Special Issue "Glycation and Dicarbonyl Stress in Aging and Disease"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 September 2019).

Special Issue Editor

Prof. Fernanda Amicarelli *
E-Mail Website
Guest Editor
Dept. of Life, Health and Environmental Sciences,University of L’Aquila, via Vetoio – Coppito, 67100 L’Aquila, Italy
Tel. +39(0)862433266
Interests: reactive oxygen species; oxidative stress; redox-responsive pathways; dicarbonyl stress; glycation; methylglyoxal; aging; adaptive response; hormesis; stress response
* h-index: 26

Special Issue Information

Dear Colleagues,

Aging and several age-related diseases share important biochemical and molecular features, in which dicarbonyl stress (DS) and the subsequent glycation process play a key role. DS originates from the increased formation and/or decreased removal of toxic dicarbonyl metabolites, especially methylglyoxal. This, if not counteracted by cellular defense mechanisms, leads to the formation of advanced glycation end-products (AGEs), with consequent cell and tissue dysfunction. Moreover, DS may also derive from exposure to or the intake of exogenous dicarbonyls and AGEs (e.g. through the diet). The accumulation of AGEs has been linked to the activation of pro-inflammatory and pro-oxidant pathways, thus exacerbating the cellular stress. These events are frequently observed in many age-associated pathologies, such as diabetes, cancer, neurodegenerations and cardiovascular diseases. Due to the relevant socio-economic impact, great efforts are currently being undertaken to identify molecular targets able to prevent or limit DS-dependent cell damage.

The aim of this Special Issue is to provide a collection of original and review articles aimed at improving the understanding of the mechanisms underlying the toxicity of AGEs and dicarbonyls in cells and tissues. Studies on innovative strategies, including nutraceutical approaches, to modulate DS-activated intracellular signalling are also welcome.

Prof. Fernanda Amicarelli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Dicarbonyl stress
  • dicarbonyl compounds
  • methylglyoxal
  • glyoxalases
  • advanced glycation end products (AGEs)
  • advanced lipoxidation end products (ALEs)
  • oxidative stress
  • stress response
  • aging
  • diabetes
  • neurodegenerative disease
  • cancer
  • nutraceutical

Published Papers (7 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle
Effect of High Glucose-Induced Oxidative Stress on Paraoxonase 2 Expression and Activity in Caco-2 Cells
Cells 2019, 8(12), 1616; https://doi.org/10.3390/cells8121616 - 11 Dec 2019
Abstract
(1) Background: Hyperglycemia leads to several biochemical and physiological consequences, such as the generation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), which are involved in the development of several human diseases. Intestinal cells are continuously exposed to pro-oxidants and [...] Read more.
(1) Background: Hyperglycemia leads to several biochemical and physiological consequences, such as the generation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), which are involved in the development of several human diseases. Intestinal cells are continuously exposed to pro-oxidants and lipid peroxidation products from ingested foods, and also to glyco-oxidative damage. It has been reported that free radical generation may be linked to the development of inflammation-related gastrointestinal diseases. (2) Methods: The effects of high glucose (HG) treatment (50 mM) were assessed in terms of free radical production, lipid peroxidation, and AGEs formation. Furthermore, the expression and the antiapoptotic and antioxidant activity of the paraoxonase-2 (PON2) enzyme in intestinal cells has been investigated. (3) Results: Caco-2 cells treated with media supplied with high glucose (HG) (50 mM) showed, with respect to physiological glucose concentration (25 mM), an increase in ROS production, lipid peroxidation, and AGEs formation. Moreover, a lower PON2 expression and activity in HG-treated cells was related to activation of the apoptotic pathways. (4) Conclusions: Our results demonstrated that high glucose concentrations triggered glyco-oxidative stress in intestinal cells; the downregulation of PON2 could result in a higher oxidative stress and might contribute to intestinal dysfunction. Full article
(This article belongs to the Special Issue Glycation and Dicarbonyl Stress in Aging and Disease)
Open AccessArticle
Wnt Glycation Inhibits Canonical Signaling
Cells 2019, 8(11), 1320; https://doi.org/10.3390/cells8111320 - 25 Oct 2019
Abstract
Glycation occurs as a non-enzymatic reaction between amino and thiol groups of proteins, lipids, and nucleotides with reducing sugars or α-dicarbonyl metabolites. The chemical reaction underlying is the Maillard reaction leading to the formation of a heterogeneous group of compounds named advanced glycation [...] Read more.
Glycation occurs as a non-enzymatic reaction between amino and thiol groups of proteins, lipids, and nucleotides with reducing sugars or α-dicarbonyl metabolites. The chemical reaction underlying is the Maillard reaction leading to the formation of a heterogeneous group of compounds named advanced glycation end products (AGEs). Deleterious effects have been observed to accompany glycation such as alterations of protein structure and function resulting in crosslinking and accumulation of insoluble protein aggregates. A substantial body of evidence associates glycation with aging. Wnt signaling plays a fundamental role in stem cell biology as well as in regeneration and repair mechanisms. Emerging evidence implicates that changes in Wnt/β-catenin pathway activity contribute to the aging process. Here, we investigated the effect of glycation of Wnt3a on its signaling activity. Methods: Glycation was induced by treatment of Wnt3a-conditioned medium (CM) with glyoxal (GO). Effects on Wnt3a signaling activity were analyzed by Topflash/Fopflash reporter gene assay, co-immunoprecipitation, and quantitative RT-PCR. Results: Our data show that GO-treatment results in glycation of Wnt3a. Glycated Wnt3a suppresses β-catenin transcriptional activity in reporter gene assays, reduced binding of β-catenin to T-cell factor 4 (TCF-4) and extenuated transcription of Wnt/β-catenin target genes. Conclusions: GO-induced glycation impairs Wnt3a signaling function. Full article
(This article belongs to the Special Issue Glycation and Dicarbonyl Stress in Aging and Disease)
Show Figures

Figure 1

Open AccessArticle
1 h Postload Glycemia Is Associated with Low Endogenous Secretory Receptor for Advanced Glycation End Product Levels and Early Markers of Cardiovascular Disease
Cells 2019, 8(8), 910; https://doi.org/10.3390/cells8080910 - 16 Aug 2019
Abstract
We investigated the correlation of the soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) with markers of cardiovascular disease in subjects with normal glucose tolerance (NGT) and 1 h postload glucose ≥155 mg/dL after an oral glucose tolerance [...] Read more.
We investigated the correlation of the soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) with markers of cardiovascular disease in subjects with normal glucose tolerance (NGT) and 1 h postload glucose ≥155 mg/dL after an oral glucose tolerance test. We stratified 282 subjects without a previous diagnosis of diabetes into three groups: 123 controls (NGT and 1 h postload glycemia <155 mg/dL), 84 NGT and 1 h postload glycemia ≥155 mg/dL (NGT 1 h high), and 75 subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT). NGT 1 h high subjects exhibited lower esRAGE (0.36 ± 0.18 vs. 0.4 5 ± 0.2, p < 0.05) and higher S100A12 levels than controls (5684 (3193.2–8295.6) vs. 3960.1 (2101.8–7419), p < 0.05). Furthermore, they showed an increased pulse wave velocity (PWV) and intima–media thickness (IMT). No differences were found between the NGT 1 h high group and the IFG/IGT group regarding cardiometabolic profiles. After multiple regression analyses, esRAGE was associated with glycated hemoglobin (HbA1c) and high-sensitivity C-reactive protein (hs-CRP). Age, HbA1c, and esRAGE were the determinants of IMT, whereas S100A12 and systolic pressure were the determinants of PWV. The NGT 1 h high group exhibited low esRAGE levels and an altered cardiometabolic profile. HbA1c, S100A12, and hs-CRP were associated with these alterations. In conclusion, subjects with NGT are not a homogeneous population, and they present different cardiovascular and glycometabolic risks. Full article
(This article belongs to the Special Issue Glycation and Dicarbonyl Stress in Aging and Disease)
Show Figures

Figure 1

Open AccessArticle
Methylglyoxal Acts as a Tumor-Promoting Factor in Anaplastic Thyroid Cancer
Cells 2019, 8(6), 547; https://doi.org/10.3390/cells8060547 - 06 Jun 2019
Cited by 2
Abstract
Methylglyoxal (MG) is a potent inducer of advanced glycation end products (AGEs). MG, long considered a highly cytotoxic molecule with potential anticancer value, is now being re-evaluated to a protumorigenic agent in some malignancies. Anaplastic thyroid cancer (ATC) is an extremely aggressive and [...] Read more.
Methylglyoxal (MG) is a potent inducer of advanced glycation end products (AGEs). MG, long considered a highly cytotoxic molecule with potential anticancer value, is now being re-evaluated to a protumorigenic agent in some malignancies. Anaplastic thyroid cancer (ATC) is an extremely aggressive and highly lethal cancer for which conventional therapies have proved ineffective. Successful therapeutic intervention in ATC is undermined by our poor understanding of its molecular etiology. In the attempt to understand the role of MG in ATC aggressiveness, we used immunohistochemistry to examine the level of MG protein adducts in ATC and slow-growing papillary thyroid cancer (PTC). We detected a high level of MG adducts in ATC compared to PTC ones, suggesting a protumor role for MG-mediated dicarbonyl stress in ATC. Accordingly, MG adduct accumulation in ATC cells in vitro was associated with a marked mesenchymal phenotype and increased migration/invasion, which were both reversed by aminoguanidine (AG)—a scavenger of MG—and resveratrol—an activator of Glyoxalase 1 (Glo1), the key metabolizing enzyme of MG. Our study represents the first demonstration that MG, via AGEs, acts as a tumor-promoting factor in ATC and suggests that MG scavengers and/or Glo1 activators merit investigations as potential therapeutic strategies for this malignancy. Full article
(This article belongs to the Special Issue Glycation and Dicarbonyl Stress in Aging and Disease)
Show Figures

Graphical abstract

Open AccessArticle
Pinocembrin Protects from AGE-Induced Cytotoxicity and Inhibits Non-Enzymatic Glycation in Human Insulin
Cells 2019, 8(5), 385; https://doi.org/10.3390/cells8050385 - 26 Apr 2019
Cited by 2
Abstract
Advanced glycation end products (AGEs) are the end products of the glycation reaction and have a great importance in clinical science for their association with oxidative stress and inflammation, which play a major role in most chronic diseases, such as cardiovascular disease, neurodegenerative [...] Read more.
Advanced glycation end products (AGEs) are the end products of the glycation reaction and have a great importance in clinical science for their association with oxidative stress and inflammation, which play a major role in most chronic diseases, such as cardiovascular disease, neurodegenerative diseases, and diabetes. Their pathogenic effects are generally induced by the interaction between AGEs and the receptor for advanced glycation end product (RAGE) on the cell surface, which triggers reactive oxygen species production, nuclear factor kB (NF-kB) activation, and inflammation. Pinocembrin, the most abundant flavonoid in propolis, has been recently proven to interfere with RAGE activation in Aβ–RAGE-induced toxicity. In the present study, we investigated the ability of pinocembrin to interfere with RAGE signaling pathways activated by AGEs. Interestingly, pinocembrin was able to inhibit oxidative stress and NF-kB activation in cells exposed to AGEs. In addition, it was able to block caspase 3/7 and 9 activation, thus suggesting an active role of this molecule in counteracting AGE–RAGE-induced toxicity mediated by NF-kB signaling pathways. The ability of pinocembrin to affect the glycation reaction has been also tested. Our data suggest that pinocembrin might be a promising molecule in protecting from AGE-mediated pathogenesis. Full article
(This article belongs to the Special Issue Glycation and Dicarbonyl Stress in Aging and Disease)
Show Figures

Figure 1

Open AccessArticle
Antiglycative Activity and RAGE Expression in Rett Syndrome
Cells 2019, 8(2), 161; https://doi.org/10.3390/cells8020161 - 15 Feb 2019
Cited by 1
Abstract
Rett syndrome (RTT) is a human neurodevelopmental disorder, whose pathogenesis has been linked to both oxidative stress and subclinical inflammatory status (OxInflammation). Methylglyoxal (MG), a glycolytic by-product with cytotoxic and pro-oxidant power, is the major precursor in vivo of advanced glycation end products [...] Read more.
Rett syndrome (RTT) is a human neurodevelopmental disorder, whose pathogenesis has been linked to both oxidative stress and subclinical inflammatory status (OxInflammation). Methylglyoxal (MG), a glycolytic by-product with cytotoxic and pro-oxidant power, is the major precursor in vivo of advanced glycation end products (AGEs), which are known to exert their detrimental effect via receptor- (e.g., RAGE) or non-receptor-mediated mechanisms in several neurological diseases. On this basis, we aimed to compare fibroblasts from healthy subjects (CTR) with fibroblasts from RTT patients (N = 6 per group), by evaluating gene/protein expression patterns, and enzymatic activities of glyoxalases (GLOs), along with the levels of MG-dependent damage in both basal and MG-challenged conditions. Our results revealed that RTT is linked to an alteration of the GLOs system (specifically, increased GLO2 activity), that ensures unchanged MG-dependent damage levels. However, RTT cells underwent more pronounced cell death upon exogenous MG-treatment, as compared to CTR, and displayed lower RAGE levels than CTR, with no alterations following MG-treatment, thus suggesting that an adaptive response to dicarbonyl stress may occur. In conclusion, besides OxInflammation, RTT is associated with reshaping of the major defense systems against dicarbonyl stress, along with an altered cellular stress response towards pro-glycating insults. Full article
(This article belongs to the Special Issue Glycation and Dicarbonyl Stress in Aging and Disease)
Show Figures

Figure 1

Review

Jump to: Research

Open AccessReview
Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging
Cells 2019, 8(7), 749; https://doi.org/10.3390/cells8070749 - 19 Jul 2019
Cited by 3
Abstract
Dicarbonyl stress occurs when dicarbonyl metabolites (i.e., methylglyoxal, glyoxal and 3-deoxyglucosone) accumulate as a consequence of their increased production and/or decreased detoxification. This toxic condition has been associated with metabolic and age-related diseases, both of which are characterized by a pro-inflammatory and pro-oxidant [...] Read more.
Dicarbonyl stress occurs when dicarbonyl metabolites (i.e., methylglyoxal, glyoxal and 3-deoxyglucosone) accumulate as a consequence of their increased production and/or decreased detoxification. This toxic condition has been associated with metabolic and age-related diseases, both of which are characterized by a pro-inflammatory and pro-oxidant state. Methylglyoxal (MGO) is the most reactive dicarbonyl and the one with the highest endogenous flux. It is the precursor of the major quantitative advanced glycated products (AGEs) in physiological systems, arginine-derived hydroimidazolones, which accumulate in aging and dysfunctional tissues. The aging process is characterized by a decline in the functional properties of cells, tissues and whole organs, starting from the perturbation of crucial cellular processes, including mitochondrial function, proteostasis and stress-scavenging systems. Increasing studies are corroborating the causal relationship between MGO-derived AGEs and age-related tissue dysfunction, unveiling a previously underestimated role of dicarbonyl stress in determining healthy or unhealthy aging. This review summarizes the latest evidence supporting a causal role of dicarbonyl stress in age-related diseases, including diabetes mellitus, cardiovascular disease and neurodegeneration. Full article
(This article belongs to the Special Issue Glycation and Dicarbonyl Stress in Aging and Disease)
Show Figures

Graphical abstract

Back to TopTop