Advanced Glycation End-products Inhibitors Research Articles

(+)-Neocadambine A and (-)-nauclederine Isolated from the Bark of Neolamarckia cadamba (Rubiaceae) as Natural Advanced Glycation End Products (AGEs) Inhibitors

The phytochemical study on the dichloromethane extract of Neolamarckia cadamba (Roxb.) Bosser has afforded two indole alkaloids, (+)-neocadambine A (1) and (-)-nauclederine (2). Their structures were confirmed by extensive spectroscopic analysis and by comparing with the reported data. (+)-Neocadambine A (1) and (-)-nauclederine (2) exhibited potent inhibition activity of advanced glycation end products (AGEs) with IC50 values of 1.2 and 0.95 mM, respectively, while the latter was almost two times more potent than the standard, aminoguanidine (1.8 mM). This is the first report on the compounds isolated from this plant with AGEs inhibition activity. In addition, (-)-nauclederine (2) was isolated for the first time in the genus of Neolamarckia. Complete 1H-NMR and 13C-NMR of compound 2 were also reported.

Comparative Analysis of In Vitro Enzyme Inhibitory Activities and Phytochemicals from Platycladus orientalis (L.) Franco via Solvent Partitioning Method.

The extraction of plant bioactive compounds from Platycladus orientalis (L.) Franco remains a great challenge due to the different chemical groups. This study aimed to compare the bioactive compounds with enzyme inhibitory effect from P. orientalis via solvent partitioning method. Dried leaf samples were macerated and fractionated with six solvents of different polarities. The phenolic, flavonoid, tannin, saponin, alkaloid and pharmacological activities including anti-inflammatory, anti-diabetic, antioxidant and anti-glycation potential were compared across the six plant fractions. Toxicity assessment was performed with an in vivo brine shrimp model. The varying levels of bioactive compounds in ethyl acetate (phenolics, flavonoids), hexane (saponins, tannins) and chloroform (alkaloids) fractions clearly demonstrated the significant impact of solvent polarity on the extraction of bioactive compounds. The reducing potential (r = 0.67), IC50 of α-amylase inhibition (r = -0.71), IC50 of advanced glycation end-product inhibition (r = -0.93) and dicarbonyl compound inhibition (r = 0.57) in the plant fractions were correlated (p<0.05) with the flavonoids. Besides, the alkaloid, saponin and tannin were associated with cyclooxygenase-1 inhibitory activity. Principal component analysis confirmed that solvent polarity (23.9%) and plant extraction yield (37.1%) collectively contributed to 61% of bioactivity variation in P. orientalis. Among the six plant fractions, ethyl acetate fraction exhibited relatively high anti-inflammatory, anti-diabetic, antioxidant and anti-glycation potential while the non-toxic methanolic and aqueous fractions displayed optimal hyaluronidase and lipoxygenase inhibitory activities, respectively. The current study has identified semi-polar ethyl acetate fraction of P. orientalis as a good alternative source of bioactive compounds for future pharmaceutical product development.

Exploring molecular targets in diabetic kidney disease.

Diabetic kidney disease is the leading cause of end-stage kidney disease, and it remains a major challenge. Many factors, such as glomerular hyperfiltration, oxidative stress, inflammation, hypoxia, and epigenetics, are associated with the progression of diabetic kidney disease; however, the whole mechanism is not yet completely understood. No specific treatment for diabetic kidney disease has been established, so new approaches are being explored extensively. Sodium-glucose cotransporter 2 inhibitors have shown renoprotective effects in several human clinical trials. Glucagon-like peptide 1 receptor agonists and mineralocorticoid receptor antagonists have been reported to be effective in diabetic kidney disease, and novel therapeutic candidates are also being examined. In the TSUBAKI trial, a nuclear factor erythroid 2-related factor 2 activator, bardoxolone methyl, improved the glomerular filtration rate of diabetic kidney disease patients. Similarly, new agents that act in the oxidative stress and inflammation pathways are of major interest, such as pentoxifylline, apoptosis signal-regulating kinase-1 inhibitors, C-C chemokine receptor 2 inhibitors, and Janus kinase-1/2 inhibitors. Endothelin-1 receptor A antagonists and soluble guanylate cyclase stimulators are also expected to affect renal hemodynamics. Some preclinical studies suggest that hypoxia-inducible factor prolyl hydroxylase inhibitors, which influence multiple inflammations and oxidative stress pathways, reduce albuminuria in diabetic kidney disease. Advanced glycation end-product inhibitors and treatments related to epigenetics have also shown promise as potential diabetic kidney disease treatments in preclinical studies. The discovery of new targets could provide new therapeutic options for overcoming diabetic kidney disease.

Correction: Natural Products as a Source of Inspiration for Novel Inhibitors of Advanced Glycation Endproducts (AGEs) Formation.

Correction: Natural Products as a Source of Inspiration for Novel Inhibitors of Advanced Glycation Endproducts (AGEs) Formation.

Natural Products as a Source of Inspiration for Novel Inhibitors of Advanced Glycation Endproducts (AGEs) Formation.

Protein glycation, a post-translational modification found in biological systems, is often associated with a core defect in glucose metabolism. In particular, advanced glycation endproducts are complex heterogeneous sugar-derived protein modifications implicated in the progression of pathological conditions such as atherosclerosis, diabetic complications, skin diseases, rheumatism, hypertension, and neurodegenerative diseases. Undoubtedly, there is the need to expand the knowledge about antiglycation agents that can offer a therapeutic approach in preventing and treating health issues of high social and economic importance. Although various compounds have been under consideration, little data from clinical trials are available, and there is a lack of approved and registered antiglycation agents. Next to the search for novel synthetic advanced glycation endproduct inhibitors, more and more the efforts of scientists are focusing on researching antiglycation compounds from natural origin. The main purpose of this review is to provide a thorough overview of the state of scientific knowledge in the field of natural products from plant origin (e.g., extracts and pure compounds) as inhibitors of advanced glycation endproduct formation in the period between 1990 and 2019. Moreover, the objectives of the summary also include basic chemistry of AGEs formation and classification, pathophysiological significance of AGEs, mechanisms for inhibiting AGEs formation, and examples of several synthetic anti-AGEs drugs.

A fragment-based approach to discovery of Receptor for Advanced Glycation End products inhibitors.

The Receptor for Advanced Glycation End products (RAGE) is a pattern recognition receptor that signals for inflammation via the NF-κB pathway. RAGE has been pursued as a potential target to suppress symptoms of diabetes and is of interest in a number of other diseases associated with chronic inflammation, such as inflammatory bowel disease and bronchopulmonary dysplasia. Screening and optimization have previously produced small molecules that inhibit the activity of RAGE in cell-based assays, but efforts to develop a therapeutically viable direct-binding RAGE inhibitor have yet to be successful. Here, we show that a fragment-based approach can be applied to discover fundamentally new types of RAGE inhibitors that specifically target the ligand-binding surface. A series of systematic assays of structural stability, solubility, and crystallization were performed to select constructs of the RAGE ligand-binding domain and optimize conditions for NMR-based screening and co-crystallization of RAGE with hit fragments. An NMR-based screen of a highly curated ~14 000-member fragment library produced 21 fragment leads. Of these, three were selected for elaboration based on structure-activity relationships generated through cycles of structural analysis by X-ray crystallography, structure-guided design principles, and synthetic chemistry. These results, combined with crystal structures of the first linked fragment compounds, demonstrate the applicability of the fragment-based approach to the discovery of RAGE inhibitors.

Optimization of Ultrasound-Assisted Extraction of Anti-Glycation Agents from Ecklonia cava

ABSTRACT Ultrasound-assisted extraction conditions were optimized to improve the extraction of advanced glycation end products (AGEs) inhibitors from Ecklonia cava extracts using response surface methodology. Conditions considered were extraction temperature (30–70°C), ethanol concentration (20–100%), and extraction time (10–50 min). Dependent variables were dieckol content, yield, and degree of AGEs inhibition measured in three anti-glycation assay models; namely, bovine serum albumin (BSA)-fructose (Fru), BSA-methylglyoxal (MGO), and BSA-glyoxal (GO). Overall, dieckol content increased, but AGEs formation and yield decreased, with increasing ethanol concentration. In the BSA-MGO model, AGEs inhibition decreased with increasing extraction temperature. The four-dimensional graphs were superimposed to select optimum conditions. The optimum conditions were determined as 50–60°C of extraction temperature, 70%–85% of ethanol concentration, and 25–35 min of extraction time. The suitability of the prediction model was evaluated by comparing the actual and predicted values of responses, and the results confirmed that our prediction model is suitable. IC50 of Ecklonia cava extract against BSA-Fru, BSA-MGO, and BSA-GO was 0.44, 0.56, and 0.73 mg/mL, respectively. The AGEs inhibition effect of Ecklonia cava extract in the BSA-MGO model was better than that of aminoguanidine at the same concentration.

α-Glucosidase and advanced glycation end products inhibition with Vernonia amygdalina root and leaf extracts: new data supporting the antidiabetic properties.

This study aims to investigate antidiabetic activity of several Vernonia amygdalina extracts to study their potential use in medicine. Aqueous and ethanol extracts were obtained by maceration and Soxhlet extraction from roots and leaves of V. amygdalina. The extracts were tested as inhibitors of α-glucosidase activity and of advanced glycation end products (AGEs) formation. Further, radical scavenging activity was examined detecting the oxygen radical absorbance capacity, while the potential cytotoxicity of extracts was estimated with MTT assay. In aqueous and ethanol extracts, several polyphenolic compounds were identified; in detail, (-)-catechin and luteolin were found in leaf extracts, while caffeic acid, chlorogenic acid and the terpenoid vernodalol were recognized in root extracts. Regarding antidiabetic activity, the aqueous root extracts efficiently inhibited α-glucosidase activity in a concentration-dependent manner (IC50 = 5.6 µg/ml and 39.8 µg/ml, respectively of macerated and Soxhlet extracts), whereas those obtained from leaves exhibited lower potency. Furthermore, AGEs formation was reduced by all V. amygdalina extracts starting from 10 µg/ml. The aqueous extracts of V. amygdalina roots obtained by maceration and Soxhlet extraction show remarkable anti-α-glucosidase activity, and all extracts have favourable antiglycation and antioxidant activities.

Self-assembled elastin-like polypeptide fusion protein coacervates as competitive inhibitors of advanced glycation end-products enhance diabetic wound healing

Chronic and non-healing skin wounds are some of the most significant complications in patients with advanced diabetes. A contributing mechanism to this pathology is the non-enzymatic glycation of proteins due to hyperglycemia, leading to the formation of advanced glycation end products (AGEs). AGEs bind to the receptor for AGEs (RAGE), which triggers pro-inflammatory signals that may inhibit the proliferative phase of wound healing. Soluble forms of RAGE (sRAGE) may be used as a competitive inhibitor of AGE-mediated signaling; however, sRAGE is short-lived in the highly proteolytic wound environment. We developed a recombinant fusion protein containing the binding domain of RAGE (vRAGE) linked to elastin-like polypeptides (ELPs) that self-assembles into coacervates at around 30–31 °C. The coacervate size was concentration and temperature-dependent, ranging between 500 and 1600 nm. vRAGE-ELP reversed several AGE-mediated changes in cultured human umbilical vein endothelial cells, including a decrease in viable cell number, an increase in levels of reactive oxygen species (ROS), and an increased expression of the pro-inflammatory marker, intercellular adhesion molecule-1 (ICAM-1). vRAGE-ELP was stable in elastase in vitro for 7 days. When used in a single topical application on full-thickness excisional skin wounds in diabetic mice, wound closure was accelerated, with 90% and 100% wound closure on post-wounding days 28 and 35, respectively, compared to 62% and 85% on the same days in animals treated with vehicle control, consisting of ELP alone. This coacervate system topically delivering a competitive inhibitor of AGEs has potential for the treatment of diabetic wounds.

Variation in Anti-Glycation and Cross-Link Breaking Effects of Crude Extracts of Moringa oleifera Leaf, Seed and Root

Study and comparing the anti-glycation and cross-link breaking effects of Moringa oleifera leaf, seed and root extracts with aminoguanidine, a known inhibitor of advanced glycation end-products (AGEs). Their phytochemical composition and extraction yields were also assessed. All seed and root extracts demonstrated significantly higher anti-glycation effect than aminoguanidine against total immunogenic AGEs (p &lt; 0.05). Both seed and root polar (methanol and water) extracts exhibited significantly higher anti-glycation effect against N′-(carboxymethyl)lysine than aminoguanidine (p &lt; 0.05). Polar extracts of all M. oleifera tested parts demonstrated higher anti-glycation activity against fluorescent AGEs than aminoguanidine (p &lt; 0.05). With exception to the aqueous root extracts, all leaf, seed and root extracts of M. oleifera demonstrated an ability to break AGE-protein cross-links. The highest cross-link breaking effect was exhibited by ethyl acetate extract of leaves.The methanol extract of seeds of M. oleifera showed the presence of all tested secondary metabolites.

저온 플라즈마 처리된 녹차 유래의 최종당화산물 생성 억제물질의 동정

Green tea (Camellia sinensis) with abundant phenolic compounds is considered to a major dietary source of flavan 3-ols such as (−)-epigallocatechin gallate (EGCG). Here, we assessed the effects of non-thermal dielectric barrier discharge (DBD) plasma on green tea extract using spectroscopy and bioassays. Plasma-induced structural changes in EGCG in green tea resulted in the isolation of two methylene-bridge dimers, oolonghomobisflavan A (1) and B (2). The structures of these compounds were characterized using nuclear magnetic resonance and mass spectroscopy data. The symmetric dimer 1 connected by a methylene linkage was the most potent inhibitor of advanced glycation end products (AGEs) formation (IC50, 8.2±0.5 μM). The radical scavenging capacity of against hydroxyl, and stereoisomers 1 and 2 was more potent than that of the positive control ((+)-catechin). These major products purified by treating green tea with DBD plasma for 60 min were quantified by HPLC. Our results provide evidence that structural changes of EGCG in green tea extract induced by plasma might enhance biological efficacy.

PARADOXAL ACTIVITY OF AMINOGUANIDINE IN THE MODEL OF GLYCOXIDATION WITH COPPER CATIONS

The well-known inhibitor of advanced glycation-end products (AGEs) formation aminoguanidine, was studied using a previously tuned model of glycoxidation in copper-contained media (glucose 0,5 M, HEPES 0,1 M, CuSO4x5H2O 40 μM). As a result of the research, it was confirmed that aminoguanidine (1, 3, 10 mM) under conditions of glyoxidation with copper does not suppress the formation of argpyrimidine by detection of argpirimidine's self-fluorescence (Aex 330 nm, Aem 360-450 nm). Possible reasons of the enormous reaction are discussed.

Advanced Glycation End Product Inhibition by Alkaloids from Ocotea paranapiacabensis for the Prevention of Skin Aging.

A bioassay-guided study aiming at identifying inhibitors of the glycation process on the leaves of Ocotea paranapiacabensis afforded four benzylisoquinoline alkaloids (1-4), with 1 and 2 identified as new naturals products, while 3 and 4 were previously described in the literature, with 3 being identified as magnocurarine. Purification was performed by column chromatography and high-performance liquid chromatography. The structures of the isolated compounds were elucidated by spectroscopic methods including UV, NMR, and HRMS. The process of skin aging has been recently associated with advanced glycation end products (AGEs), and strategies inhibiting their formation have been addressed by pharmaceutical companies for the development of novel antiaging compounds. Alkaloids 1-4 were evaluated for their potential to inhibit AGE formation and showed inhibition of 62.9%, 83.3%, 26.1%, and 98.2% (150 μM), respectively. The antiaging potential of compounds 1 and 4 were evaluated with a reconstructed human skin model in vitro, and results showed a decrease in dermis contraction (8.7% and 4.2% respectively for 1 and 4) when compared to the glycated control (57.4%). Additionally, absorption, distribution, metabolism, and excretion (ADME) and toxicity properties were predicted using in silico methods, and the results were considered significantly promising for alkaloids 1 and 4 to continue the development of these alkaloids with skincare properties.

Polyphenols in Alzheimer's Disease and in the Gut-Brain Axis.

Polyphenolic antioxidants, including dietary plant lignans, modulate the gut–brain axis, which involves transformation of these polyphenolic compounds into physiologically active and neuroprotector compounds (called human lignans) through gut bacterial metabolism. These gut bacterial metabolites exert their neuroprotective effects in various neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and also have protective effects against other diseases, such as cardiovascular diseases, cancer, and diabetes. For example, enterolactone and enterodiol, the therapeutically relevant polyphenols, are formed as the secondary gut bacterial metabolites of lignans, the non-flavonoid polyphenolic compounds found in plant-based foods. These compounds are also acetylcholinesterase inhibitors, and thereby have potential applications as therapeutics in AD and other neurological diseases. Polyphenols are also advanced glycation end product (AGE) inhibitors (antiglycating agents), and thereby exert neuroprotective effects in cases of AD. Thus, gut bacterial metabolism of lignans and other dietary polyphenolic compounds results in the formation of neuroprotective polyphenols—some of which have enhanced blood–brain barrier permeability. It is hypothesized that gut bacterial metabolism-derived polyphenols, when combined with the nanoparticle-based blood–brain barrier (BBB)-targeted drug delivery, may prove to be effective therapeutics for various neurological disorders, including traumatic brain injury (TBI), AD, and PD. This mini-review addresses the role of polyphenolic compounds in the gut–brain axis, focusing on AD.

Biosynthesized ZnO-NPs from Morus indica Attenuates Methylglyoxal-Induced Protein Glycation and RBC Damage: In-Vitro, In-Vivo and Molecular Docking Study

The development of advanced glycation end-products (AGEs) inhibitors is considered to have therapeutic potential in diabetic complications inhibiting the loss of the biomolecular function. In the present study, zinc oxide nanoparticles (ZnO-NPs) were synthesized from aqueous leaf extract of Morus indica and were characterized by various techniques such as ultraviolet (UV)-Vis spectroscopy, Powder X-Ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FT-IR), Scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS). Further, the inhibition of AGEs formation after exposure to ZnO-NPs was investigated by in-vitro, in-vivo, and molecular docking studies. Biochemical and histopathological changes after exposure to ZnO-NPs were also studied in streptozotocin-induced diabetic rats. ZnO-NPs showed an absorption peak at 359 nm with a purity of 92.62% and ~6–12 nm in size, which is characteristic of nanoparticles. The images of SEM showed agglomeration of smaller ZnO-NPs and EDS authenticating that the synthesized nanoparticles were without impurities. The biosynthesized ZnO-NPs showed significant inhibition in the formation of AGEs. The particles were effective against methylglyoxal (MGO) mediated glycation of bovine serum albumin (BSA) by inhibiting the formation of AGEs, which was dose-dependent. Further, the presence of MGO resulted in complete damage of biconcave red blood corpuscles (RBCs) to an irregular shape, whereas the morphological changes were prevented when they were treated with ZnO-NPs leading to the prevention of complications caused due to glycation. The administration of ZnO-NPs (100 mg Kg−1) in streptozotocin(STZ)-induced diabetic rats reversed hyperglycemia and significantly improved hepatic enzymes level and renal functionality, also the histopathological studies revealed restoration of kidney and liver damage nearer to normal conditions. Molecular docking of BSA with ZnO-NPs confirms that masking of lysine and arginine residues is one of the possible mechanisms responsible for the potent antiglycation activity of ZnO-NPs. The findings strongly suggest scope for exploring the therapeutic potential of diabetes-related complications.

Moracin derivatives from Morus Radix as dual BACE1 and cholinesterase inhibitors with antioxidant and anti-glycation capacities

AimsMorus, a member of the family Moraceae and commonly known as the mulberry, comprises a pharmaceutically important plant group whose major constituents are the moracins. Moracin derivatives have received great attention because they exhibit a diverse range of biological functionalities. However, no studies have considered the anti-Alzheimer's disease (AD) and anti-glycation potential of moracin derivatives. Main methodsWe designed the current study to explore the anti-AD activity of moracin derivatives via in vitro inhibition of BACE1 and cholinesterase, their antioxidant activity via scavenging ONOO− and ABTS+ radicals, and their anti-diabetic activity through inhibition of advanced glycation end-products (AGEs) formation. Moreover, to define the mechanism of action of moracin derivatives in depth, we performed in silico molecular modeling using a computer-assisted drug design and modeling program. Key findingsAmong the four Morus-derived moracins tested, moracin S, which has a prenyl moiety in the 2-aryl benzofuran scaffold, possessed the highest BACE1 inhibitory activity. It also, in a dose-dependent fashion, decreased ONOO−-mediated bovine serum albumin (BSA) nitration and formation of AGEs and amyloid cross-β structures in the glycated BSA system, and it showed notable radical scavenging activity. In addition, enzyme kinetic and molecular docking studies demonstrated that moracin S is a potent, competitive BACE1 inhibitor that could interact with key catalytic aspartyl residues. SignificanceThe prenyl moiety in the 2-aryl benzofuran structure plays a crucial role in inhibition of BACE1. These in vitro and in silico results provide valuable information for the design of anti-AD drugs.

Antioxidant therapy of type 2 diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a nerve damage caused by chronically high blood glucose and dia-betes. It leads to loss of sensation and sometimes pain in feet, legs and hands. More than 50% of type 2 diabetic patients will develop this complication. To date, the pathogenesis of DPN remains unclear. However, hyperglycemia, metabolic imbal-ance, and oxidative stress appear in the neurons of DPN patients. In addition, oxidative stress results in the change of poly-ADP-ribose polymerase, advanced glycation end products, polyol, protein kinase C, and hexosamine and causes endothelial cell damage and vascular dysfunction, consequently causing peripheral nerve ischemia and hypoxia. According to the oxi-dative stress and related pathways of DPN, some drugs are used in clinical treatment, such as taurine, acetyl-L-carnitine, aldose reductase inhibitors (epalrestat, ranirestat), α-lipoic acid (ALA), protein kinase C inhibitor (ruboxistaurin), inhibitor of poly ADPribose polymerase (nicotinamide), angiotensin-converting enzyme inhibitor (trandolapril), and advanced gly-cation end product inhibitors (aspirin, benfotiamine). However, no drugs can completely cure it. In this review, we sum-marize the pathogenesis of DPN and suggest that amifostine, which is clinically used as an antioxidant, might be used for the treatment of DPN.

D‐Ribose Induced NLRP3 Inflammasome Activation in Podocytes by Increase in Advanced Glycation End‐Products

Recent studies have demonstrated that D‐ribose levels are increased in patients with type II diabetes mellitus and that increased blood D‐ribose levels are involved in the development of diabetic complications such as diabetic encephalopathy and nephropathy. However, the mechanisms mediating the pathogenic role of D‐ribose remain poorly understood. In the present study, we treated podocytes with different concentrations of D‐ribose and examined its potential effects on NLRP3 inflammasome activation and podocyte function. Using confocal microscopy, D‐ribose was found to markedly increase the co‐localization of caspase‐1 and NLRP3 by 1.8 folds compared to control, which suggests enhanced NLRP3 inflammasome formation. By ELISA, we demonstrated that in podocytes treated with D‐ribose, a major product of NLRP3 inflammasome‐IL‐1β was significantly increased by 2.05 folds, indicating the activation of NLRP3 inflammasomes. Western blot analysis further confirmed that D‐ribose increased the level of active caspase‐1 in podocytes by 2.09 folds, another parameter for activation of NLRP3 inflammasomes, which was substantially attenuated by caspase‐1 inhibitor, YvAD and ROS scavenger, NAC, respectively. In addition, D‐ribose‐induced NLRP3 inflammasome activation could be blocked by inhibitor of advanced glycation end‐products (AGEs) formation and their chemical breaker or receptor antagonist, aminoguanidine, aylthiazolium chloride and RAGE siRAGE by 43%, 50% and 73%, respectively. These results suggest that D‐ribose induces NLRP3 inflammasome activation in podocytes in an AGE‐dependent manner, which may be a triggering mechanism of diabetic nephropathy.Support or Funding InformationSupported by NIH grants DK54927 and HL075316 to Pinlan Li, NSFC grants 81573763 to Weiwei Li, and NSFC grants 81530099 to Xuemei WangThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Inhibition of advanced glycation endproducts during fish sausage preparation by transglutaminase and chitosan oligosaccharides induced enzymatic glycosylation.

Advanced glycation endproducts (AGEs) are the harmful products of non-enzymatic reactions in foods formed during the heating process. In order to reduce the content of AGEs in foods, the inhibitory effect of different proportions of transglutaminase (TGase) and chitosan oligosaccharides (COS) on the AGEs of seabream fish meat sausage was studied. The results indicated that the TGase/COS ratio of 1 : 1 could inhibit the formation of AGEs, showing especially a decreased Nε-carboxymethyl-lysine (CML) content and a twice higher inhibition rate (36.4%) than that by aminoguanidine (17.4%), a commonly effective positive inhibitor of AGEs. The data of lysine, fructosamine, and glucosamine contents, combined with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analyses, demonstrated that cross-linking of proteins and glycosylation of glutamine induced by TGase and COS resulted in steric hindrance that inhibited glycation. These findings revealed that TGase catalyzed glycosylation with COS differently from general antioxidants had potential as an effective treatment to inhibit the formation of AGEs in fishery products.

Inhibition of advanced glycation endproduct (AGE) rescues against streptozotocin-induced diabetic cardiomyopathy: Role of autophagy and ER stress

Diabetes mellitus leads to oxidative stress and contractile dysfunction in the heart. Although several rationales have been speculated, the precise mechanism behind diabetic cardiomyopathy remains elusive. This study was designed to assess the role of inhibition of advanced glycation endproducts (AGE) in streptozotocin (STZ)-induced diabetic cardiac dysfunction. Cardiac contractile function was assessed in normal C57BL/6 and STZ (200mg/kg, single injection and maintained for 2 wks)-induced diabetic mice treated with or without the AGE inhibitor aminoguanidine (50mg/kg/d in drinking water) for 2 weeks using echocardiography and IonOptix MyoCam techniques. Diabetes compromised cardiac contractile function shown as reduced fractional shortening and ejection fraction, enlarged left ventricular end systolic/diastolic diameters, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged shortening and relengthening duration as well as impaired intracellular Ca2+ homeostasis, the effects of which were alleviated or reversed by aminoguanidine treatment. Diabetes also inhibited autophagy, increased ER stress and phosphorylation of pro-hypertrophic signaling molecules Akt and mTOR, the effect of which was reversed by aminoguanidine. In vitro study revealed that methylglyoxal-derived AGE (MG-AGE) incubation in isolated cardiomyocytes promoted oxidation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) and production of superoxide, the effects of which were negated by the autophagy inducer rapamycin, the ER stress chaperone TUDCA or the antioxidant N-acetylcysteine. Taken together, these data revealed that inhibition of AGE formation rescues against experimental diabetes-induced cardiac remodeling and contractile dysfunction possible through regulation of autophagy and ER stress.