Identification of RAGE Inhibitors from Curcuma caesia Roxb: Implications in Treatment against Diabetic Complications.

Oxidative stress, hyper-inflammatory responses, and protein glycation are the chief contributing factors in the pathogenesis of several diseases. This study aimed to explore the therapeutic role of myrrh in health management through in vitro and in silico studies. Antioxidant potential, anti-inflammatory potential, antiglycation, and advanced glycation end products (AGEs) formation inhibition activities were determined by various in vitro assays. Molecular docking was performed to predict the non-covalent binding of macromolecules (receptor) and a small molecule (ligand). Myrrh extract contained significant antioxidant activity as reflected by FRAP value (16.12 µg ascorbic acid/100 mg dry weight), the maximum percentage of DPPH scavenging (57.71%), and maximum hydrogen peroxide reducing activity (58.71%) at a concentration of 600 µg/mL. Further, the extract exhibited maximum protection from bovine serum albumin (BSA) denaturation inhibition (53.47%), anti-proteinase action (43.517%), and egg albumin denaturation inhibition (44.95%) at a dose of 600 µg/mL concentration. Myrrh is used in pharmacy as an antiseptic, anti-inflammatory, antimicrobial, antifungal, and anti-venom remedy. This study aimed to explore the antioxidant, anti-inflammatory, antiarthritic, antiglycation, and advanced glycation end products (AGEs) formation inhibition ability of methanolic myrrh extract. It was found that myrrh has good antioxidant potential due to plenty of flavonoids and polyphenolic compounds, as reflected by results of the 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH) assay, FRAP (ferric reducing antioxidant power) test, and hydrogen peroxide reducing test. Furthermore, myrrh methanolic extract was found to be significantly effective against heat-induced albumin denaturation, and percent inhibition of denaturation increases with increased extract concentration. The presence of myrrh extract at a dose of 600 μg/mL decreased browning intensity (59.38%), percent aggregation index (59.88%), and percentage amyloid structure (56.13%). We used molecular docking tools to study the role of myrrh in oxidative stress (Catalase), antioxidant property (Superoxide dismutase), and antiviral property (spike protein S). The molecular docking analysis confirmed four phytoconstituents; 2,3-Furandione, Curzerene, delta-Elemene, and Furanoeudesma-1,3-Diene interact with catalase and superoxide dismutase. Curzerene and Furanoeudesma-1,3-Diene showed remarkable interaction with SARS-CoV-2 spike protein S. Our data suggest that myrrh resin extract can be used to develop a suitable alternative therapy for various diseases linked with oxidative stress, inflammation, glycation, and AGEs.

the receptor for advanced glycation end products (RAGE) interacts with a diverse range of endogenous ligands termed advanced glycation end products (AGEs), which are formed by the Maillard reaction, a nonenzymatic process linking reducing sugar groups to proteins, lipids, and nucleic acids. AGEs

The increased formation of advanced glycation endproducts (AGEs) constitutes a potential mechanism of hyperglycaemia-induced micro- and macrovascular disease in diabetes. In vitro and animal experiments have shown that various interventions can inhibit formation and/or actions of AGEs, in particular the specific AGE inhibitor aminoguanidine and the AGEs crosslink breaker alagebrium, and the B vitamins pyridoxamine and thiamine, and the latter's synthetic derivative, benfotiamine. The potential clinical value of these interventions, however, remains to be established. The present review provides, from the clinical point of view, an overview of current evidence on interventions in the glycation pathway relating to (i) the clinical benefits of specific AGE inhibitors and AGE breakers and (ii) the potential AGE-inhibiting effects of therapies developed for purposes unrelated to the glycation pathway. We found that safety and/or efficacy in clinical studies with the specific AGE inhibitor, aminoguanidine and the AGE breaker, alagebrium, appeared to be a concern. The clinical evidence on the potential AGE-inhibiting effects of B vitamins is still limited. Finally, current evidence for AGE inhibition by therapies developed for purposes unrelated to glycation is limited due to a large heterogeneity in study designs and/or measurement techniques, which have often been sub-optimal. We conclude that, clinical evidence on interventions to inhibit formation and/or action of AGEs is currently weak and unconvincing.

Markers of and Risk Factors for the Development and Progression of Diabetic Kidney Disease

In this study, bovine serum albumin (BSA)/methylglyoxal (MGO) non-enzymatic glycosylation reaction system was used for the evaluation of the inhibitory effects of Moutan Cortex extracts on the formation of AGEs. The HPLC-LC-ESI-MS/MS technology was adopted to test and indentify active components in Moutan Cortex against AGEs formation. The different concentrations of extracts (crude herb concentration 50, 100, 150, 200, 250 g•L⁻¹) from Moutan Cortexwas determined by fluorospectrophotometry, indicating an activity against AGEs formation in different concentrations of extracts, the inhibition ratio were (36.2±5.3)%, (43.5±6.2)%, (55.4±7.8)%, (68.6±6.7)%, (70.4±8.2)%, respectively after 6-day reaction in a dose dependent manner. Besides, the forming speed of AGEs tended to be steady after 24 h reaction. The HPLC technology was used to analyze chromatograms before and after the incubation of Moutan Cortex and methylglyoxal, identify changes in five chromatographic peaks and show decrease or increase in chromatographic peaks. These substances were trigalloyl glucose, tetragalloyl glucose, galloylpaeoniflorin, hexagalloyl glucose and benzoylpaeoniflorin after LC-ESI-MS/MS identification. Extracts from Moutan Cortex showed the remarkable inhibitory effects against formation of AGEs in BSA/glucose system. Furthermore, these potential active components might be associated with the efficacy of Moutan Cortex on treatment of diabetic nephropathy, which enriches basic studies for Moutan Cortex and provides ideas and reference basis for subsequent studies.

Formation of advanced glycation end-products in silver carp (Hypophthalmichthys molitrix) surimi products during heat treatment as affected by freezing-thawing cycles

Various mechanisms including polyol pathway along with a complex integrating paradigm with oxidative stress and advanced glycation end products (AGE) formation have been implicated in the pathogenesis of diabetic nephropathy. The present study was aimed at investigating a well known antioxidant, pterostilbene for its therapeutic role in streptozotocin-induced diabetic nephropathy in rats. The effect of pterostilbene was investigated by assessing the key markers of kidney function along with the morphological changes in the kidney. Further, the effect of pterostilbene on the formation of AGEs, aldose reductase (AR) inhibition and lipid peroxidation was compared with that of a standard AR inhibitor, fidarestat. The results revealed that pterostilbene significantly decreased the blood glucose levels, urinary protein excretion, serum creatinine and blood urea nitrogen in diabetic rats. Administration of pterostilbene to diabetic rats decreased kidney lipid peroxides and nitrate levels along with decrease in AGEs formation. In addition, pterostilbene was found to inhibit kidney AR activity with a decrease in serum TGF β levels. Thus, the results obtained in this study underline the potential of pterostilbene as a possible therapeutic agent against diabetic complications such as nephropathy.

The advanced stage of the glycation process (also called the "Maillard reaction") that leads to the formation of advanced glycation end-products (AGEs) plays an important role in the pathogenesis of angiopathy in diabetic patients and in the aging process. AGEs elicit a wide range of cell-mediated responses that might contribute to diabetic complications, vascular disease, renal disease, and Alzheimer's disease. Recently, it has been proposed that AGE are not only created from glucose per se, but also from dicarbonyl compounds derived from glycation, sugar autoxidation, and sugar metabolism. However, this advanced stage of glycation is still only partially characterized and the structures of the different AGEs that are generated in vivo have not been completely determined. Because of their heterogeneity and the complexity of the chemical reactions involved, only some AGEs have been characterized in vivo, including N-carboxymethyllysine (CML), pentosidine, pyrraline, and crosslines. In this article, we provide a brief overview of the pathways of AGE formation and of the immunochemical methods for detection of AGEs, and we also provide direct immunological evidence for the existence of five distinct AGE classes (designated as AGE-1 to -5) within the AGE-modified proteins and peptides in the serum of diabetic patients on hemodialysis. We also propose pathways for the in vivo formation of various AGEs by glycation, sugar autoxidation, and sugar metabolism.

BackgroundMethylglyoxal (MG) is one of the most reactive glycating agents, which result the formation of advanced glycation end-products (AGEs) that have been implicated in the progression of age-related diseases. Inhibition of MG-induced AGE formation is the imperative approach for alleviating diabetic complications. The objective of this study was to investigate the MG-trapping abilities of herbal medicines and their inhibitory activities on the formation of MG-derived AGEs.MethodsThe aqueous extract of herbal medicines was measured for the content of total phenolic compounds and the antioxidant activity by Folin-Ciocalteu assay and the 1,1-diphenyl 2-picrylhydrazyl (DPPH) radical scavenging activity, respectively. The extracts were investigated the MG-trapping ability by high performance liquid chromatography (HPLC). The extracts were incubated with BSA and MG at 37 °C for 1 day. The formation of MG-derived AGEs was measured.ResultsTotal phenolic compounds of eleven herbal medicines showed marked variations, ranging from 12.16 to 272.36 mg gallic acid equivalents/g extract. All extracts (1 mg/mL) markedly exhibited the DPPH radical scavenging activity (0.31–73.52 %) and the MG-trapping abilities (13.97–58.97 %). In addition, they also inhibited the formation of MG-derived AGEs by 4.01–79.98 %. The results demonstrated that Rhinacanthus nasutus, Syzygium aromaticum, and Phyllanthus amarus were the potent inhibitors against the formation of MG-derived AGEs. The positive correlations between the contents of phenolics and % MG trapping (r = 0.912, p < 0.01) and % inhibition of MG-derived AGEs (r = 0.716, p < 0.01) were observed in the study. Furthermore, there was a moderate positive correlation between % MG trapping and % inhibition of MG-derived AGEs (r =0.584, p < 0.01).ConclusionsRhinacanthus nasutus, Syzygium aromaticum, and Phyllanthus amarus could reduce the formation of MG-derived AGEs through their MG-trapping abilities. These findings are relevant for focusing on potential herbal medicines to prevent or ameliorate AGE-mediated diabetic complications.

Available data indicate that the development of diabetic nephropathy is linked to hyperglycaemia. Glucose reacts nonenzymatically with proteins to form Schiff base and Amadori products. Further incubation of these early products leads to the formation of advanced glycation end-products (AGEs). AGEs seem to play a central role in the progression of diabetic nephropathy. Immunohistochemically, AGEs were also detected in an expanded mesangial matrix, especially in nodular lesions from patients with diabetic nephropathy. AGEs staining was noted in the Bowman's capsule, periglomerular fibrosis in sclerosing glomeruli. In our ultrastructural study of mesangial matrix from patients with diabetic nephropathy by high-resolution scanning electron microscopy after cellular removal, the meshwork structure was evident at higher magnification. In nodular lesions, the loose meshwork structure appeared to be composed of various sized strands, ranging from 6 to 24 nm (mean +/- SD: 11.4 +/- 3.8 nm). The pore sizes were variable, ranging from 4 to 70 nm (mean +/- SD: 23.6 +/- 12.3 nm), and were statistically larger than those of normal controls. As the AGEs are localized most notably in nodular lesions, advanced glycations play a role in the progression of diabetic nephropathy through impairment of the assembly of matrix proteins in vivo. Because type V and type VI collagens are the major components of nodular lesions, increases in these interstitial and fibril or microfibril collagens may contribute to the formation of wider strands in the mesangial matrix of a nodular lesion. As no metalloprotease that is specific for type VI collagen has been identified thus far, AGEs formation might occur preferentially in type VI collagen-rich nodular lesions, which are sites of slow turnover.

α-Amylase inhibition, anti-glycation property and characterization of the binding interaction of citric acid with α-amylase using multiple spectroscopic, kinetics and molecular docking approaches

Prevention and treatment of diabetic nephropathy

The dicarbonyl compound methylglyoxal (MGO) is a major precursor in the formation of advanced glycation endproducts (AGEs). MGO and AGEs are increased in subjects with diabetes and are associated with fatal and non-fatal cardiovascular disease. Previously we have shown that plasma MGO concentrations rapidly increase in the postprandial phase, with a higher increase in individuals with type 2 diabetes. In current study, we investigated whether postprandial MGO formation in plasma and tissues originates from exogenous glucose and whether the increased plasma MGO concentration leads to a fast formation of MGO-derived AGEs. We performed a stable isotope labelled oral glucose tolerance test (OGTT) in 12 healthy males with universally labelled D(+)13C glucose. Analysis of plasma labelled 13C3 MGO and glucose levels at eleven time-points during the OGTT revealed that the newly formed MGO during OGTT is completely derived from exogenous glucose. Moreover, a fast formation of protein-bound MGO-derived AGEs during the OGTT was observed. In accordance, ex vivo incubation of MGO with plasma or albumin showed a rapid decrease of MGO and a fast increase of MGO-derived AGEs. In an intraperitoneal glucose tolerance test in C57BL/6J mice, we confirmed that the formation of postprandial MGO is derived from exogenous glucose in plasma and also showed in tissues that MGO is increased and this is also from exogenous glucose.Collectively, increased formation of MGO during a glucose tolerance test arises from exogenous glucose both in plasma and in tissues, and this leads to a fast formation of MGO-derived AGEs.

Novel role of AGE-R1/OST48 in the metabolome and proteome promoting ER stress in the kidney and liver

Objective To study the molecular mechanisms of prohibitin in the diabetic nephropathy and its effect. Methods C57BLKS/J db/db mice were selected randomly as diabetic model group (DM group, n=8) and the db/m mice were selected as control group (CC, n=8), and C57BLKS/J db/db mice lavage treated with GSPB2 for 10 weeks were considered as treatment group (30mg/kg body weight/day, DMT, n=8). At the end of 18 weeks, fasting blood glucose (FBG), advanced glycation end products (AGEs) and monocyte chemotactic protein 1 (MCP1) were determined. Morphological changes of the kidney tissue were examined by light microscopy and transmission electron microscope. The expression of prohibitin in the kidney tissue was determined by Western blot. Results The body weight was higher in DM groups than in control group at 8, 12, 16, 18 weeks (all P<0.01). The body weight was significantly inhibited at 12, 16, 18 weeks after GSPB2 administration in the DMT group as compared to the DM group (all P<0.05). Serum FBG, AGEs and MCP-1 levels were significantly higher in DM group than in control group (all P<0.01). GSPB2 significantly decreased the serum levels of FBG, AGEs and MCP-1 in db/db mice (all P<0.01). The glomerular volume, mesangial cell proliferation, extracellular matrix in DM group was significantly increased as compared with CC group by light microscopy. GSPB2 significantly reduced the glomerular volume, mesangial cell proliferation in db/db mice. The result of ultrastructural microscopy showed that in DM group, mesangial cell was inserted into the sub-endothelium, basement membrane became thicken, the number of podocytes was decreased and the podocytes were fused, and the thicken basement membrane and podocytes injure were improved in the DMT group. Moreover, the protein expression of prohibitin was higher in DM group than in control group (P<0.01), while GSPB2 could decrease the protein expression of prohibitin (P<0.01). Conclusions The mechanism of protective effects of GSPB2in diabetic nephropathy can be attributed to its anti-glycation, anti-inflammatory and the increase of prohibitin expression, which will provide a theoretical basis for the prevention and treatment of diabetic nephropathy. Key words: Diabetic nephropathy; Ceu prohibitin; Procyanidins