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Article: Methylglyoxal-Derived Nucleoside Adducts Drive Vascular Dysfunction in a RAGE-Dependent Manner.

Lai, Seigmund Wai Tsuen / Bhattacharya, Supriyo / Lopez Gonzalez, Edwin De Jesus / Shuck, Sarah C

2024 Volume 13, Issue 1

Abstract: Diabetic kidney disease (DKD) is a leading cause of death in patients with diabetes. An early precursor to DKD is endothelial cell dysfunction (ECD), which often precedes and exacerbates vascular disease progression. We previously discovered that ... ...

Abstract	Diabetic kidney disease (DKD) is a leading cause of death in patients with diabetes. An early precursor to DKD is endothelial cell dysfunction (ECD), which often precedes and exacerbates vascular disease progression. We previously discovered that covalent adducts formed on DNA, RNA, and proteins by the reactive metabolic by-product methylglyoxal (MG) predict DKD risk in patients with type 1 diabetes up to 16 years pre-diagnosis. However, the mechanisms by which MG adducts contribute to vascular disease onset and progression remain unclear. Here, we report that the most predominant MG-induced nucleoside adducts,
Language	English
Publishing date	2024-01-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox13010085
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Article ; Online: Elevated glucose increases genomic instability by inhibiting nucleotide excision repair.

Ciminera, Alexandra K / Shuck, Sarah C / Termini, John

Life science alliance

2021 Volume 4, Issue 10

Abstract: We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide ... ...

Abstract	We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide excision repair (NER) pathway, promoted DNA strand breaks, and increased levels of the DNA glycation adduct
MeSH term(s)	Cell Line ; DNA Damage ; DNA Repair/physiology ; Genomic Instability ; Glucose/physiology ; HEK293 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/physiology ; Prolyl Hydroxylases/metabolism
Chemical Substances	HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Prolyl Hydroxylases (EC 1.14.11.-) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202101159
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Article ; Online: Diet and Obesity-Induced Methylglyoxal Production and Links to Metabolic Disease.

Hernandez-Castillo, Carlos / Shuck, Sarah C

Chemical research in toxicology

2021 Volume 34, Issue 12, Page(s) 2424–2440

Abstract: The obesity rate in the United States is 42.4% and has become a national epidemic. Obesity is a complex condition that is influenced by socioeconomic status, ethnicity, genetics, age, and diet. Increased consumption of a Western diet, one that is high in ...

Abstract	The obesity rate in the United States is 42.4% and has become a national epidemic. Obesity is a complex condition that is influenced by socioeconomic status, ethnicity, genetics, age, and diet. Increased consumption of a Western diet, one that is high in processed foods, red meat, and sugar content, is associated with elevated obesity rates. Factors that increase obesity risk, such as socioeconomic status, also increase consumption of a Western diet because of a limited access to healthier options and greater affordability of processed foods. Obesity is a public health threat because it increases the risk of several pathologies, including atherosclerosis, diabetes, and cancer. The molecular mechanisms linking obesity to disease onset and progression are not well understood, but a proposed mechanism is physiological changes caused by altered lipid peroxidation, glycolysis, and protein metabolism. These metabolic pathways give rise to reactive molecules such as the abundant electrophile methylglyoxal (MG), which covalently modifies nucleic acids and proteins. MG-adducts are associated with obesity-linked pathologies and may have potential for biomonitoring to determine the risk of disease onset and progression. MG-adducts may also play a role in disease progression because they are mutagenic and directly impact protein stability and function. In this review, we discuss how obesity drives metabolic alterations, how these alterations lead to MG production, the association of MG-adducts with disease, and the potential impact of MG-adducts on cellular function.
MeSH term(s)	Diet ; Humans ; Metabolic Diseases/metabolism ; Molecular Structure ; Obesity/metabolism ; Pyruvaldehyde/chemistry ; Pyruvaldehyde/metabolism
Chemical Substances	Pyruvaldehyde (722KLD7415)
Language	English
Publishing date	2021-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.1c00221
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Article: Extracellular vesicles: A dive into their role in the tumor microenvironment and cancer progression.

Lopez, Kassandra / Lai, Seigmund Wai Tsuen / Lopez Gonzalez, Edwin De Jesus / Dávila, Raúl G / Shuck, Sarah C

Frontiers in cell and developmental biology

2023 Volume 11, Page(s) 1154576

Abstract: Extracellular vesicles (EVs) encompass a diverse set of membrane-derived particles released from cells and are found in numerous biological matrices and the extracellular space. Specific classes of EVs include apoptotic bodies, exosomes, and ... ...

Abstract	Extracellular vesicles (EVs) encompass a diverse set of membrane-derived particles released from cells and are found in numerous biological matrices and the extracellular space. Specific classes of EVs include apoptotic bodies, exosomes, and microvesicles, which vary in their size, origin, membrane protein expression, and interior cargo. EVs provide a mechanism for shuttling cargo between cells, which can influence cell physiology by transporting proteins, DNA, and RNA. EVs are an abundant component of the tumor microenvironment (TME) and are proposed to drive tumor growth and progression by communicating between fibroblasts, macrophages, and tumor cells in the TME. The cargo, source, and type of EV influences the pro- or anti-tumoral role of these molecules. Therefore, robust EV isolation and characterization techniques are required to ensure accurate elucidation of their association with disease. Here, we summarize different EV subclasses, methods for EV isolation and characterization, and a selection of current clinical trials studying EVs. We also review key studies exploring the role and impact of EVs in the TME, including how EVs mediate intercellular communication, drive cancer progression, and remodel the TME.
Language	English
Publishing date	2023-03-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2023.1154576
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Article ; Online: Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease.

Lai, Seigmund Wai Tsuen / Lopez Gonzalez, Edwin De Jesus / Zoukari, Tala / Ki, Priscilla / Shuck, Sarah C

Chemical research in toxicology

2022 Volume 35, Issue 10, Page(s) 1720–1746

Abstract: Metabolism is an essential part of life that provides energy for cell growth. During metabolic flux, reactive electrophiles are produced that covalently modify macromolecules, leading to detrimental cellular effects. Methylglyoxal (MG) is an abundant ... ...

Abstract	Metabolism is an essential part of life that provides energy for cell growth. During metabolic flux, reactive electrophiles are produced that covalently modify macromolecules, leading to detrimental cellular effects. Methylglyoxal (MG) is an abundant electrophile formed from lipid, protein, and glucose metabolism at intracellular levels of 1-4 μM. MG covalently modifies DNA, RNA, and protein, forming advanced glycation end products (MG-AGEs). MG and MG-AGEs are associated with the onset and progression of many pathologies including diabetes, cancer, and liver and kidney disease. Regulating MG and MG-AGEs is a potential strategy to prevent disease, and they may also have utility as biomarkers to predict disease risk, onset, and progression. Here, we review recent advances and knowledge surrounding MG, including its production and elimination, mechanisms of MG-AGEs formation, the physiological impact of MG and MG-AGEs in disease onset and progression, and the latter in the context of its receptor RAGE. We also discuss methods for measuring MG and MG-AGEs and their clinical application as prognostic biomarkers to allow for early detection and intervention prior to disease onset. Finally, we consider relevant clinical applications and current therapeutic strategies aimed at targeting MG, MG-AGEs, and RAGE to ultimately improve patient outcomes.
MeSH term(s)	Glucose/metabolism ; Glycation End Products, Advanced/metabolism ; Humans ; Lipids ; Pyruvaldehyde/metabolism ; RNA ; Receptor for Advanced Glycation End Products/metabolism
Chemical Substances	Glycation End Products, Advanced ; Lipids ; Receptor for Advanced Glycation End Products ; RNA (63231-63-0) ; Pyruvaldehyde (722KLD7415) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-10-05
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.2c00160
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Article: Methylglyoxal products in pre-symptomatic type 1 diabetes.

Shuck, Sarah C / Achenbach, Peter / Roep, Bart O / Termini, John S / Hernandez-Castillo, Carlos / Winkler, Christiane / Weiss, Andreas / Ziegler, Anette-Gabriele

Frontiers in endocrinology

2023 Volume 14, Page(s) 1108910

Abstract: Introduction: Progression to type 1 diabetes has emerged as a complex process with metabolic alterations proposed to be a significant driver of disease. Monitoring products of altered metabolism is a promising tool for determining the risk of type 1 ... ...

Abstract	Introduction: Progression to type 1 diabetes has emerged as a complex process with metabolic alterations proposed to be a significant driver of disease. Monitoring products of altered metabolism is a promising tool for determining the risk of type 1 diabetes progression and to supplement existing predictive biomarkers. Methylglyoxal (MG) is a reactive product produced from protein, lipid, and sugar metabolism, providing a more comprehensive measure of metabolic changes compared to hyperglycemia alone. MG forms covalent adducts on nucleic and amino acids, termed MG-advanced glycation end products (AGEs) that associate with type 1 diabetes. Methods: We tested their ability to predict risk of disease and discriminate which individuals with autoimmunity will progress to type 1 diabetes. We measured serum MG-AGEs from 141 individuals without type 1 diabetes and 271 individuals with type 1 diabetes enrolled in the Fr1da cohort. Individuals with type 1 diabetes were at stages 1, 2, and 3. Results: We examined the association of MG-AGEs with type 1 diabetes. MG-AGEs did not correlate with HbA1c or differ between stages 1, 2, and 3 type 1 diabetes. Yet, RNA MG-AGEs were significantly associated with the rate of progression to stage 3 type 1 diabetes, with lower serum levels increasing risk of progression. Discussion: MG-AGEs were able to discriminate which individuals with autoantibodies would progress at a faster rate to stage 3 type 1 diabetes providing a potential new clinical biomarker for determining rate of disease progression and pointing to contributing metabolic pathways.
MeSH term(s)	Humans ; Diabetes Mellitus, Type 1 ; Pyruvaldehyde ; Glycation End Products, Advanced/metabolism ; Biomarkers ; Dietary Supplements
Chemical Substances	Pyruvaldehyde (722KLD7415) ; Glycation End Products, Advanced ; Biomarkers
Language	English
Publishing date	2023-01-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1108910
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Article ; Online: Product Studies and Mechanistic Analysis of the Reaction of Methylglyoxal with Deoxyguanosine.

Shuck, Sarah C / Wuenschell, Gerald E / Termini, John S

Chemical research in toxicology

2018 Volume 31, Issue 2, Page(s) 105–115

Abstract: Methylglyoxal (MG) is a highly reactive electrophile produced endogenously as a byproduct of glucose metabolism and protein catabolism and exogenously as a food contaminant. MG reacts spontaneously with proteins, lipids, and nucleic acids to form ... ...

Abstract	Methylglyoxal (MG) is a highly reactive electrophile produced endogenously as a byproduct of glucose metabolism and protein catabolism and exogenously as a food contaminant. MG reacts spontaneously with proteins, lipids, and nucleic acids to form advanced glycation end products (AGEs), modifying or inhibiting their function. Protein AGEs are associated with pathological complications of diabetes, cancer, and neurodegenerative diseases, while the physiological impact of DNA, RNA, and lipid AGE formation is less well explored. Conflicting reports in the literature on the biologically significant DNA-AGE product distribution and mechanisms of formation prompted a re-examination of the reaction products of MG with dG, oligonucleotides, and plasmid DNA under varying conditions of MG:dG stoichiometry, pH, and reaction time. Major products identified using sequential mass fragmentation and authentic standards were N
MeSH term(s)	Deoxyguanosine/chemistry ; Molecular Structure ; Pyruvaldehyde/chemical synthesis ; Pyruvaldehyde/chemistry
Chemical Substances	Pyruvaldehyde (722KLD7415) ; Deoxyguanosine (G9481N71RO)
Language	English
Publishing date	2018-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.7b00274
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Article ; Online: DJ-1 is not a deglycase and makes a modest contribution to cellular defense against methylglyoxal damage in neurons.

Mazza, Melissa Conti / Shuck, Sarah C / Lin, Jiusheng / Moxley, Michael A / Termini, John / Cookson, Mark R / Wilson, Mark A

Journal of neurochemistry

2022 Volume 162, Issue 3, Page(s) 245–261

Abstract: Human DJ-1 is a cytoprotective protein whose absence causes Parkinson's disease and is also associated with other diseases. DJ-1 has an established role as a redox-regulated protein that defends against oxidative stress and mitochondrial dysfunction. ... ...

Abstract	Human DJ-1 is a cytoprotective protein whose absence causes Parkinson's disease and is also associated with other diseases. DJ-1 has an established role as a redox-regulated protein that defends against oxidative stress and mitochondrial dysfunction. Multiple studies have suggested that DJ-1 is also a protein/nucleic acid deglycase that plays a key role in the repair of glycation damage caused by methylglyoxal (MG), a reactive α-keto aldehyde formed by central metabolism. Contradictory reports suggest that DJ-1 is a glyoxalase but not a deglycase and does not play a major role in glycation defense. Resolving this issue is important for understanding how DJ-1 protects cells against insults that can cause disease. We find that DJ-1 reduces levels of reversible adducts of MG with guanine and cysteine in vitro. The steady-state kinetics of DJ-1 acting on reversible hemithioacetal substrates are fitted adequately with a computational kinetic model that requires only a DJ-1 glyoxalase activity, supporting the conclusion that deglycation is an apparent rather than a true activity of DJ-1. Sensitive and quantitative isotope-dilution mass spectrometry shows that DJ-1 modestly reduces the levels of some irreversible guanine and lysine glycation products in primary and cultured neuronal cell lines and whole mouse brain, consistent with a small but measurable effect on total neuronal glycation burden. However, DJ-1 does not improve cultured cell viability in exogenous MG. In total, our results suggest that DJ-1 is not a deglycase and has only a minor role in protecting neurons against methylglyoxal toxicity.
MeSH term(s)	Animals ; Glycosylation ; Guanine ; Humans ; Mice ; Neurons/metabolism ; Oxidative Stress ; Protein Deglycase DJ-1/metabolism ; Pyruvaldehyde/chemistry ; Pyruvaldehyde/metabolism
Chemical Substances	Guanine (5Z93L87A1R) ; Pyruvaldehyde (722KLD7415) ; Protein Deglycase DJ-1 (EC 3.1.2.-)
Language	English
Publishing date	2022-07-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.15656
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Article ; Online: Methylglyoxal Adducts Are Prognostic Biomarkers for Diabetic Kidney Disease in Patients With Type 1 Diabetes.

Lai, Seigmund Wai Tsuen / Hernandez-Castillo, Carlos / Gonzalez, Edwin De Jesus Lopez / Zoukari, Tala / Talley, Min / Paquin, Nadia / Chen, Zhuo / Roep, Bart O / Kaddis, John S / Natarajan, Rama / Termini, John / Shuck, Sarah C

Diabetes

2023 Volume 73, Issue 4, Page(s) 611–617

MeSH term(s)	Humans ; Diabetes Mellitus, Type 1/complications ; Diabetic Nephropathies/metabolism ; Pyruvaldehyde ; Follow-Up Studies ; Prognosis ; Glycated Hemoglobin ; Biomarkers/metabolism ; Glomerular Filtration Rate
Chemical Substances	Pyruvaldehyde (722KLD7415) ; Glycated Hemoglobin ; Biomarkers
Language	English
Publishing date	2023-11-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db23-0277
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Article: Metal-Assisted Protein Quantitation (MAPq): Multiplex Analysis of Protein Expression Using Lanthanide-Modified Antibodies with Detection by Inductively Coupled Plasma Mass Spectrometry

Shuck, Sarah C / Nguyen, Cu / Chan, Yin / O’Connor, Timothy / Ciminera, Alexandra K / Kahn, Michael / Termini, John

Analytical chemistry. 2020 May 05, v. 92, no. 11

2020

Abstract: Understanding the complex relationships between genomics, transcriptomics, and proteomics requires the development of more sensitive and rapid methods of multiplexed protein analysis. This is necessary to understand the relationship between cellular ... ...

Abstract	Understanding the complex relationships between genomics, transcriptomics, and proteomics requires the development of more sensitive and rapid methods of multiplexed protein analysis. This is necessary to understand the relationship between cellular responses to environmental stresses, disease progression, and/or drug treatment; however, most methods are limited by low sensitivity, nonspecificity, and minimal multiplexing capacity. To more fully explore the relationship between multiple cellular pathways, we have developed a novel antibody-based multiplex assay using inductively coupled plasma mass spectrometry (ICP-MS), which we term metal-assisted protein quantitation (MAPq). MAPq utilizes lanthanide-conjugated antibodies to simultaneously quantify up to 35 proteins with low pg/mL sensitivity. This method is especially advantageous for low-abundance proteins, a significant limitation of many multiplex MS methods. We observed a limit of detection of 0.5 pg/mL and a limit of quantitation of 5 pg/mL with virtually no background signal. We applied this method to both cultured cells and mouse tissues to investigate changes in low-abundance nuclear and cytoplasmic proteins following drug or environmental stresses. MAPq was found to be at least 10 times more sensitive than Western blots and could detect quantitative changes in protein expression not readily observed using conventional approaches.
Keywords	analytical chemistry ; atomic absorption spectrometry ; detection limit ; disease progression ; drug therapy ; drugs ; genomics ; mice ; protein synthesis ; proteomics ; transcriptomics
Language	English
Dates of publication	2020-0505
Size	p. 7556-7564.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.0c00058
Database	NAL-Catalogue (AGRICOLA)

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