International Journal of Molecular Sciences

Editorial

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8 pages, 259 KiB

Open AccessEditorial

An Introduction to the Special Issue “Protein Glycation in Food, Nutrition, Health and Disease”

by Naila Rabbani and Paul J. Thornalley

Int. J. Mol. Sci. 2022, 23(21), 13053; https://doi.org/10.3390/ijms232113053 - 27 Oct 2022

Cited by 2 | Viewed by 1881

Abstract

On 20–24 September 2021, leading researchers in the field of glycation met online at the 14th International Symposium on the Maillard Reaction (IMARS-14), hosted by the authors of this introductory editorial, who are from Doha, Qatar [...] Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

Research

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13 pages, 12542 KiB

Open AccessArticle

Analysis of Serum Advanced Glycation Endproducts Reveals Methylglyoxal-Derived Advanced Glycation MG-H1 Free Adduct Is a Risk Marker in Non-Diabetic and Diabetic Chronic Kidney Disease

by Naila Rabbani, Antonysunil Adaikalakoteswari, James R. Larkin, Sianna Panagiotopoulos, Richard J. MacIsaac, Dennis K. Yue, Gregory R. Fulcher, Matthew A. Roberts, Merlin Thomas, Elif Ekinci and Paul J. Thornalley

Int. J. Mol. Sci. 2023, 24(1), 152; https://doi.org/10.3390/ijms24010152 - 21 Dec 2022

Cited by 9 | Viewed by 2707

Abstract

Accumulation of advanced glycation endproducts (AGEs) is linked to decline in renal function, particularly in patients with diabetes. Major forms of AGEs in serum are protein-bound AGEs and AGE free adducts. In this study, we assessed levels of AGEs in subjects with and [...] Read more.

Accumulation of advanced glycation endproducts (AGEs) is linked to decline in renal function, particularly in patients with diabetes. Major forms of AGEs in serum are protein-bound AGEs and AGE free adducts. In this study, we assessed levels of AGEs in subjects with and without diabetes, with normal renal function and stages 2 to 4 chronic kidney disease (CKD), to identify which AGE has the greatest progressive change with decline in renal function and change in diabetes. We performed a cross-sectional study of patients with stages 2–4 CKD, with and without diabetes, and healthy controls (n = 135). Nine protein-bound and free adduct AGEs were quantified in serum. Most protein-bound AGEs increased moderately through stages 2–4 CKD whereas AGE free adducts increased markedly. Methylglyoxal-derived hydroimidazolone MG-H1 free adduct was the AGE most responsive to CKD status, increasing 8-fold and 30-fold in stage 4 CKD in patients without and with diabetes, respectively. MG-H1 Glomerular filtration flux was increased 5-fold in diabetes, likely reflecting increased methylglyoxal glycation status. We conclude that serum MG-H1 free adduct concentration was strongly related to stage of CKD and increased in diabetes status. Serum MG-H1 free adduct is a candidate AGE risk marker of non-diabetic and diabetic CKD. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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16 pages, 1309 KiB

Open AccessArticle

A 4-Week Diet Low or High in Advanced Glycation Endproducts Has Limited Impact on Gut Microbial Composition in Abdominally Obese Individuals: The deAGEing Trial

by Armand M. A. Linkens, Niels van Best, Petra M. Niessen, Nicole E. G. Wijckmans, Erica E. C. de Goei, Jean L. J. M. Scheijen, Martien C. J. M. van Dongen, Christel C. J. A. W. van Gool, Willem M. de Vos, Alfons J. H. M. Houben, Coen D. A. Stehouwer, Simone J. M. P. Eussen, John Penders and Casper G. Schalkwijk

Int. J. Mol. Sci. 2022, 23(10), 5328; https://doi.org/10.3390/ijms23105328 - 10 May 2022

Cited by 15 | Viewed by 2949

Abstract

Dietary advanced glycation endproducts (AGEs), abundantly present in Westernized diets, are linked to negative health outcomes, but their impact on the gut microbiota has not yet been well investigated in humans. We investigated the effects of a 4-week isocaloric and macronutrient-matched diet low [...] Read more.

Dietary advanced glycation endproducts (AGEs), abundantly present in Westernized diets, are linked to negative health outcomes, but their impact on the gut microbiota has not yet been well investigated in humans. We investigated the effects of a 4-week isocaloric and macronutrient-matched diet low or high in AGEs on the gut microbial composition of 70 abdominally obese individuals in a double-blind parallel-design randomized controlled trial (NCT03866343). Additionally, we investigated the cross-sectional associations between the habitual intake of dietary dicarbonyls, reactive precursors to AGEs, and the gut microbial composition, as assessed by 16S rRNA amplicon-based sequencing. Despite a marked percentage difference in AGE intake, we observed no differences in microbial richness and the general community structure. Only the Anaerostipes spp. had a relative abundance >0.5% and showed differential abundance (0.5 versus 1.11%; p = 0.028, after low- or high-AGE diet, respectively). While the habitual intake of dicarbonyls was not associated with microbial richness or a general community structure, the intake of 3-deoxyglucosone was especially associated with an abundance of several genera. Thus, a 4-week diet low or high in AGEs has a limited impact on the gut microbial composition of abdominally obese humans, paralleling its previously observed limited biological consequences. The effects of dietary dicarbonyls on the gut microbiota composition deserve further investigation. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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18 pages, 1364 KiB

Open AccessArticle

In Vitro Reactivity of the Glucose Degradation Product 3,4-Dideoxyglucosone-3-ene (3,4-DGE) towards Abundant Components of the Human Blood Circulatory System

by Andrea Auditore, Sabrina Gensberger-Reigl and Monika Pischetsrieder

Int. J. Mol. Sci. 2022, 23(9), 4557; https://doi.org/10.3390/ijms23094557 - 20 Apr 2022

Cited by 4 | Viewed by 2225

Abstract

3,4-Dideoxyglucosone-3-ene (3,4-DGE) is a glucose degradation product present in processed foods and medicinal products. Additionally, its constant formation from 3-deoxyglucosone in plasma has been suggested. Due to its α,β-unsaturated dicarbonyl moiety, 3,4-DGE is highly reactive and has shown harmful effects in vitro. Here, [...] Read more.

3,4-Dideoxyglucosone-3-ene (3,4-DGE) is a glucose degradation product present in processed foods and medicinal products. Additionally, its constant formation from 3-deoxyglucosone in plasma has been suggested. Due to its α,β-unsaturated dicarbonyl moiety, 3,4-DGE is highly reactive and has shown harmful effects in vitro. Here, we investigated the impact of major components of the human blood circulatory system on 3,4-DGE in vitro. Under physiological conditions, plasma concentrations of human serum albumin (HSA) reacted efficiently with 3,4-DGE, resulting in only 8.5% of the initial 3,4-DGE concentration after seven hours (vs. 83.4% without HSA, p < 0.001). Thereby, accessible thiol groups were reduced from 0.121 to 0.064 mol/mol HSA, whereas ketoprofen binding and esterase-like activity of HSA were not affected. Plasma concentrations of glutathione (GSH) reacted immediately and completely with 3,4-DGE, leading to two stereoisomeric adducts. Plasma concentrations of immunoglobulin G (IgG) bound to 3,4-DGE to a lower extent, resulting in 62.6% 3,4-DGE after seven hours (vs. 82.2% in the control, p < 0.01). Immobilized human collagen type IV did not alter 3,4-DGE concentrations. The results indicated that particularly HSA, GSH, and IgG readily scavenge 3,4-DGE after its appearance in the blood stream, which may be associated with a reduced antioxidative and cytoprotective activity for the living cells and, thus, the human organism by blocking free thiol groups. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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11 pages, 1704 KiB

Open AccessArticle

Methylglyoxal Impairs Sister Chromatid Separation in Lymphocytes

by Leigh Donnellan, Clifford Young, Bradley S. Simpson, Varinderpal S. Dhillon, Maurizio Costabile, Peter Hoffmann, Michael Fenech and Permal Deo

Int. J. Mol. Sci. 2022, 23(8), 4139; https://doi.org/10.3390/ijms23084139 - 8 Apr 2022

Cited by 2 | Viewed by 2006

Abstract

The accurate segregation of sister chromatids is complex, and errors that arise throughout this process can drive chromosomal instability and tumorigenesis. We recently showed that methylglyoxal (MGO), a glycolytic by-product, can cause chromosome missegregation events in lymphocytes. However, the underlying mechanisms of this [...] Read more.

The accurate segregation of sister chromatids is complex, and errors that arise throughout this process can drive chromosomal instability and tumorigenesis. We recently showed that methylglyoxal (MGO), a glycolytic by-product, can cause chromosome missegregation events in lymphocytes. However, the underlying mechanisms of this were not explored. Therefore, in this study, we utilised shotgun proteomics to identify MGO-modified proteins, and label-free quantitation to measure changes in protein abundance following exposure to MGO. We identified numerous mitotic proteins that were modified by MGO, including those involved in the separation and cohesion of sister chromatids. Furthermore, the protein abundance of Securin, an inhibitor of sister chromatid separation, was increased following treatment with MGO. Cytological examination of chromosome spreads showed MGO prevented sister chromatid separation, which was associated with the formation of complex nuclear anomalies. Therefore, results from this study suggest MGO may drive chromosomal instability by preventing sister chromatid separation. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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15 pages, 2094 KiB

Open AccessArticle

Proteomic Analysis of Methylglyoxal Modifications Reveals Susceptibility of Glycolytic Enzymes to Dicarbonyl Stress

by Leigh Donnellan, Clifford Young, Bradley S. Simpson, Mitchell Acland, Varinderpal S. Dhillon, Maurizio Costabile, Michael Fenech, Peter Hoffmann and Permal Deo

Int. J. Mol. Sci. 2022, 23(7), 3689; https://doi.org/10.3390/ijms23073689 - 28 Mar 2022

Cited by 18 | Viewed by 2912

Abstract

Methylglyoxal (MGO) is a highly reactive cellular metabolite that glycates lysine and arginine residues to form post-translational modifications known as advanced glycation end products. Because of their low abundance and low stoichiometry, few studies have reported their occurrence and site-specific locations in proteins. [...] Read more.

Methylglyoxal (MGO) is a highly reactive cellular metabolite that glycates lysine and arginine residues to form post-translational modifications known as advanced glycation end products. Because of their low abundance and low stoichiometry, few studies have reported their occurrence and site-specific locations in proteins. Proteomic analysis of WIL2-NS B lymphoblastoid cells in the absence and presence of exogenous MGO was conducted to investigate the extent of MGO modifications. We found over 500 MGO modified proteins, revealing an over-representation of these modifications on many glycolytic enzymes, as well as ribosomal and spliceosome proteins. Moreover, MGO modifications were observed on the active site residues of glycolytic enzymes that could alter their activity. We similarly observed modification of glycolytic enzymes across several epithelial cell lines and peripheral blood lymphocytes, with modification of fructose bisphosphate aldolase being observed in all samples. These results indicate that glycolytic proteins could be particularly prone to the formation of MGO adducts. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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10 pages, 2568 KiB

Open AccessArticle

Insight into Isomeric Diversity of Glycated Amino Acids in Maillard Reaction Mixtures

by Haoran Xing and Varoujan Yaylayan

Int. J. Mol. Sci. 2022, 23(7), 3430; https://doi.org/10.3390/ijms23073430 - 23 Mar 2022

Cited by 11 | Viewed by 2331

Abstract

Maillard reactions generate a wide array of amino acid- and sugar-derived intermediates; the isomeric mixtures of glycated amino acids are of particular interest. Excluding stereoisomers, regioisomers, and various anomers, most amino acids can form two monoglycated and three N,N-diglycated isomers [...] Read more.

Maillard reactions generate a wide array of amino acid- and sugar-derived intermediates; the isomeric mixtures of glycated amino acids are of particular interest. Excluding stereoisomers, regioisomers, and various anomers, most amino acids can form two monoglycated and three N,N-diglycated isomers when reacted with sugars during the Maillard reaction. Using synthetic Schiff bases and Amadori compounds as standards, we have demonstrated that diagnostic ions obtained from MS/MS fragmentations in negative ionization mode can be used effectively for the discrimination between glucose-derived Schiff bases and their corresponding Amadori compounds in both mono- and diglycated forms. The utilization of these diagnostic ions and isotopic labeling in the glycine/glucose model system revealed that milling glucose/glycine mixtures for 30 min/30 Hz at ambient temperature produced monoglycated glycine in equal proportions of Amadori and Schiff base forms, whereas diglycated glycine was a mixture of the three isomers: Schiff-Schiff, Schiff-Amadori, or Amadori-Amadori in approximately equal molar proportions. The above results were further corroborated using a synthetic histidine Amadori product, N,N-difructosyl-β-alanine, dipeptides, and ribose. Using mechanochemistry as a convenient synthetic tool in combination with MS/MS diagnostic ions, the isomeric diversity of the early stages of the Maillard reaction can be revealed. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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11 pages, 1793 KiB

Open AccessArticle

Protein Modification with Ribose Generates N^δ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine

by Ikuho Ban, Hikari Sugawa and Ryoji Nagai

Int. J. Mol. Sci. 2022, 23(3), 1224; https://doi.org/10.3390/ijms23031224 - 22 Jan 2022

Cited by 14 | Viewed by 2409

Abstract

Advanced glycation end products (AGEs) are associated with diabetes and its complications. AGEs are formed by the non-enzymatic reactions of proteins and reducing sugars, such as glucose and ribose. Ribose is widely used in glycation research as it generates AGEs more rapidly than [...] Read more.

Advanced glycation end products (AGEs) are associated with diabetes and its complications. AGEs are formed by the non-enzymatic reactions of proteins and reducing sugars, such as glucose and ribose. Ribose is widely used in glycation research as it generates AGEs more rapidly than glucose. This study analyzed the AGE structures generated from ribose-modified protein by liquid chromatography–quadrupole time-of-flight mass spectrometry. Among these AGEs, N^δ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine (MG-H1) was the most abundant in ribose-glycated bovine serum albumin (ribated-BSA) among others, such as N^ε-(carboxymethyl) lysine, N^ε-(carboxyethyl) lysine, and N^ω-(carboxymethyl) arginine. Surprisingly, MG-H1 was produced by ribated-BSA in a time-dependent manner, whereas methylglyoxal levels (MG) were under the detectable level. In addition, Trapa bispinosa Roxb. hot water extract (TBE) possesses several anti-oxidative compounds, such as ellagic acid, and has been reported to inhibit the formation of MG-H1 in vivo. Thus, we evaluated the inhibitory effects of TBE on MG-H1 formation using ribose- or MG-modified proteins. TBE inhibited MG-H1 formation in gelatin incubated with ribose and ribated-BSA, but not in MG-modified gelatin. Furthermore, MG-H1 formation was inhibited by diethylenetriaminepentaacetic acid. These results demonstrated that ribose reacts with proteins to generate Amadori compounds and form MG-H1 via oxidation. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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Review

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15 pages, 1750 KiB

Open AccessReview

Dicarbonyl Stress in Diabetic Vascular Disease

by Bernd Stratmann

Int. J. Mol. Sci. 2022, 23(11), 6186; https://doi.org/10.3390/ijms23116186 - 31 May 2022

Cited by 17 | Viewed by 2625

Abstract

Late vascular complications play a prominent role in the diabetes-induced increase in morbidity and mortality. Diabetes mellitus is recognised as a risk factor driving atherosclerosis and cardiovascular mortality; even after the normalisation of blood glucose concentration, the event risk is amplified—an effect called [...] Read more.

Late vascular complications play a prominent role in the diabetes-induced increase in morbidity and mortality. Diabetes mellitus is recognised as a risk factor driving atherosclerosis and cardiovascular mortality; even after the normalisation of blood glucose concentration, the event risk is amplified—an effect called “glycolytic memory”. The hallmark of this glycolytic memory and diabetic pathology are advanced glycation end products (AGEs) and reactive glucose metabolites such as methylglyoxal (MGO), a highly reactive dicarbonyl compound derived mainly from glycolysis. MGO and AGEs have an impact on vascular and organ structure and function, contributing to organ damage. As MGO is not only associated with hyperglycaemia in diabetes but also with other risk factors for diabetic vascular complications such as obesity, dyslipidaemia and hypertension, MGO is identified as a major player in the development of vascular complications in diabetes both on micro- as well as macrovascular level. In diabetes mellitus, the detoxifying system for MGO, the glyoxalase system, is diminished, accounting for the increased MGO concentration and glycotoxic load. This overview will summarise current knowledge on the effect of MGO and AGEs on vascular function. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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16 pages, 4576 KiB

Open AccessReview

AGEomics Biomarkers and Machine Learning—Realizing the Potential of Protein Glycation in Clinical Diagnostics

by Naila Rabbani

Int. J. Mol. Sci. 2022, 23(9), 4584; https://doi.org/10.3390/ijms23094584 - 21 Apr 2022

Cited by 2 | Viewed by 2706

Abstract

Protein damage by glycation, oxidation and nitration is a continuous process in the physiological system caused by reactive metabolites associated with dicarbonyl stress, oxidative stress and nitrative stress, respectively. The term AGEomics is defined as multiplexed quantitation of spontaneous modification of proteins damage [...] Read more.

Protein damage by glycation, oxidation and nitration is a continuous process in the physiological system caused by reactive metabolites associated with dicarbonyl stress, oxidative stress and nitrative stress, respectively. The term AGEomics is defined as multiplexed quantitation of spontaneous modification of proteins damage and other usually low-level modifications associated with a change of structure and function—for example, citrullination and transglutamination. The method of quantitation is stable isotopic dilution analysis liquid chromatography—tandem mass spectrometry (LC-MS/MS). This provides robust quantitation of normal and damaged or modified amino acids concurrently. AGEomics biomarkers have been used in diagnostic algorithms using machine learning methods. In this review, I describe the utility of AGEomics biomarkers and provide evidence why these are close to the phenotype of a condition or disease compared to other metabolites and metabolomic approaches and how to train and test algorithms for clinical diagnostic and screening applications with high accuracy, sensitivity and specificity using machine learning approaches. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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18 pages, 1186 KiB

Open AccessReview

The RAGE/DIAPH1 Signaling Axis & Implications for the Pathogenesis of Diabetic Complications

by Ravichandran Ramasamy, Alexander Shekhtman and Ann Marie Schmidt

Int. J. Mol. Sci. 2022, 23(9), 4579; https://doi.org/10.3390/ijms23094579 - 21 Apr 2022

Cited by 15 | Viewed by 3056

Abstract

Increasing evidence links the RAGE (receptor for advanced glycation end products)/DIAPH1 (Diaphanous 1) signaling axis to the pathogenesis of diabetic complications. RAGE is a multi-ligand receptor and through these ligand–receptor interactions, extensive maladaptive effects are exerted on cell types and tissues targeted for [...] Read more.

Increasing evidence links the RAGE (receptor for advanced glycation end products)/DIAPH1 (Diaphanous 1) signaling axis to the pathogenesis of diabetic complications. RAGE is a multi-ligand receptor and through these ligand–receptor interactions, extensive maladaptive effects are exerted on cell types and tissues targeted for dysfunction in hyperglycemia observed in both type 1 and type 2 diabetes. Recent evidence indicates that RAGE ligands, acting as damage-associated molecular patterns molecules, or DAMPs, through RAGE may impact interferon signaling pathways, specifically through upregulation of IRF7 (interferon regulatory factor 7), thereby heralding and evoking pro-inflammatory effects on vulnerable tissues. Although successful targeting of RAGE in the clinical milieu has, to date, not been met with success, recent approaches to target RAGE intracellular signaling may hold promise to fill this critical gap. This review focuses on recent examples of highlights and updates to the pathobiology of RAGE and DIAPH1 in diabetic complications. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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19 pages, 1380 KiB

Open AccessReview

Emerging Glycation-Based Therapeutics—Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors

by Naila Rabbani and Paul J. Thornalley

Int. J. Mol. Sci. 2022, 23(5), 2453; https://doi.org/10.3390/ijms23052453 - 23 Feb 2022

Cited by 21 | Viewed by 5817

Abstract

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded [...] Read more.

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)—a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer—particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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19 pages, 1557 KiB

Open AccessReview

Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes

by Naila Rabbani, Mingzhan Xue and Paul J. Thornalley

Int. J. Mol. Sci. 2022, 23(4), 2165; https://doi.org/10.3390/ijms23042165 - 16 Feb 2022

Cited by 24 | Viewed by 8822

Abstract

The recent discovery of the glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis in cell dysfunction in model hyperglycemia has revealed a likely key initiating factor contributing to the development of insulin resistance and vascular complications in diabetes. Consequently, the increased flux of glucose [...] Read more.

The recent discovery of the glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis in cell dysfunction in model hyperglycemia has revealed a likely key initiating factor contributing to the development of insulin resistance and vascular complications in diabetes. Consequently, the increased flux of glucose metabolism without a change in the expression and activity of glycolytic enzymes produces a wave of increased glycolytic intermediates driving mitochondrial dysfunction and increased reactive oxygen species (ROS) formation, the activation of hexosamine and protein kinase C pathways, the increased formation of methylglyoxal-producing dicarbonyl stress, and the activation of the unfolded protein response. This is called HK2-linked glycolytic overload and unscheduled glycolysis. The conditions required to sustain this are GLUT1 and/or GLUT3 glucose uptake and the expression of HK2. A metabolic biomarker of its occurrence is the abnormally increased deposition of glycogen, which is produced by metabolic channeling when HK2 becomes detached from mitochondria. These conditions and metabolic consequences are found in the vasculature, kidneys, retina, peripheral nerves, and early-stage embryo development in diabetes and likely sustain the development of diabetic vascular complications and embryopathy. In insulin resistance, HK2-linked unscheduled glycolysis may also be established in skeletal muscle and adipose tissue. This may explain the increased glucose disposal by skeletal uptake in the fasting phase in patients with type 2 diabetes mellitus, compared to healthy controls, and the presence of insulin resistance in patients with type 1 diabetes mellitus. Importantly, glyoxalase 1 inducer—trans-resveratrol and hesperetin in combination (tRES-HESP)—corrected HK2-linked glycolytic overload and unscheduled glycolysis and reversed insulin resistance and improved vascular inflammation in overweight and obese subjects in clinical trial. Further studies are now required to evaluate tRES-HESP for the prevention and reversal of early-stage type 2 diabetes and for the treatment of the vascular complications of diabetes. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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10 pages, 5881 KiB

Open AccessReview

Dual Nature of RAGE in Host Reaction and Nurturing the Mother–Infant Bond

by Yu Oshima, Ai Harashima, Seiichi Munesue, Kumi Kimura, Nontaphat Leerach, Hisanori Goto, Mariko Tanaka, Akane Niimura, Kenjiro Hayashi, Hiroshi Yamamoto, Haruhiro Higashida and Yasuhiko Yamamoto

Int. J. Mol. Sci. 2022, 23(4), 2086; https://doi.org/10.3390/ijms23042086 - 14 Feb 2022

Cited by 8 | Viewed by 2816

Abstract

Non-enzymatic glycation is an unavoidable reaction that occurs across biological taxa. The final products of this irreversible reaction are called advanced glycation end-products (AGEs). The endogenously formed AGEs are known to be bioactive and detrimental to human health. Additionally, exogenous food-derived AGEs are [...] Read more.

Non-enzymatic glycation is an unavoidable reaction that occurs across biological taxa. The final products of this irreversible reaction are called advanced glycation end-products (AGEs). The endogenously formed AGEs are known to be bioactive and detrimental to human health. Additionally, exogenous food-derived AGEs are debated to contribute to the development of aging and various diseases. Receptor for AGEs (RAGE) is widely known to elicit biological reactions. The binding of RAGE to other ligands (e.g., high mobility group box 1, S100 proteins, lipopolysaccharides, and amyloid-β) can result in pathological processes via the activation of intracellular RAGE signaling pathways, including inflammation, diabetes, aging, cancer growth, and metastasis. RAGE is now recognized as a pattern-recognition receptor. All mammals have RAGE homologs; however, other vertebrates, such as birds, amphibians, fish, and reptiles, do not have RAGE at the genomic level. This evidence from an evolutionary perspective allows us to understand why mammals require RAGE. In this review, we provide an overview of the scientific knowledge about the role of RAGE in physiological and pathological processes. In particular, we focus on (1) RAGE biology, (2) the role of RAGE in physiological and pathophysiological processes, (3) RAGE isoforms, including full-length membrane-bound RAGE (mRAGE), and the soluble forms of RAGE (sRAGE), which comprise endogenous secretory RAGE (esRAGE) and an ectodomain-shed form of RAGE, and (4) oxytocin transporters in the brain and intestine, which are important for maternal bonding and social behaviors. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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13 pages, 1677 KiB

Open AccessReview

The Role of AGE-RAGE Signalling as a Modulator of Gut Permeability in Diabetes

by Matthew Snelson, Elisa Lucut and Melinda T. Coughlan

Int. J. Mol. Sci. 2022, 23(3), 1766; https://doi.org/10.3390/ijms23031766 - 3 Feb 2022

Cited by 33 | Viewed by 6099

Abstract

There is increasing evidence for the role of intestinal permeability as a contributing factor in the pathogenesis of diabetes; however, the molecular mechanisms are poorly understood. Advanced glycation endproducts, of both exogenous and endogenous origin, have been shown to play a role in [...] Read more.

There is increasing evidence for the role of intestinal permeability as a contributing factor in the pathogenesis of diabetes; however, the molecular mechanisms are poorly understood. Advanced glycation endproducts, of both exogenous and endogenous origin, have been shown to play a role in diabetes pathophysiology, in part by their ligation to the receptor for advanced glycation endproducts (RAGE), leading to a proinflammatory signalling cascade. RAGE signalling has been demonstrated to play a role in the development of intestinal inflammation and permeability in Crohn’s disease and ulcerative colitis. In this review, we explore the role of AGE-RAGE signalling and intestinal permeability and explore whether activation of RAGE on the intestinal epithelium may be a downstream event contributing to the pathogenesis of diabetes complications. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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10 pages, 559 KiB

Open AccessReview

Organelle Stress and Metabolic Derangement in Kidney Disease

by Reiko Inagi

Int. J. Mol. Sci. 2022, 23(3), 1723; https://doi.org/10.3390/ijms23031723 - 2 Feb 2022

Cited by 10 | Viewed by 3399

Abstract

Advanced multiomics analysis has revealed novel pathophysiological mechanisms in kidney disease. In particular, proteomic and metabolomic analysis shed light on mitochondrial dysfunction (mitochondrial stress) by glycation in diabetic or age-related kidney disease. Further, metabolic damage often results from organelle stress, such as mitochondrial [...] Read more.

Advanced multiomics analysis has revealed novel pathophysiological mechanisms in kidney disease. In particular, proteomic and metabolomic analysis shed light on mitochondrial dysfunction (mitochondrial stress) by glycation in diabetic or age-related kidney disease. Further, metabolic damage often results from organelle stress, such as mitochondrial stress and endoplasmic reticulum (ER) stress, as well as interorganelle communication, or “organelle crosstalk”, in various kidney cells. These contribute to progression of the disease phenotype. Aberrant tubular mitochondrial lipid metabolism leads to tubular inflammation and fibrosis. This review article summarizes updated evidence regarding organelle stress, organelle crosstalk, and metabolic derangement in kidney disease. Full article

(This article belongs to the Special Issue Protein Glycation in Food, Nutrition, Health and Disease)

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