intracellular and extracellular TAGE, which are secreted from certain organs, remain unclear. We examined the cytotoxicity of intracellular TAGE by a slot blot analysis, and TAGE-modified bovine serum albumin (TAGE-BSA), a model of extracellular TAGE, in normal human cardiac fibroblasts (HCF). Intracellular TAGE induced cell death in normal HCF, whereas TAGE-BSA did not, even at aberrantly high non-physiological levels. Therefore, only intracellular TAGE induced cell death in HCF under physiological conditions, possibly inhibiting the role of HCF.

Glyceraldehyde-derived advanced glycation end-products are associated with left ventricular ejection fraction and brain natriuretic peptide in patients with diabetic adverse cardiac remodeling.

Objectives: Glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs) have a strong binding affinity for their cognate receptor and elicit oxidative stress and inflammation. However, it remains unknown whether the levels of Glycer-AGEs correlate with the severity of cardiac function and heart failure in patients with diabetic adverse cardiac remodeling (DbCR). Fourteen heart failure patients with type 2 diabetes mellitus (DM) without other cardiac disorders (DbCR group) were enrolled. Another 14 patients with idiopathic dilated cardiomyopathy (DCM) without DM were served as a control (DCM group). All patients were assessed for serum Glycer-AGEs, nitrotyrosine (NT), and tumor necrosis factor alpha (TNFα) and for plasma brain natriuretic peptide (BNP). The left ventricular ejection fraction (LVEF) was evaluated by echocardiography. Results: The mean serum levels of Glycer-AGEs, NT, and TNFα in the DbCR group were significantly higher than those in the DCM group (for Glycer-AGEs, p = .0073; for NT, p = .005; for TNFα, p < .0001, respectively). In the patients with DbCR, the levels of serum Glycer-AGEs and TNFα were closely associated with LVEF and BNP values. Conclusions: Both Glycer-AGEs and TNFα showed close associations with LVEF and the levels of BNP in patients with DbCR. Glycer-AGEs and TNFα may play a pathological role in the development of DbCR.

Pyridoxamine and Aminoguanidine Attenuate the Abnormal Aggregation of ß-Tubulin and Suppression of Neurite Outgrowth by Glyceraldehyde-Derived Toxic Advanced Glycation End-Products.

Diabetes mellitus (DM) has been identified as a risk factor for the onset and progression of Alzheimer's disease (AD). In our previous study, we demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (toxic AGEs, TAGE) induced similar alterations to those observed in AD. GA induced dysfunctional neurite outgrowth via TAGE-ß-tubulin aggregation, which resulted in the TAGE-dependent abnormal aggregation of ß-tubulin and tau phosphorylation in human neuroblastoma SH-SY5Y cells. However, the effects of inhibitors of AGE formation on dysfunctional neurite outgrowth caused by GA-induced abnormalities in the aggregation of ß-tubulin and tau phosphorylation remain unknown. Aminoguanidine (AG), an AGE inhibitor, and pyridoxamine (PM), a natural form of vitamin B6 (VB6), are effective AGE inhibitors. Therefore, the present study investigated whether AG or PM ameliorate TAGE-ß-tubulin aggregation and the suppression of neurite outgrowth by GA. The results obtained showed that AG and PM inhibited the formation of TAGE-ß-tubulin, mitigated the GA-induced suppression of neurite outgrowth, and reduced GA-mediated increases in tau phosphorylation levels. Collectively, these results suggest the potential of AG and PM to prevent the DM-associated onset and progression of AD.

The Association between Accumulation of Toxic Advanced Glycation End-Products and Cytotoxic Effect in MC3T3-E1 Cells.

In diabetic patients, the metabolism of excess glucose increases the toxicity of the aldehyde group of sugar. Aldehydes, including glyceraldehyde (GA), react with intracellular proteins to form advanced glycation end-products (AGEs), which deteriorate bone quality and cause osteoporosis. One of the causes of osteoporotic fractures is impaired osteoblast osteogenesis; however, the cytotoxic effects of aldehydes and the subsequent formation of AGEs in osteoblasts have not yet been examined in detail. Therefore, the present study investigated the cytotoxicity of intracellular GA and GA-derived AGEs, named toxic AGEs (TAGE), in the mouse osteoblastic cell line MC3T3-E1. Treatment with GA induced MC3T3-E1 cell death, which was accompanied by TAGE modifications in several intracellular proteins. Furthermore, the downregulated expression of Runx2, a transcription factor essential for osteoblast differentiation, and collagen correlated with the accumulation of TAGE. The GA treatment also reduced the normal protein levels of collagen in cells, suggesting that collagen may be modified by TAGE and form an abnormal structure. Collectively, the present results show for the first time that GA and TAGE exert cytotoxic effects in osteoblasts, inhibit osteoblastic differentiation, and decrease the amount of normal collagen. The suppression of GA production and associated accumulation of TAGE has potential as a novel therapeutic target for osteoporosis under hyperglycemic conditions.

Intracellular Toxic Advanced Glycation End-Products in 1.4E7 Cell Line Induce Death with Reduction of Microtubule-Associated Protein 1 Light Chain 3 and p62.

BACKGROUND: The death of pancreatic islet ß-cells (ß-cells), which are the insulin-producing cells, promote the pathology in both Type 1 and Type 2 diabetes mellitus (DM) (T1DM and T2DM), and they are protected by autophagy which is one of the mechanisms of cell survival. Recently, that some advanced glycation end-products (AGEs), such as methylglyoxial-derived AGEs and Nε-carboxymethyllysine, induced the death of ß-cells were revealed. In contrast, we had reported AGEs derived from glyceraldehyde (GA, the metabolism intermediate of glucose and fructose) are considered to be toxic AGEs (TAGE) due to their cytotoxicity and role in the pathogenesis of T2DM. More, serum levels of TAGE are elevated in patients with T1 and T2DM, where they exert cytotoxicity. AIM: We researched the cytotoxicity of intracellular and extracellular TAGE in ß-cells and the possibility that intracellular TAGE were associated with autophagy. METHODS: 1.4E7 cells (a human ß-cell line) were treated with GA, and analyzed viability, quantity of TAGE, microtubule-associated protein 1 light chain 3 (LC3)-I, LC3-II, and p62. We also examined the viability of 1.4E7 cells treated with TAGE-modified bovine serum albumin, a model of TAGE in the blood. RESULTS: Intracellular TAGE induced death of 1.4E7 cells, decrease of LC3-I, LC3-II, and p62. Extracellular TAGE didn't show cytotoxicity in the physiological concentration. CONCLUSION: Intracellular TAGE induced death of ß-cells more strongly than extracellular TAGE, and may suppress autophagy via reduction of LC3-I, LC3-II, and p62 to inhibit the degradation of them.

Accumulation of Toxic Advanced Glycation End-Products Induces Cytotoxicity and Inflammation in Hepatocyte-Like Cells Differentiated from Human Induced Pluripotent Stem Cells.

Nonalcoholic steatohepatitis (NASH), the aggressive form of the most common chronic liver disease nonalcoholic fatty liver disease, is characterized by inflammation and damage in the liver. Although hepatocyte injury and cell death have been identified as cardinal pathological features of NASH, its pathogenesis has not yet been elucidated in detail. Immortalized cell lines and primary cultured cells have been used as in vitro models of NASH. However, these cells have several disadvantages, such as specialized characteristics by immortalization or limited growth potential. To overcome these difficulties and develop a strategy to analyze the pathology of NASH, we employed hepatocyte-like cells differentiated from human induced pluripotent stem cells (hiPSC-HLCs) as an in vitro model of NASH to clarify the intracellular effects of glyceraldehyde-derived advanced glycation end-products (AGEs), also named toxic AGEs (TAGE). The viability of hiPSC-HLCs decreased with the accumulation of TAGE in the cells, which was consistent with previous findings on human hepatocellular carcinoma cells and human primary cultured hepatocytes. In addition, the TAGE accumulation up-regulated the expression of inflammation-related genes (interleukin 6, interleukin 8, and monocyte chemoattractant protein-1) in hiPSC-HLCs. These results indicated that the accumulation of TAGE induced hiPSC-HLC cytotoxicity and inflammation, which are features of the pathology of NASH. Therefore, we suggest the use of hiPSC-HLCs as an important strategy for analyses of the pathology of NASH.

Trapa bispinosa Roxb. extract lowers advanced glycation end-products and increases live births in older patients with assisted reproductive technology: a randomized controlled trial.

BACKGROUND: Advanced glycation end-products (AGE), which accumulate with insulin resistance and aging, impair folliculogenesis and may decrease endometrial receptivity. Hishi (Trapa bispinosa Roxb.) extract, a safe herbal medicine, strongly inhibits AGE formation in vitro. We determined whether Hishi lowers AGE and increases live births in older assisted reproductive technology (ART) patients. METHODS: This prospective randomized open-label controlled trial included 64 patients 38 to 42 years old undergoing ART with or without Hishi extract between June 11, 2015 and July 12, 2019. None had over 2 ART failures, diabetes, uterine anomalies, or exhausted ovarian reserve. After allocation, the Hishi group received Hishi extract (100 mg/day) until late pregnancy or failure. The control group received no extract. Both groups underwent 1 cycle of conventional infertility treatment; 1 long-protocol cycle of ovarian stimulation, oocyte retrieval, in vitro fertilization/intracytoplasmic sperm injection, and fresh embryo transfer (ET); and, if needed, cryopreserved ET until live birth or embryo depletion. Serum AGE were measured before and during ART, as were AGE in follicular fluid (FF). RESULTS: Cumulative live birth rate among 32 Hishi patients was 47%, significantly higher than 16% among 31 controls (p<0.01; RR, 4.6; 95% CI, 1.4 - 15.0; 1 control dropped out). Live birth rate per ET, including fresh and cryopreserved, was significantly higher with Hishi (28% in 47 ET vs. 10% in 49 ET; p<0.05; RR, 3.4; 95% CI, 1.1-10.4). Among variables including age, day-3 FSH, anti-Müllerian hormone, and Hishi, logistic regression identified only Hishi as significantly associated with increased cumulative live birth (p<0.05; OR, 5.1; 95% CI, 1.4 - 18.3). Hishi significantly enhanced oocyte developmental potential, improved endometrial receptivity in natural cycles, and decreased AGE in serum and FF. Larger serum AGE decreases with Hishi were associated with more oocytes becoming day-2 embryos. CONCLUSIONS: Hishi decreased AGE in serum and FF and improved oocyte developmental potential and endometrial receptivity, increasing live births in older patients. Treatment of infertility by AGE reduction represents a new addition to infertility treatment. Therapeutic trials of Hishi for other AGE-associated diseases might be considered. TRIAL REGISTRATION: UMIN registration in Japan ( UMIN000017758 ) on June 1, 2015. https://www.umin.ac.jp/ctr/index.htm.

Serum levels of 1,5-anhydroglucitol and 1,5-anhydrofructose-derived advanced glycation end products in patients undergoing hemodialysis.

BACKGROUND: 1,5-anhydroglucitol is a reduction product of 1,5-anhydrofructose. Circulating 1,5-anhydroglucitol is usually excreted by the kidneys and is reabsorbed via sodium-glucose co-transporter 4 in the renal tubules. In patients on hemodialysis, serum levels of 1,5-anhydroglucitol have been reported to be low; however, the underlying mechanism remains unclear. METHODS: We measured inter-dialysis changes in the levels of serum 1,5-anhydroglucitol and 1,5-anhydrofructose-derived advanced glycation end products (AGEs) in 78 patients on hemodialysis. Serum levels of 1,5-anhydrofructose-derived AGEs were also determined using a polyclonal antibody. RESULTS: The serum 1,5-anhydroglucitol level was decreased to as low as 2.0 µg/mL in the regular hemodialysis group; however, we could not verify changes in the serum 1,5-anhydroglucitol level during inter-dialysis days because of undetectable levels in 29 patients. The measured serum level of 1,5-anhydrofructose-derived AGEs was significantly increased in both patient groups. In addition, the 1,5-anhydrofructose-derived AGEs/1,5-anhydroglucitol ratio was higher in patients on hemodialysis than in controls. CONCLUSIONS: Accelerated glycation of 1,5-anhydrofructose is one possible mechanism by which serum 1,5-anhydroglucitol levels are lowered in patients on HD, and we propose that the 1,5-anhydrofructose-derived AGEs/1,5-anhydroglucitol ratio should be measured in clinical settings in which patients have low serum levels of 1,5-AG.

Protective Effects of Collagen Tripeptides in Human Aortic Endothelial Cells by Restoring ROS-Induced Transcriptional Repression.

Collagen tripeptide (CTP) is defined as a functional food material derived from collagenase digests of type I collagen and contains a high concentration of tripeptides with a Gly-X-Y sequence. CTP has several biological effects, including the acceleration of fracture healing, ameliorating osteoarthritis, and improving dryness and photoaging of the skin. Recently, an antiatherosclerotic effect of CTP has been reported, although its molecular mechanism is yet to be determined. In this study, we examined the effects of CTP on primary cultured human aortic endothelial cells (HAECs) under oxidative stress, because oxidative endothelial dysfunction is a trigger of atherosclerosis. DNA microarray and RT-qPCR analyses showed that CTP treatment recovered the downregulated expression of several genes, including the interleukin-3 receptor subunit alpha (IL3RA), which were suppressed by reactive oxygen species (ROS) treatment in HAECs. Furthermore, IL3RA knockdown significantly decreased the viability of HAECs compared with control cells. RT-qPCR analysis also showed that solute carrier 15 family peptide transporters, which are involved in CTP absorption into cells, were expressed in HAECs at levels more than comparable to those of a CTP-responsive human osteoblastic cell line. These results indicated that CTP exerts a protective effect for HAECs, at least in part, by regulating the recovery of ROS-induced transcriptional repression.

Intracellular Toxic AGEs (TAGE) Triggers Numerous Types of Cell Damage.

The habitual intake of large amounts of sugar, which has been implicated in the onset/progression of lifestyle-related diseases (LSRD), induces the excessive production of glyceraldehyde (GA), an intermediate of sugar metabolism, in neuronal cells, hepatocytes, and cardiomyocytes. Reactions between GA and intracellular proteins produce toxic advanced glycation end-products (toxic AGEs, TAGE), the accumulation of which contributes to various diseases, such as Alzheimer's disease, non-alcoholic steatohepatitis, and cardiovascular disease. The cellular leakage of TAGE affects the surrounding cells via the receptor for AGEs (RAGE), thereby promoting the onset/progression of LSRD. We demonstrated that the intracellular accumulation of TAGE triggered numerous cellular disorders, and also that TAGE leaked into the extracellular space, thereby increasing extracellular TAGE levels in circulating fluids. Intracellular signaling and the production of reactive oxygen species are affected by extracellular TAGE and RAGE interactions, which, in turn, facilitate the intracellular generation of TAGE, all of which may contribute to the pathological changes observed in LSRD. In this review, we discuss the relationships between intracellular TAGE levels and numerous types of cell damage. The novel concept of the "TAGE theory" is expected to open new perspectives for research into LSRD.

RasGRP2 inhibits glyceraldehyde-derived toxic advanced glycation end-products from inducing permeability in vascular endothelial cells.

Advanced glycation end-products (AGEs) are formed by the non-enzymatic reaction of sugars and proteins. Among the AGEs, glyceraldehyde-derived toxic AGEs (TAGE) are associated with various diseases, including diabetic complications such as diabetic retinopathy (DR). The risk of developing DR is strongly associated with poor glycemic control, which causes AGE accumulation and increases AGE-induced vascular permeability. We previously reported that Ras guanyl nucleotide releasing protein 2 (RasGRP2), which activates small G proteins, may play an essential role in the cell response to toxicity when exposed to various factors. However, it is not known whether RasGRP2 prevents the adverse effects of TAGE in vascular endothelial cells. This study observed that TAGE enhanced vascular permeability by disrupting adherens junctions and tight junctions via complex signaling, such as ROS and non-ROS pathways. In particular, RasGRP2 protected adherens junction disruption, thereby suppressing vascular hyper-permeability. These results indicate that RasGRP2 is an essential protective factor of vascular permeability and may help develop novel therapeutic strategies for AGE-induced DR.

Suppression of Hepatic Stellate Cell Death by Toxic Advanced Glycation End-Products.

Advanced glycation end-products (AGEs) are produced by the non-enzymatic reaction of sugars with proteins. It has been revealed that glyceraldehyde-derived toxic AGEs (TAGE) are elevated in the serum of non-alcoholic steatohepatitis (NASH) patients. NASH causes liver fibrosis and progresses to cirrhosis and hepatocellular carcinoma. However, the impact of TAGE in liver fibrosis caused by extracellular matrix accumulation remains poorly understood. In this study, we examined the effect of TAGE on the activation of hepatic stellate cells that are involved in liver fibrosis. LX-2 cells treated with transforming growth factor-ß1 (TGF-ß1) significantly reduced cell viability by apoptosis. However, the decrease in cell viability with TGF-ß1 treatment was significantly suppressed by TAGE co-treatment. The levels of α-smooth muscle actin (α-SMA) and platelet-derived growth factor (PDGF)-Rß and its ligand PDGF-B were increased in LX-2 cells following TGF-ß1 treatment, suggesting that these cells were activated; however, these increases were unaffected by TAGE co-treatment. Moreover, collagen I level was increased with TGF-ß1 treatment, and this increase was further increased by TAGE co-treatment. These results suggested that the suppression of apoptosis in activated LX-2 cells by TGF-ß1 and TAGE co-treatment is related to an increase in the production of the extracellular matrix such as collagen I. Therefore, it was suggested that TAGE might aggravate the liver fibrosis of chronic hepatitis, such as NASH.

Toxic AGEs (TAGE) theory: a new concept for preventing the development of diseases related to lifestyle.

BACKGROUND: The habitual excessive intake of sugar (i.e., sucrose and high-fructose corn syrup), which has been implicated in the onset of diabetes mellitus, induces excessive production of glyceraldehyde, a metabolite produced during glucose and fructose metabolism, in hepatocytes, neuronal cells, and cardiomyocytes. MAIN TEXT: Toxic advanced glycation end-products (toxic AGEs, TAGE) are formed from reactions between glyceraldehyde and intracellular proteins, and their accumulation contributes to various cellular disorders. TAGE leakage from cells affects the surrounding cells and increases serum TAGE levels, promoting the onset and/or development of lifestyle-related diseases (LSRD). Therefore, serum TAGE levels have potential as a novel biomarker for predicting the onset and/or progression of LSRD, and minimizing the effects of TAGE might help to prevent the onset and/or progression of LSRD. Serum TAGE levels are closely related to LSRD associated with the excessive ingestion of sugar and/or dietary AGEs. CONCLUSIONS: The TAGE theory is also expected to open new perspectives for research into numerous other diseases.