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1
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Rojas Echeverri JC, Milkovska-Stamenova S, Wagner U, Hoffmann R. Screening of Protein Carbonylation Sites in Human Serum by Ion Mobility Mass Spectrometry. J Proteome Res 2025. [PMID: 40515705 DOI: 10.1021/acs.jproteome.5c00093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2025]
Abstract
Excessive oxidative stress, associated with various diseases, can induce protein carbonylation-nonenzymatic modifications involving aldehyde or keto group formation. These modifications are structurally diverse and low in abundance, which complicates their detection and quantitation. Here, we developed a strategy to identify and quantify protein carbonylation in human serum proteins from 39 rheumatoid arthritis patients and 29 healthy donors. Reactive carbonyl groups were derivatized with an aldehyde reactive probe (ARP), digested with trypsin, enriched via avidin affinity chromatography, and analyzed using RP-HPLC-ESI-IMS-MS/MS. Ion mobility spectrometry (IMS) was applied in both data-dependent (DDA) and data-independent acquisition (DIA) modes. DDA generated spectral libraries of ARP-derivatized peptides (ARP-peptides), which enabled peptide-centric detection in DIA data. We manually confirmed 86 ARP-peptides, with 93.8% of peak areas showing signal-to-background ratios >3. Among the 32 unique carbonylation sites, 28 were on human serum albumin, with hotspots at Cys58, Lys214, Lys219, Lys223, Lys456, Lys543, Lys549, and Lys565. Six previously unreported species were identified using IMS, DIA, ARP-reporter ions, and de novo sequencing. The ARP-peptides were quantified with ≥ 75% intrabatch reproducibility (coefficient of variation <20%). Similar modification levels were observed in both groups, suggesting basal, disease-independent carbonylation in abundant serum proteins.
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Affiliation(s)
- Juan C Rojas Echeverri
- Institute of Bioanalytical Chemistry, Faculty of Chemistry, Universität Leipzig, Leipzig 04103, Germany
- Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig 04103, Germany
| | - Sanja Milkovska-Stamenova
- Institute of Bioanalytical Chemistry, Faculty of Chemistry, Universität Leipzig, Leipzig 04103, Germany
- Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig 04103, Germany
| | - Ulf Wagner
- Division of Rheumatology, Department of Endocrinology, Nephrology, Rheumatology, Universität Leipzig, Leipzig 04103, Germany
| | - Ralf Hoffmann
- Institute of Bioanalytical Chemistry, Faculty of Chemistry, Universität Leipzig, Leipzig 04103, Germany
- Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig 04103, Germany
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2
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Xiao YB, Ravazzano L, Grano M, Colaianni G, Baldock C, Libonati F, Tarakanova A. Influence of Non-Cross-Linking AGEs on Mechanical Properties and Morphological Features of Tropocollagen Peptides: A Molecular Dynamics Study. ACS Biomater Sci Eng 2025. [PMID: 40343761 DOI: 10.1021/acsbiomaterials.5c00089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2025]
Abstract
Collagen, a protein known for its long lifespan, is susceptible to accumulation of advanced glycation end products (AGEs) with age. These AGEs are considered markers that indicate the aging severity and influence the mechanics of tissues, leading to fragile bones and hardened skin. While many cross-linking AGEs have been widely studied for their ability to reduce the elasticity of biological tissues, contributing to skin hardening and fragile bones, through strong covalent bonds, non-cross-linking AGEs, or AGE adducts, are typically investigated as indicators of aging or as signaling factors in pathological conditions. However, recent experimental findings have revealed that the number of AGE adducts in aged bone is comparable to enzymatic cross-links, which are significantly more abundant than cross-linking AGEs. Based on these observations, we consider one of the most abundant AGE adducts - carboxymethyllysine (CML) - and employ molecular dynamics simulations to explore its direct impact on the mechanical and conformational properties of single tropocollagen molecules. Our models demonstrate that tropocollagen peptides, constructed based on sequences experimentally identified with sites of CML modifications in type I collagen derived from human cortical bone, exhibit heterogeneous behaviors under tensile testing. Still, most of these modified peptides display compromised structural stability, reduction in structural strength, and diminished energy dissipation ability when tension is applied. This study highlights the potential impact of non-cross-linking AGEs on collagen behavior at molecular scale and provides insights into the mechanisms underlying these modifications. Gaining a deeper understanding of the role of AGE adducts and their contribution to the aging process may pave the way for future solutions in antiaging research.
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Affiliation(s)
- Yu-Bai Xiao
- School of Mechanical, Aerospace, and Manufacturing Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Linda Ravazzano
- Center for Nano Science and Technology@PoliMi, Istituto Italiano di Tecnologia, Via Rubattino 81, Milano 20134, Italy
| | - Maria Grano
- Department of Precision and Regenerative Medicine and Ionian Area - DiMePRe-J, University of Bari Aldo Moro, Bari 70124, Italy
| | - Graziana Colaianni
- Department of Precision and Regenerative Medicine and Ionian Area - DiMePRe-J, University of Bari Aldo Moro, Bari 70124, Italy
| | - Clair Baldock
- Manchester Cell-Matrix Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, U.K
| | - Flavia Libonati
- Center for Nano Science and Technology@PoliMi, Istituto Italiano di Tecnologia, Via Rubattino 81, Milano 20134, Italy
- Department of Mechanical, Energy, Management and Transportation Engineering (DIME), University of Genoa, Via all'Opera Pia 15/A, Genova 16145, Italy
| | - Anna Tarakanova
- School of Mechanical, Aerospace, and Manufacturing Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
- Department of Biomedical Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
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3
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Panja S, Rankenberg J, Michel C, Cooksley G, Glomb MA, Nagaraj RH. Proximal cysteine residues in proteins promote N ε-carboxyalkylation of lysine residues by α-dicarbonyl compounds. J Biol Chem 2025; 301:108377. [PMID: 40049410 PMCID: PMC11994404 DOI: 10.1016/j.jbc.2025.108377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 02/12/2025] [Accepted: 02/26/2025] [Indexed: 04/01/2025] Open
Abstract
Advanced glycation end products (AGEs) are protein modifications resulting from the chemical reaction between lysine and arginine residues in proteins, and carbonyl compounds, including glyoxal (GO) and methylglyoxal (MGO). Nε-carboxymethyllysine (CML) and Nε-carboxyethyllysine (CEL), formed by glycation from GO and MGO, are among the major AGEs in tissue proteins. Incubation with GO or MGO resulted in higher CML and CEL formation in the two cysteine residues containing αA-crystallin (αAC) than in the cysteine lacking αB-crystallin (αBC). Mass spectrometric data showed K70 and K166 to be heavily modified with CML and CEL in GO- and MGO-modified αAC. In silico analysis of the structure of αAC showed K70 and K166 to be proximal to C142. Mutation or reductive alkylation of cysteine residues in αAC significantly reduced CML and CEL formation. The addition of GSH or N-acetylcysteine enhanced CML and CEL formation in αBC. The introduction of a cysteine residue proximal to a lysine residue in αBC increased the CML and CEL accumulation. Our data showed that CML and CEL formation occurs through a hemithioacetal intermediate formed from the reaction between thiols and GO or MGO. Together, these results highlight a mechanism by which thiols influence protein AGE levels. In addition, CML and CEL are ligands for RAGE, a receptor for AGEs, which has been implicated in several aging and diabetes-associated diseases. Therefore, further understanding of the biosynthesis of CML and CEL could lead to the development of new therapies against those diseases.
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Affiliation(s)
- Sudipta Panja
- Department of Ophthalmology, School of Medicine, University of Colorado, Aurora, Colorado, USA.
| | - Johanna Rankenberg
- Department of Ophthalmology, School of Medicine, University of Colorado, Aurora, Colorado, USA
| | - Cole Michel
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, USA
| | - Grace Cooksley
- Department of Ophthalmology, School of Medicine, University of Colorado, Aurora, Colorado, USA
| | - Marcus A Glomb
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Halle(Saale), Germany
| | - Ram H Nagaraj
- Department of Ophthalmology, School of Medicine, University of Colorado, Aurora, Colorado, USA; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, USA.
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4
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Martin MS, Jacob-Dolan JW, Pham VTT, Sjoblom NM, Scheck RA. The chemical language of protein glycation. Nat Chem Biol 2025; 21:324-336. [PMID: 38942948 PMCID: PMC12020258 DOI: 10.1038/s41589-024-01644-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 05/10/2024] [Indexed: 06/30/2024]
Abstract
Glycation is a non-enzymatic post-translational modification (PTM) that is correlated with many diseases, including diabetes, cancer and age-related disorders. Although recent work points to the importance of glycation as a functional PTM, it remains an open question whether glycation has a causal role in cellular signaling and/or disease development. In this Review, we contextualize glycation as a specific mechanism of carbon stress and consolidate what is known about advanced glycation end-product (AGE) structures and mechanisms. We highlight the current understanding of glycation as a PTM, focusing on mechanisms for installing, removing or recognizing AGEs. Finally, we discuss challenges that have hampered a more complete understanding of the biological consequences of glycation. The development of tools for predicting, modulating, mimicking or capturing glycation will be essential for interpreting a post-translational glycation network. Therefore, continued insights into the chemistry of glycation will be necessary to advance understanding of glycation biology.
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Kumar N, Samanta B, Km J, Raghunathan V, Sen P, Bhat R. Demonstration of Enhancement of Tumor Intravasation by Dicarbonyl Stress Using a Microfluidic Organ-on-chip. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2405998. [PMID: 39745135 DOI: 10.1002/smll.202405998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 11/28/2024] [Indexed: 02/13/2025]
Abstract
Cancer metastasis involves cell migration from their primary organ foci into vascular channels, followed by dissemination to prospective colonization sites. Vascular entry of tumor cells or intravasation involves their breaching stromal and endothelial extracellular matrix (ECM) and the endothelial barriers. How the kinetics of this breach are confounded by chronic inflammatory stresses seen in diabetes and aging remains ill-investigated. To study the problem, a histopathology-motivated, imaging-tractable, microfluidic multi-organ-on-chip platform is constructed, that seamlessly integrates a breast tumor-like compartment: invasive MDA-MB-231 in a 3D Collagen I scaffold, and a flow-implemented vascular channel: immortalized human aortic endothelia (TeloHAEC) on laminin-rich basement membrane (lrBM). The chip showcases the complexity of intravasation, wherein tumor cells and endothelia cooperate to form anastomotic structures, which facilitate cancer cell migration into the vascular channel. Upon entry, cancer cells adhere to and flow within the vascular channel. Exposure to methylglyoxal (MG), a dicarbonyl stressor associated with diabetic circulatory milieu increases cancer cell intravasation and adhesion through the vascular channel. This can be driven by MG-induced endothelial senescence and shedding, but also by the ability of MG to degrade lrBM and pathologically cross-link Collagen I, diminishing cell-ECM adhesion. Thus, dicarbonyl stress attenuates homeostatic barriers to cancer intravasation, exacerbating metastasis.
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Affiliation(s)
- Nilesh Kumar
- Centre for Nano Science and Engineering, Indian Institute of Science, Bengaluru, 560012, India
| | - Bidita Samanta
- Department of Bioengineering, Indian Institute of Science, Bengaluru, 560012, India
| | - Jyothsna Km
- Department of Electrical and Communications Engineering, Bengaluru, 560012, India
| | - Varun Raghunathan
- Department of Electrical and Communications Engineering, Bengaluru, 560012, India
| | - Prosenjit Sen
- Centre for Nano Science and Engineering, Indian Institute of Science, Bengaluru, 560012, India
- Department of Bioengineering, Indian Institute of Science, Bengaluru, 560012, India
| | - Ramray Bhat
- Department of Bioengineering, Indian Institute of Science, Bengaluru, 560012, India
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bengaluru, 560012, India
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6
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Takeuchi M. Toxic AGEs (TAGE) Cause Lifestyle-Related Diseases. Antioxidants (Basel) 2024; 13:1372. [PMID: 39594514 PMCID: PMC11591050 DOI: 10.3390/antiox13111372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/01/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Advanced glycation end-products (AGEs) play a role in the onset/progression of lifestyle-related diseases (LSRD), suggesting that the suppression of AGE-induced effects can be exploited to prevent and treat LSRD. However, AGEs have a variety of structures with different biological effects. Glyceraldehyde (GA) is an intermediate of glucose, and fructose metabolism and GA-derived AGEs (GA-AGEs) have been associated with LSRD, leading to the concept of toxic AGEs (TAGE). Elevated blood TAGE levels have been implicated in the onset/progression of LSRD; therefore, the measurement of TAGE levels may enable disease prediction at an early stage. Moreover, recent studies have revealed the structures and degradation pathways of TAGE. Herein, we provide an overview of the research on TAGE. The TAGE theory provides novel insights into LSRD and is expected to elucidate new targets for many diseases.
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Affiliation(s)
- Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan
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7
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Sroga GE, Vashishth D. In vivo glycation-interplay between oxidant and carbonyl stress in bone. JBMR Plus 2024; 8:ziae110. [PMID: 39386996 PMCID: PMC11458925 DOI: 10.1093/jbmrpl/ziae110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 06/18/2024] [Accepted: 07/28/2024] [Indexed: 10/12/2024] Open
Abstract
Metabolic syndromes (eg, obesity, type 2 diabetes (T2D), atherosclerosis, and neurodegenerative diseases) and aging, they all have a strong component of carbonyl and reductive-oxidative (redox) stress. Reactive carbonyl (RCS) and oxidant (ROS) stress species are commonly generated as products or byproducts of cellular metabolism or are derived from the environment. RCS and ROS can play a dual role in living organisms. Some RCS and ROS function as signaling molecules, which control cellular defenses against biological and environmental assaults. However, due to their high reactivity, RCS and ROS inadvertently interact with different cellular and extracellular components, which can lead to the formation of undesired posttranslational modifications of bone matrix proteins. These are advanced glycation (AGEs) and glycoxidation (AGOEs) end products generated in vivo by non-enzymatic amino-carbonyl reactions. In this review, metabolic processes involved in generation of AGEs and AGOEs within and on protein surfaces including extracellular bone matrix are discussed from the perspective of cellular metabolism and biochemistry of certain metabolic syndromes. The impact of AGEs and AGOEs on some characteristics of mineral is also discussed. Different therapeutic approaches with the potential to prevent the formation of RCS, ROS, and the resulting formation of AGEs and AGOEs driven by these chemicals are also briefly reviewed. These are antioxidants, scavenging agents of reactive species, and newly emerging technologies for the development of synthetic detoxifying systems. Further research in the area of in vivo glycation and glycoxidation should lead to the development of diverse new strategies for halting the progression of metabolic complications before irreversible damage to body tissues materializes.
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Affiliation(s)
- Grażyna E Sroga
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States
- Shirley Ann Jackson PhD Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United States
| | - Deepak Vashishth
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States
- Shirley Ann Jackson PhD Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United States
- Center for Engineering and Precision Medicine, Rensselaer-Icahn School of Medicine at Mount Sinai, 619 West 54th Street, New York, NY 10019, United States
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8
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Sugawa H, Ikeda T, Tominaga Y, Katsuta N, Nagai R. Rapid formation of N ε-(carboxymethyl)lysine (CML) from ribose depends on glyoxal production by oxidation. RSC Chem Biol 2024:d4cb00183d. [PMID: 39323732 PMCID: PMC11420854 DOI: 10.1039/d4cb00183d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 09/13/2024] [Indexed: 09/27/2024] Open
Abstract
N ε-(Carboxymethyl)lysine (CML) is a major advanced glycation end-product (AGE) involved in protein dysfunction and inflammation in vivo. Its accumulation increases with age and is enhanced with the pathogenesis of diabetic complications. Therefore, the pathways involved in CML formation should be elucidated to understand the pathological conditions involved in CML. Ribose is widely used in glycation research because it shows a high reactivity with proteins to form AGEs. We previously demonstrated that ribose generates CML more rapidly than other reducing sugars, such as glucose; however, the underlying mechanism remains unclear. In this study, we focused on the pathway of CML formation from ribose. As a result, glyoxal (GO) was the most abundant product generated from ribose among the tested reducing sugars and was significantly correlated with CML formation from ribose-modified protein. The coefficient of determination (R 2) for CML formation between the ribose-modified protein and Amadori products or the ribose degradation product (RDP)-modified protein was higher for the RDP-modified protein. CML formation from ribose degradation products (RDP) incubated with protein significantly correlated with CML formation from GO-modified protein (r s = 0.95, p = 0.0000000869). GO and CML formation were inhibited by diethylenetriaminepentaacetic acid (DTPA) and enhanced by iron chloride. Additionally, flavonoid compounds such as isoquercetin, which are known to inhibit CML, also inhibited GO formation from ribose and CML formation. In conclusion, ribose undergoes auto-oxidation and oxidative cleavage between C-2 and C-3 to generate GO and enhance CML accumulation.
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Affiliation(s)
- Hikari Sugawa
- Department of Food and Life Sciences, School of Agriculture, Tokai University Japan
| | - Tsuyoshi Ikeda
- Faculty of Pharmaceutical Sciences, Sojo University Japan
| | - Yuki Tominaga
- Department of Food and Life Sciences, School of Agriculture, Tokai University Japan
| | - Nana Katsuta
- Research Institute of Agriculture, Tokai University Japan
| | - Ryoji Nagai
- Department of Food and Life Sciences, School of Agriculture, Tokai University Japan
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9
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Blidi S, Troise AD, Zazzaroni M, De Pascale S, Cottin S, Sturrock K, Scaloni A, Fiore A. Effect of brewer's spent grain melanoidins on maillard reaction products during storage of whey protein model systems. Curr Res Food Sci 2024; 8:100767. [PMID: 38774268 PMCID: PMC11107219 DOI: 10.1016/j.crfs.2024.100767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 05/04/2024] [Accepted: 05/07/2024] [Indexed: 05/24/2024] Open
Abstract
Maillard reaction readily takes place in dairy products because of the association between thermal treatments, extended storage and the matrix composition. Along with the impairment of protein digestion, the formation of glycation and α-dicarbonyl compounds is a concern for quality attributes of whey proteins when used as ingredients. In this paper, we outline the capacity of brewer's spent grain melanoidins in reducing the accumulation of α-dicarbonyl compounds, thus controlling the formation of dietary advanced glycation end-products in accelerated shelf life at 35 °C. Results revealed that brewer's spent grain melanoidins targeted methylglyoxal and glyoxal reactivity leading to the reduction of N-ε-carboxymethyllysine and methylglyoxal-hydroimidazolone up to 27 and 60%, respectively. We here describe that the presence of melanoidins is instrumental in limiting the undesired effects of α-dicarbonyl compounds on whey proteins.
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Affiliation(s)
- Slim Blidi
- School of Applied Sciences, Division of Engineering and Food Science, University of Abertay, Bell Street, DD1 1HG, Dundee, Scotland, United Kingdom
| | - Antonio Dario Troise
- Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, National Research Council, 80055 Portici, Italy
| | - Mattia Zazzaroni
- School of Applied Sciences, Division of Engineering and Food Science, University of Abertay, Bell Street, DD1 1HG, Dundee, Scotland, United Kingdom
| | - Sabrina De Pascale
- Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, National Research Council, 80055 Portici, Italy
| | - Sarah Cottin
- School of Applied Sciences, Division of Engineering and Food Science, University of Abertay, Bell Street, DD1 1HG, Dundee, Scotland, United Kingdom
| | - Keith Sturrock
- School of Applied Sciences, Division of Psychology and Forensic Science, University of Abertay, Bell Street, DD1 1HG, Dundee, Scotland, United Kingdom
| | - Andrea Scaloni
- Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, National Research Council, 80055 Portici, Italy
| | - Alberto Fiore
- School of Applied Sciences, Division of Engineering and Food Science, University of Abertay, Bell Street, DD1 1HG, Dundee, Scotland, United Kingdom
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10
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Kong LR, Gupta K, Wu AJ, Perera D, Ivanyi-Nagy R, Ahmed SM, Tan TZ, Tan SLW, Fuddin A, Sundaramoorthy E, Goh GS, Wong RTX, Costa ASH, Oddy C, Wong H, Patro CPK, Kho YS, Huang XZ, Choo J, Shehata M, Lee SC, Goh BC, Frezza C, Pitt JJ, Venkitaraman AR. A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2. Cell 2024; 187:2269-2287.e16. [PMID: 38608703 DOI: 10.1016/j.cell.2024.03.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 02/01/2024] [Accepted: 03/07/2024] [Indexed: 04/14/2024]
Abstract
Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.
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Affiliation(s)
- Li Ren Kong
- Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Department of Pharmacology, National University of Singapore, Singapore 117600, Singapore
| | - Komal Gupta
- Cancer Science Institute of Singapore, Singapore 117599, Singapore; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK
| | - Andy Jialun Wu
- Cancer Science Institute of Singapore, Singapore 117599, Singapore
| | - David Perera
- MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK
| | | | - Syed Moiz Ahmed
- Cancer Science Institute of Singapore, Singapore 117599, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, Singapore 117599, Singapore
| | - Shawn Lu-Wen Tan
- MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Institute of Molecular and Cell Biology (IMCB), A(∗)STAR, Singapore 138673, Singapore
| | | | | | | | | | - Ana S H Costa
- MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK
| | - Callum Oddy
- Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK
| | - Hannan Wong
- Cancer Science Institute of Singapore, Singapore 117599, Singapore
| | - C Pawan K Patro
- Cancer Science Institute of Singapore, Singapore 117599, Singapore
| | - Yun Suen Kho
- Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore
| | - Xiao Zi Huang
- Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore
| | - Joan Choo
- Department of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Mona Shehata
- MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK
| | - Soo Chin Lee
- Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore; Department of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Boon Cher Goh
- Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore; Department of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Christian Frezza
- MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; University of Cologne, 50923 Köln, Germany
| | - Jason J Pitt
- Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore; Genome Institute of Singapore, A(∗)STAR, Singapore 138673, Singapore
| | - Ashok R Venkitaraman
- Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Institute of Molecular and Cell Biology (IMCB), A(∗)STAR, Singapore 138673, Singapore; Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK; Department of Medicine, National University of Singapore, Singapore 119228, Singapore.
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11
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Guo P, Chu X, Wu C, Qiao T, Guan W, Zhou C, Wang T, Tian C, He G, Chen G. Peptide Stapling by Crosslinking Two Amines with α-Ketoaldehydes through Diverse Modified Glyoxal-Lysine Dimer Linkers. Angew Chem Int Ed Engl 2024; 63:e202318893. [PMID: 38376389 DOI: 10.1002/anie.202318893] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 02/21/2024]
Abstract
α-Ketoaldehydes play versatile roles in the ubiquitous natural processes of protein glycation. However, leveraging the reactivity of α-ketoaldehydes for biomedical applications has been challenging. Previously, the reactivity of α-ketoaldehydes with guanidine has been harnessed to design probes for labeling Arg residues on proteins in an aqueous medium. Herein, a highly effective, broadly applicable, and operationally simple protocol for stapling native peptides by crosslinking two amino groups through diverse imidazolium linkers with various α-ketoaldehyde reagents is described. The use of hexafluoroisopropanol as a solvent facilitates rapid and clean reactions under mild conditions and enables unique selectivity for Lys over Arg. The naturally occurring GOLD/MOLD linkers have been expanded to encompass a wide range of modified glyoxal-lysine dimer (OLD) linkers. In a proof-of-concept trial, these modular stapling reactions enabled a convenient two-round strategy to streamline the structure-activity relationship (SAR) study of the wasp venom peptide anoplin, leading to enhanced biological activities.
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Affiliation(s)
- Pan Guo
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Xin Chu
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Chengjin Wu
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Tianjiao Qiao
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Wenli Guan
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Chuanzheng Zhou
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Tao Wang
- Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230026, China
| | - Changlin Tian
- Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230026, China
| | - Gang He
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Gong Chen
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
- Frontiers Science Center for New Organic Matter, Nankai University, Tianjin, 300071, China
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, 300192, China
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12
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McGary LC, Fetter CM, Gu M, Hamilton MC, Kumar H, Kuehm OP, Douglas CD, Bearne SL. Interrogating l-fuconate dehydratase with tartronate and 3-hydroxypyruvate reveals subtle differences within the mandelate racemase-subgroup of the enolase superfamily. Arch Biochem Biophys 2024; 754:109924. [PMID: 38354877 DOI: 10.1016/j.abb.2024.109924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 01/27/2024] [Accepted: 02/05/2024] [Indexed: 02/16/2024]
Abstract
Enzymes of the enolase superfamily share a conserved structure and a common partial reaction (i.e., metal-assisted, Brønsted base-catalyzed enol(ate) formation). The architectures of the enolization apparatus at the active sites of the mandelate racemase (MR)-subgroup members MR and l-fuconate dehydratase (FucD) are almost indistinguishable at the structural level. Tartronate and 3-hydroxypyruvate (3-HP) recognize the enolization apparatus and can be used to interrogate the active sites for differences that may not be apparent from structural data. We report a circular dichroism-based assay of FucD activity that monitors the change in ellipticity at 216 nm (Δ[Θ]S-P = 8985 ± 87 deg cm2 mol-1) accompanying the conversion of l-fuconate to 2-keto-3-deoxy-l-fuconate. Tartronate was a linear mixed-type inhibitor of FucD (Ki = 8.4 ± 0.7 mM, αKi = 63 ± 11 mM), binding 18-fold weaker than l-fuconate, compared with 2-fold weaker binding of tartronate by MR relative to mandelate. 3-HP irreversibly inactivated FucD (kinact/KI = 0.018 ± 0.002 M-1s-1) with an efficiency that was ∼4.6 × 103-fold less than that observed with MR. The inactivation arose predominantly from modifications at multiple sites and Tris-HCl, but not l-fuconate, afforded protection against inactivation. Similar to the reaction of 3-HP with MR, 3-HP modified the Brønsted base catalyst (Lys 220) at the active site of FucD, which was facilitated by the Brønsted acid catalyst His 351. Thus, the interactions of tartronate and 3-HP with MR and FucD revealed differences in binding affinity and reactivity that differentiated between the enzymes' enolization apparatuses.
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Affiliation(s)
- Laura C McGary
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, B3H 4R2, Canada
| | - Christopher M Fetter
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, B3H 4R2, Canada
| | - Minglu Gu
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, B3H 4R2, Canada
| | - Meghan C Hamilton
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, B3H 4R2, Canada
| | - Himank Kumar
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, B3H 4R2, Canada
| | - Oliver P Kuehm
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, B3H 4R2, Canada
| | - Colin D Douglas
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, B3H 4R2, Canada
| | - Stephen L Bearne
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, B3H 4R2, Canada; Department of Chemistry, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
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13
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Sakai-Sakasai A, Takeda K, Suzuki H, Takeuchi M. Structures of Toxic Advanced Glycation End-Products Derived from Glyceraldehyde, A Sugar Metabolite. Biomolecules 2024; 14:202. [PMID: 38397439 PMCID: PMC10887030 DOI: 10.3390/biom14020202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/01/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Advanced glycation end-products (AGEs) have recently been implicated in the onset/progression of lifestyle-related diseases (LSRDs); therefore, the suppression of AGE-induced effects may be used in both the prevention and treatment of these diseases. Various AGEs are produced by different biological pathways in the body. Glyceraldehyde (GA) is an intermediate of glucose and fructose metabolism, and GA-derived AGEs (GA-AGEs), cytotoxic compounds that accumulate and induce damage in mammalian cells, contribute to the onset/progression of LSRDs. The following GA-AGE structures have been detected to date: triosidines, GA-derived pyridinium compounds, GA-derived pyrrolopyridinium lysine dimers, methylglyoxal-derived hydroimidazolone 1, and argpyrimidine. GA-AGEs are a key contributor to the formation of toxic AGEs (TAGE) in many cells. The extracellular leakage of TAGE affects the surrounding cells via interactions with the receptor for AGEs. Elevated serum levels of TAGE, which trigger different types of cell damage, may be used as a novel biomarker for the prevention and early diagnosis of LSRDs as well as in evaluations of treatment efficacy. This review provides an overview of the structures of GA-AGEs.
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Affiliation(s)
- Akiko Sakai-Sakasai
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan; (A.S.-S.); (K.T.)
- General Medicine Center, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan
| | - Kenji Takeda
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan; (A.S.-S.); (K.T.)
- Department of Cardiology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan
| | - Hirokazu Suzuki
- Department of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Ishikawa, Japan;
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan; (A.S.-S.); (K.T.)
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14
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Niu L, Lai K, Huang Y. Sodium chloride inhibits the heat-induced formation of advanced glycation end-products in myofibrillar protein–reducing sugar–oleic acid model systems. JOURNAL OF FOOD MEASUREMENT AND CHARACTERIZATION 2024; 18:1293-1301. [DOI: 10.1007/s11694-023-02288-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 11/16/2023] [Indexed: 01/03/2025]
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15
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Brings S, Mier W, Beijer B, Kliemank E, Herzig S, Szendroedi J, Nawroth PP, Fleming T. Non-cross-linking advanced glycation end products affect prohormone processing. Biochem J 2024; 481:33-44. [PMID: 38112318 DOI: 10.1042/bcj20230321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 12/01/2023] [Accepted: 12/19/2023] [Indexed: 12/21/2023]
Abstract
Advanced glycation end products (AGEs) are non-enzymatic post-translational modifications of amino acids and are associated with diabetic complications. One proposed pathomechanism is the impaired processing of AGE-modified proteins or peptides including prohormones. Two approaches were applied to investigate whether substrate modification with AGEs affects the processing of substrates like prohormones to the active hormones. First, we employed solid-phase peptide synthesis to generate unmodified as well as AGE-modified protease substrates. Activity of proteases towards these substrates was quantified. Second, we tested the effect of AGE-modified proinsulin on the processing to insulin. Proteases showed the expected activity towards the unmodified peptide substrates containing arginine or lysine at the C-terminal cleavage site. Indeed, modification with Nε-carboxymethyllysine (CML) or methylglyoxal-hydroimidazolone 1 (MG-H1) affected all proteases tested. Cysteine cathepsins displayed a reduction in activity by ∼50% towards CML and MG-H1 modified substrates. The specific proteases trypsin, proprotein convertases subtilisin-kexins (PCSKs) type proteases, and carboxypeptidase E (CPE) were completely inactive towards modified substrates. Proinsulin incubation with methylglyoxal at physiological concentrations for 24 h resulted in the formation of MG-modified proinsulin. The formation of insulin was reduced by up to 80% in a concentration-dependent manner. Here, we demonstrate the inhibitory effect of substrate-AGE modifications on proteases. The finding that PCSKs and CPE, which are essential for prohormone processing, are inactive towards modified substrates could point to a yet unrecognized pathomechanism resulting from AGE modification relevant for the etiopathogenesis of diabetes and the development of obesity.
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Affiliation(s)
- Sebastian Brings
- Department of Endocrinology, Metabolism and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Walter Mier
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Barbro Beijer
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Elisabeth Kliemank
- Department of Endocrinology, Metabolism and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephan Herzig
- German Centre of Diabetes Research (DZD), Munich, Germany
- Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Munich, Germany
| | - Julia Szendroedi
- Department of Endocrinology, Metabolism and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
- German Centre of Diabetes Research (DZD), Munich, Germany
- Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Munich, Germany
- Center for Molecular Biology Heidelberg (ZMBH), Heidelberg, Germany
- Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter P Nawroth
- Department of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Fleming
- Department of Endocrinology, Metabolism and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
- German Centre of Diabetes Research (DZD), Munich, Germany
- Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Munich, Germany
- Center for Molecular Biology Heidelberg (ZMBH), Heidelberg, Germany
- Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ), Heidelberg, Germany
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16
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Wagner N, Wen L, Frazão CJR, Walther T. Next-generation feedstocks methanol and ethylene glycol and their potential in industrial biotechnology. Biotechnol Adv 2023; 69:108276. [PMID: 37918546 DOI: 10.1016/j.biotechadv.2023.108276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/13/2023] [Accepted: 10/22/2023] [Indexed: 11/04/2023]
Abstract
Microbial fermentation processes are expected to play an important role in reducing dependence on fossil-based raw materials for the production of everyday chemicals. In order to meet the growing demand for biotechnological products in the future, alternative carbon sources that do not compete with human nutrition must be exploited. The chemical conversion of the industrially emitted greenhouse gas CO2 into microbially utilizable platform chemicals such as methanol represents a sustainable strategy for the utilization of an abundant carbon source and has attracted enormous scientific interest in recent years. A relatively new approach is the microbial synthesis of products from the C2-compound ethylene glycol, which can also be synthesized from CO2 and non-edible biomass and, in addition, can be recovered from plastic waste. Here we summarize the main chemical routes for the synthesis of methanol and ethylene glycol from sustainable resources and give an overview of recent metabolic engineering work for establishing natural and synthetic microbial assimilation pathways. The different metabolic routes for C1 and C2 alcohol-dependent bioconversions were compared in terms of their theoretical maximum yields and their oxygen requirements for a wide range of value-added products. Assessment of the process engineering challenges for methanol and ethylene glycol-based fermentations underscores the theoretical advantages of new synthetic metabolic routes and advocates greater consideration of ethylene glycol, a C2 substrate that has received comparatively little attention to date.
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Affiliation(s)
- Nils Wagner
- TU Dresden, Institute of Natural Materials Technology, Bergstraße 120, 01062 Dresden, Germany
| | - Linxuan Wen
- TU Dresden, Institute of Natural Materials Technology, Bergstraße 120, 01062 Dresden, Germany
| | - Cláudio J R Frazão
- TU Dresden, Institute of Natural Materials Technology, Bergstraße 120, 01062 Dresden, Germany
| | - Thomas Walther
- TU Dresden, Institute of Natural Materials Technology, Bergstraße 120, 01062 Dresden, Germany.
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17
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Sun WJ, An XD, Zhang YH, Zhao XF, Sun YT, Yang CQ, Kang XM, Jiang LL, Ji HY, Lian FM. The ideal treatment timing for diabetic retinopathy: the molecular pathological mechanisms underlying early-stage diabetic retinopathy are a matter of concern. Front Endocrinol (Lausanne) 2023; 14:1270145. [PMID: 38027131 PMCID: PMC10680169 DOI: 10.3389/fendo.2023.1270145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Diabetic retinopathy (DR) is a prevalent complication of diabetes, significantly impacting patients' quality of life due to vision loss. No pharmacological therapies are currently approved for DR, excepted the drugs to treat diabetic macular edema such as the anti-VEGF agents or steroids administered by intraocular route. Advancements in research have highlighted the crucial role of early intervention in DR for halting or delaying disease progression. This holds immense significance in enhancing patients' quality of life and alleviating the societal burden associated with medical care costs. The non-proliferative stage represents the early phase of DR. In comparison to the proliferative stage, pathological changes primarily manifest as microangiomas and hemorrhages, while at the cellular level, there is a loss of pericytes, neuronal cell death, and disruption of components and functionality within the retinal neuronal vascular unit encompassing pericytes and neurons. Both neurodegenerative and microvascular abnormalities manifest in the early stages of DR. Therefore, our focus lies on the non-proliferative stage of DR and we have initially summarized the mechanisms involved in its development, including pathways such as polyols, that revolve around the pathological changes occurring during this early stage. We also integrate cutting-edge mechanisms, including leukocyte adhesion, neutrophil extracellular traps, multiple RNA regulation, microorganisms, cell death (ferroptosis and pyroptosis), and other related mechanisms. The current status of drug therapy for early-stage DR is also discussed to provide insights for the development of pharmaceutical interventions targeting the early treatment of DR.
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Affiliation(s)
- Wen-Jie Sun
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Xue-Dong An
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Yue-Hong Zhang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Xue-Fei Zhao
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Yu-Ting Sun
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Cun-Qing Yang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiao-Min Kang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Lin-Lin Jiang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Hang-Yu Ji
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Feng-Mei Lian
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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18
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Wang B, Vashishth D. Advanced glycation and glycoxidation end products in bone. Bone 2023; 176:116880. [PMID: 37579812 PMCID: PMC10529863 DOI: 10.1016/j.bone.2023.116880] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/21/2023] [Accepted: 08/11/2023] [Indexed: 08/16/2023]
Abstract
Hyperglycemia and oxidative stress, enhanced in diabetes and aging, result in excessive accumulation of advanced glycation and glycoxidation end products (AGEs/AGOEs) in bone. AGEs/AGOES are considered to be "the missing link" in explaining increased skeletal fragility with diabetes, aging, and osteoporosis where increased fracture risk cannot be solely explained by bone mass and/or fall incidences. AGEs/AGOEs disrupt bone turnover and deteriorate bone quality through alterations of organic matrix (collagen and non-collagenous proteins), mineral, and water content. AGEs and AGOEs are also associated with bone fragility in other conditions such as Alzheimer's disease, circadian rhythm disruption, and cancer. This review explains how AGEs and AGOEs accumulate in bone and impact bone quality and bone fracture, and how AGES/AGOEs are being targeted in preclinical and clinical investigations for inhibition or removal, and for prediction and management of diabetic, osteoporotic and insufficiency fractures.
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Affiliation(s)
- Bowen Wang
- Shirley Ann Jackson Ph.D. Center of Biotechnology and Interdisciplinary Studies, Troy, NY 12180, USA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Deepak Vashishth
- Shirley Ann Jackson Ph.D. Center of Biotechnology and Interdisciplinary Studies, Troy, NY 12180, USA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Rensselaer - Icahn School of Medicine at Mount Sinai Center for Engineering and Precision Medicine, New York, NY 10019, USA.
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19
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Hussain A, Ashique S, Afzal O, Altamimi MA, Malik A, Kumar S, Garg A, Sharma N, Farid A, Khan T, Altamimi ASA. A correlation between oxidative stress and diabetic retinopathy: An updated review. Exp Eye Res 2023; 236:109650. [PMID: 37734426 DOI: 10.1016/j.exer.2023.109650] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/09/2023] [Accepted: 09/12/2023] [Indexed: 09/23/2023]
Abstract
Oxidative stress (OS) is a cytopathic outcome of excessively generated reactive oxygen species (ROS), down regulated antioxidant defense signaling pathways, and the imbalance between the produced radicals and their clearance. It plays a role in the genesis of several illnesses, especially hyperglycemia and its effects. Diabetic retinal illness, a micro vascular side effect of the condition, is the prime reason of diabetic related blindness. The OS (directly or indirectly) is associated with diabetic retinopathy (DR) and related consequences. The OS is responsible to induce and interfere the metabolic signaling pathways to enhance influx of the polyol cascades and hexosamine pathways, stimulate Protein Kinase-C (PKC) variants, and accumulate advanced glycation end products (AGEs). Additionally, the inequity between the scavenging and generation of ROS is caused by the epigenetic alteration caused by hyperglycemia that suppresses the antioxidant defense system. Induced by an excessive buildup of ROS, retinal changes in structure and function include mitochondrial damage, cellular death, inflammation, and lipid peroxidation. Therefore, it is crucial to comprehend and clarify the mechanisms connected to oxidative stress that underlie the development of DR.
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Affiliation(s)
- Afzal Hussain
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
| | - Sumel Ashique
- Department of Pharmaceutics, Pandaveswar School of Pharmacy, Pandaveswar, West Bengal, 713346, India
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, 11942, Saudi Arabia
| | - Mohammad A Altamimi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Abdul Malik
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Shubneesh Kumar
- Department of Pharmaceutics, Bharat Institute of Technology, School of Pharmacy, Meerut, Uttar Pradesh, 250103, India
| | - Ashish Garg
- Department of Pharmaceutics, Guru Ramdas Khalsa Institute of Science and Technology (Pharmacy), Jabalpur, Madhya Pradesh, India
| | - Nidhi Sharma
- Graduate Assistant, Department of Biomedical Engineering University of Connecticut, UCONN, Storrs Campus, 263 Farmington Ave, Farmington, CT, 06030, USA
| | - Arshad Farid
- Gomal Center of Biochemistry and Biotechnology, Gomal University, D.I. Khan, KPK, Pakistan
| | - Tasneem Khan
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Abdulmalik S A Altamimi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, 11942, Saudi Arabia
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20
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Thierig M, Siegel E, Henle T. Formation of Protein-Bound Maillard Reaction Products during the Storage of Manuka Honey. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:15261-15269. [PMID: 37796058 DOI: 10.1021/acs.jafc.3c03446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
Honey from the nectar of the Manuka tree (Leptospermum scoparium) grown in New Zealand contains high amounts of antibacterial methylglyoxal (MGO). MGO can react with proteins to form peptide-bound Maillard reaction products (MRPs) such as Nε-carboxyethyllysine (CEL) and "methylglyoxal-derived hydroimidazolone 1" (MG-H1). To study the reactions of MGO with honey proteins during storage, three manuka honeys with varying amounts of MGO and a kanuka honey (Kunzea ericoides) spiked with various MGO concentrations up to 700 mg/kg have been stored at 37 °C for 10 weeks, and the formation of protein-bound MRPs has been analyzed via high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) following isolation of the protein fraction and enzymatic hydrolysis. During storage, contents of protein-bound CEL and MG-H1 increased continuously, directly depending on the MGO content. For honeys with large amounts of MGO, a slower formation of Nε-fructosyllysine (FL) was observed, indicating competing reactions of glucose and MGO with lysine. Furthermore, the lysine modification increased with storage independently from the MGO concentration. Up to 58-61% of the observed lysine modification was explainable with the formation of CEL and FL, indicating that other reactions, most likely the formation of Heyns products from lysine and fructose, may play an important role. Our results can contribute to the authentication of manuka honey.
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Affiliation(s)
- Marcus Thierig
- Chair of Food Chemistry, Technische Universität Dresden, D-01062 Dresden, Germany
| | - Eva Siegel
- Chair of Food Chemistry, Technische Universität Dresden, D-01062 Dresden, Germany
| | - Thomas Henle
- Chair of Food Chemistry, Technische Universität Dresden, D-01062 Dresden, Germany
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21
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Tallawi M, Amrein D, Gemmecker G, Aifantis KE, Drechsler K. A novel polysaccharide/zein conjugate as an alternative green plastic. Sci Rep 2023; 13:13161. [PMID: 37573459 PMCID: PMC10423201 DOI: 10.1038/s41598-023-40293-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 08/08/2023] [Indexed: 08/14/2023] Open
Abstract
The flax seed cake is a waste product from flax oil extraction. Adding value to this wasted material aligns with the concept of circularity. In this study, we explored zein protein conjugation with flax mucilage for packaging material development. Although both flax mucilage and zein have excellent film-forming properties, they lack the required mechanical properties for industrial processing and are sensitive to high humidity. We present a simple and non-toxic one-pot method for developing the novel flax mucilage/zein conjugate. Where the flax mucilage undergoes oxidation to form aldehyde groups, which then react with zein's amino groups in a glycation process. The conjugates were analyzed using different techniques. The flax mucilage conjugate had a water-holding capacity of 87-62%. Increasing the zein content improved the surface smoothness of the films. On the other hand, higher levels of zein led to a significant decrease in film solubility (p < 0.05). The flax mucilage conjugate exhibited thermoplastic and elastic properties; revealing Young's modulus of 1-3 GPa, glass transition temperature between 49 °C and 103 °C and excellent processability with various industrial techniques. Showing its potential as a sustainable alternative to traditional plastics.
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Affiliation(s)
- Marwa Tallawi
- Carbon Composite, School of Engineering and Design, Technical University of Munich, 85748, Garching, Germany.
| | - Danial Amrein
- Carbon Composite, School of Engineering and Design, Technical University of Munich, 85748, Garching, Germany
| | - Gerd Gemmecker
- School of Natural Sciences, Bavarian NMR Center, Technical University of Munich, 85748, Garching, Germany
| | - Katerina E Aifantis
- Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, 32611, USA
| | - Klaus Drechsler
- Carbon Composite, School of Engineering and Design, Technical University of Munich, 85748, Garching, Germany
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22
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Nogueira Silva Lima MT, Howsam M, Delayre-Orthez C, Jacolot P, Jaisson S, Criquet J, Billamboz M, Ghinet A, Fradin C, Boulanger E, Bray F, Flament S, Rolando C, Gillery P, Niquet-Léridon C, Tessier FJ. Glycated bovine serum albumin for use in feeding trials with animal models - In vitro methodology and characterization of a glycated substrate for modifying feed pellets. Food Chem 2023; 428:136815. [PMID: 37450953 DOI: 10.1016/j.foodchem.2023.136815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/29/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
This study investigated different methods to produce Nε-carboxymethyl-lysine (CML)-enriched bovine serum albumin (BSA) as alternatives to the classical approach using glyoxylic acid (GA) and sodium cyanoborohydride (NaBH3CN) which results in toxic hydrogen cyanide (HCN). The reaction of GA (6 mmol/L) and NaBH3CN (21 mmol/L) to produce CML remained the most effective with CML yields of 24-35%, followed by 13-24% using 300 mmol/L glyoxal (GO). GA promoted specific modification of lysine to CML, and fewer structural modifications of the BSA molecule compared with GO, as evidenced by fluorescence and proteomic analyses. GO promoted greater arginine modification compared with GA (76 vs 23%). Despite structural changes to BSA with GO, murine fecal clearance of CML was similar to literature values. Hence, BSA glycation with 300 mmol/L glyoxal is a suitable alternative to GA and NaBH3CN for generating CML-enriched protein free of HCN, but a CML-only fortification model remains to be described.
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Affiliation(s)
- M T Nogueira Silva Lima
- U1167-RID-AGE-Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Institut Pasteur de Lille, University Lille, Inserm, CHU Lille, F-59000 Lille, France
| | - M Howsam
- U1167-RID-AGE-Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Institut Pasteur de Lille, University Lille, Inserm, CHU Lille, F-59000 Lille, France
| | - C Delayre-Orthez
- Institut Polytechnique UniLaSalle, Université d'Artois, ULR 7519, 60000 Beauvais, France
| | - P Jacolot
- Institut Polytechnique UniLaSalle, Université d'Artois, ULR 7519, 60000 Beauvais, France
| | - S Jaisson
- University of Reims Champagne-Ardenne, Laboratory of Biochemistry and Molecular Biology, CNRS/URCA UMR 7369 MEDyC, Faculté de Médecine, 51095 Reims, France, University Hospital of Reims, Laboratory of Biochemistry-Pharmacology-Toxicology, 51092 Reims, France
| | - J Criquet
- Univ. Lille, Laboratory of Advanced Spectroscopy for Interactions, Reactivity and Environment, CNRS, UMR 8516 - LASIRE, Lille F-59000, France
| | - M Billamboz
- U1167-RID-AGE-Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Institut Pasteur de Lille, University Lille, Inserm, CHU Lille, F-59000 Lille, France; Junia, Health and Environment, Laboratory of Sustainable Chemistry and Health, 59000 Lille, France
| | - A Ghinet
- U1167-RID-AGE-Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Institut Pasteur de Lille, University Lille, Inserm, CHU Lille, F-59000 Lille, France; Junia, Health and Environment, Laboratory of Sustainable Chemistry and Health, 59000 Lille, France
| | - C Fradin
- U1167-RID-AGE-Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Institut Pasteur de Lille, University Lille, Inserm, CHU Lille, F-59000 Lille, France
| | - E Boulanger
- U1167-RID-AGE-Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Institut Pasteur de Lille, University Lille, Inserm, CHU Lille, F-59000 Lille, France
| | - F Bray
- Miniaturization for Synthesis, Analysis & Proteomics, UAR 3290, CNRS, University of Lille, 59655 Villeneuve d'Ascq Cedex, France
| | - S Flament
- Miniaturization for Synthesis, Analysis & Proteomics, UAR 3290, CNRS, University of Lille, 59655 Villeneuve d'Ascq Cedex, France
| | - C Rolando
- Miniaturization for Synthesis, Analysis & Proteomics, UAR 3290, CNRS, University of Lille, 59655 Villeneuve d'Ascq Cedex, France
| | - P Gillery
- University of Reims Champagne-Ardenne, Laboratory of Biochemistry and Molecular Biology, CNRS/URCA UMR 7369 MEDyC, Faculté de Médecine, 51095 Reims, France, University Hospital of Reims, Laboratory of Biochemistry-Pharmacology-Toxicology, 51092 Reims, France
| | - C Niquet-Léridon
- Institut Polytechnique UniLaSalle, Université d'Artois, ULR 7519, 60000 Beauvais, France
| | - F J Tessier
- U1167-RID-AGE-Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Institut Pasteur de Lille, University Lille, Inserm, CHU Lille, F-59000 Lille, France.
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23
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Hagenhaus V, Gorenflos López JL, Rosenstengel R, Neu C, Hackenberger CPR, Celik A, Weinert K, Nguyen MB, Bork K, Horstkorte R, Gesper A. Glycation Interferes with the Activity of the Bi-Functional UDP- N-Acetylglucosamine 2-Epimerase/ N-Acetyl-mannosamine Kinase (GNE). Biomolecules 2023; 13:biom13030422. [PMID: 36979358 PMCID: PMC10046061 DOI: 10.3390/biom13030422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/17/2023] [Accepted: 02/20/2023] [Indexed: 03/30/2023] Open
Abstract
Mutations in the gene coding for the bi-functional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme of the sialic acid biosynthesis, are responsible for autosomal-recessive GNE myopathy (GNEM). GNEM is an adult-onset disease with a yet unknown exact pathophysiology. Since the protein appears to work adequately for a certain period of time even though the mutation is already present, other effects appear to influence the onset and progression of the disease. In this study, we want to investigate whether the late onset of GNEM is based on an age-related effect, e.g., the accumulation of post-translational modifications (PTMs). Furthermore, we also want to investigate what effect on the enzyme activity such an accumulation would have. We will particularly focus on glycation, which is a PTM through non-enzymatic reactions between the carbonyl groups (e.g., of methylglyoxal (MGO) or glyoxal (GO)) with amino groups of proteins or other biomolecules. It is already known that the levels of both MGO and GO increase with age. For our investigations, we express each domain of the GNE separately, treat them with one of the glycation agents, and determine their activity. We demonstrate that the enzymatic activity of the N-acetylmannosamine kinase (GNE-kinase domain) decreases dramatically after glycation with MGO or GO-with a remaining activity of 13% ± 5% (5 mM MGO) and 22% ± 4% (5 mM GO). Whereas the activity of the UDP-N-acetylglucosamine 2-epimerase (GNE-epimerase domain) is only slightly reduced after glycation-with a remaining activity of 60% ± 8% (5 mM MGO) and 63% ± 5% (5 mM GO).
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Affiliation(s)
- Vanessa Hagenhaus
- Institute for Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
| | - Jacob L Gorenflos López
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), Campus Berlin-Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany
- Institut für Chemie, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
| | - Rebecca Rosenstengel
- Institute for Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
| | - Carolin Neu
- Institute for Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
| | - Christian P R Hackenberger
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), Campus Berlin-Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany
- Institut für Chemie, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
| | - Arif Celik
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), Campus Berlin-Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany
- Institut für Chemie, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
| | - Klara Weinert
- Institute for Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
| | - Mai-Binh Nguyen
- Institute for Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
| | - Kaya Bork
- Institute for Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
| | - Rüdiger Horstkorte
- Institute for Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
| | - Astrid Gesper
- Institute for Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
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24
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van Dongen KCW, Belzer C, Bakker W, Rietjens IMCM, Beekmann K. Inter- and Intraindividual Differences in the Capacity of the Human Intestinal Microbiome in Fecal Slurries to Metabolize Fructoselysine and Carboxymethyllysine. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:11759-11768. [PMID: 36069406 PMCID: PMC9501902 DOI: 10.1021/acs.jafc.2c05756] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 08/27/2022] [Accepted: 08/28/2022] [Indexed: 06/15/2023]
Abstract
The advanced glycation endproduct carboxymethyllysine and its precursor fructoselysine are present in heated, processed food products and are considered potentially hazardous for human health. Upon dietary exposure, they can be degraded by human colonic gut microbiota, reducing internal exposure. Pronounced interindividual and intraindividual differences in these metabolic degradations were found in anaerobic incubations with human fecal slurries in vitro. The average capacity to degrade fructoselysine was 27.7-fold higher than that for carboxymethyllysine, and degradation capacities for these two compounds were not correlated (R2 = 0.08). Analysis of the bacterial composition revealed that interindividual differences outweighed intraindividual differences, and multiple genera were correlated with the individuals' carboxymethyllysine and fructoselysine degradation capacities (e.g., Akkermansia, Alistipes).
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Affiliation(s)
- Katja C. W. van Dongen
- Division
of Toxicology, Wageningen University and
Research, P.O. Box 8000, Wageningen 6700 EA, The
Netherlands
| | - Clara Belzer
- Laboratory
of Microbiology, Wageningen University and
Research, P.O. Box 8033, Wageningen 6700 EH, The
Netherlands
| | - Wouter Bakker
- Division
of Toxicology, Wageningen University and
Research, P.O. Box 8000, Wageningen 6700 EA, The
Netherlands
| | - Ivonne M. C. M. Rietjens
- Division
of Toxicology, Wageningen University and
Research, P.O. Box 8000, Wageningen 6700 EA, The
Netherlands
| | - Karsten Beekmann
- Wageningen
Food Safety Research (WFSR), Part of Wageningen University and Research, P.O. Box 230, Wageningen 700 AE, The Netherlands
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25
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Sawai M, Miyauchi Y, Ishida T, Takechi S. Dihydropyrazine suppresses TLR4-dependent inflammatory responses by blocking MAPK signaling in human hepatoma HepG2 cells. J Toxicol Sci 2022; 47:381-387. [PMID: 36047112 DOI: 10.2131/jts.47.381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Dihydropyrazines (DHPs), including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are glycation products generated through non-enzymatic reactions in vivo and in food. They are recognized as compounds that are toxic to organisms as they produce radicals. However, our previous study indicated that DHP-3 suppressed Toll-like receptor 4 (TLR4) expression and decreased the phosphorylation of nuclear factor-κB (NF-κB) in lipopolysaccharide (LPS)-treated HepG2 cells. TLR4 signaling is involved in the onset of various inflammatory diseases, and NF-κB and mitogen-activated protein kinase (MAPK) play important roles in TLR4 signaling. Thus, we aimed to elucidate the effects of DHP-3 on MAPK signaling and in turn on the activated TLR4 signaling pathway. In LPS-stimulated HepG2 cells, DHP-3 reduced the phosphorylation of MAPK, extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38. The expression of c-jun, a subunit of activator protein-1, was decreased by DHP-3 treatment. Furthermore, DHP-3-induced suppression of MAPK signaling resulted in a decrease in various inflammatory regulators, such as interleukin-6, CC-chemokine ligand 2, and cyclooxygenase-2. These results suggest that DHP-3 exerts an inhibitory effect on TLR4-dependent inflammatory response by suppressing MAPK signaling.
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Affiliation(s)
- Madoka Sawai
- School of Pharmacy at Fukuoka, International University of Health and Welfare
| | - Yuu Miyauchi
- Faculty of Pharmaceutical Sciences, Sojo University
| | - Takumi Ishida
- School of Pharmacy at Fukuoka, International University of Health and Welfare
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26
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Eggen MD, Merboth P, Neukirchner H, Glomb MA. Lipid Peroxidation Has Major Impact on Malondialdehyde-Derived but Only Minor Influence on Glyoxal and Methylglyoxal-Derived Protein Modifications in Carbohydrate-Rich Foods. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:10271-10283. [PMID: 35968682 DOI: 10.1021/acs.jafc.2c04052] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
In the present work, the contribution of lipid peroxidation on modifications of lysine and arginine residues of proteins was investigated. Lipid peroxidation had a major impact on malondialdehyde-derived protein modifications; however, the influence on glyoxal and methylglyoxal-derived modifications in flat wafers was negligible. Therefore, vegetable oils (either linseed oil, sunflower oil, or coconut oil) were added to respective batters, and flat wafers were baked (150 °C, 3-10 min). Analysis of malondialdehyde indicated oxidation in linseed wafers, which was supported by the direct quantitation of three malondialdehyde protein adducts in the range of 0.09-23.5 mg/kg after enzymatic hydrolysis. In contrast, levels of free glyoxal and methylglyoxal were independent of the type of oil added, which was in line with the analysis of 13 advanced glycation end products. Comprehensive incubations of 40 mM N2-t-Boc-lysine (100 mM phosphate buffer, pH 7.4) with either 10% oil or an equimolar concentration of carbohydrates led to magnitudes higher (103-105) amounts of N6-carboxymethyl lysine, N6-glycolyl lysine, and N6-carboxyethyl lysine in the latter. Furthermore, malondialdehyde exceeded glyoxal and methylglyoxal in incubations of pure oils at 150 °C by factors of 30 and 100, respectively.
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Affiliation(s)
- Michael D Eggen
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle, Saale, Germany
| | - Paul Merboth
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle, Saale, Germany
| | - Helen Neukirchner
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle, Saale, Germany
| | - Marcus A Glomb
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle, Saale, Germany
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27
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Cruz N, Flores M, Urquiaga I, Ávila F. Modulation of 1,2-Dicarbonyl Compounds in Postprandial Responses Mediated by Food Bioactive Components and Mediterranean Diet. Antioxidants (Basel) 2022; 11:1513. [PMID: 36009232 PMCID: PMC9405221 DOI: 10.3390/antiox11081513] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/16/2022] [Accepted: 07/26/2022] [Indexed: 01/17/2023] Open
Abstract
Glycoxidative stress with the consequent generation of advanced glycation end products has been implied in the etiology of numerous non-communicable chronic diseases. During the postprandial state, the levels of 1,2-dicarbonyl compounds can increase, depending on numerous factors, including characteristics of the subjects mainly related to glucose metabolism disorders and nutritional status, as well as properties related to the chemical composition of meals, including macronutrient composition and the presence of dietary bioactive molecules and macromolecules. In this review, we examine the chemical, biochemical, and physiological pathways that contribute to postprandial generation of 1,2-dicarbonyl compounds. The modulation of postprandial 1,2-dicarbonyl compounds is discussed in terms of biochemical pathways regulating the levels of these compounds, as well as the effect of phenolic compounds, dietary fiber, and dietary patterns, such as Mediterranean and Western diets.
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Affiliation(s)
- Nadia Cruz
- Escuela de Nutrición y Dietética, Facultad de Ciencias de la Salud, Universidad de Talca, Campus Lircay, Talca 3460000, Chile;
| | - Marcos Flores
- Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomás, Talca 3460000, Chile;
| | - Inés Urquiaga
- Center for Molecular Nutrition and Chronic Diseases, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago 8331150, Chile;
| | - Felipe Ávila
- Escuela de Nutrición y Dietética, Facultad de Ciencias de la Salud, Universidad de Talca, Campus Lircay, Talca 3460000, Chile;
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28
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Kusama S, Miyake C, Nakanishi S, Shimakawa G. Dissection of respiratory and cyclic electron transport in Synechocystis sp. PCC 6803. JOURNAL OF PLANT RESEARCH 2022; 135:555-564. [PMID: 35680769 DOI: 10.1007/s10265-022-01401-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 06/01/2022] [Indexed: 06/15/2023]
Abstract
Cyclic electron transport (CET) is an attractive hypothesis for regulating photosynthetic electron transport and producing the additional ATP in oxygenic phototrophs. The concept of CET has been established in the last decades, and it is proposed to function in the progenitor of oxygenic photosynthesis, cyanobacteria. The in vivo activity of CET is frequently evaluated either from the redox state of the reaction center chlorophyll in photosystem (PS) I, P700, in the absence of PSII activity or by comparing PSI and PSII activities through the P700 redox state and chlorophyll fluorescence, respectively. The evaluation of CET activity, however, is complicated especially in cyanobacteria, where CET shares the intersystem chain, including plastoquinone, cytochrome b6/f complex, plastocyanin, and cytochrome c6, with photosynthetic linear electron transport (LET) and respiratory electron transport (RET). Here we sought to distinguish the in vivo electron transport rates in RET and CET in the cyanobacterium Synechocystis sp. PCC 6803. The reduction rate of oxidized P700 (P700+) decreased to less than 10% when PSII was inhibited, indicating that PSII is the dominant electron source to PSI but P700+ is also reduced by electrons derived from other sources. The oxidative pentose phosphate (OPP) pathway functions as the dominant electron source for RET, which was found to be inhibited by glycolaldehyde (GA). In the condition where the OPP pathway and respiratory terminal oxidases were inhibited by GA and KCN, the P700+ reduction rate was less than 1% of that without any inhibitors. This study indicate that the electron transport to PSI when PSII is inhibited is dominantly derived from the OPP pathway in Synechocystis sp. PCC 6803.
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Affiliation(s)
- Shoko Kusama
- Research Center for Solar Energy Chemistry, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka, 560-8531, Japan
| | - Chikahiro Miyake
- Department of Biological and Environmental Science, Faculty of Agriculture, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai, Nada, Kobe, 657-8501, Japan
| | - Shuji Nakanishi
- Research Center for Solar Energy Chemistry, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka, 560-8531, Japan
| | - Ginga Shimakawa
- Research Center for Solar Energy Chemistry, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka, 560-8531, Japan.
- Department of Bioscience, School of Biological and Environmental Sciences, Kwansei-Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
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29
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Hibiscus, Rooibos, and Yerba Mate for Healthy Aging: A Review on the Attenuation of In Vitro and In Vivo Markers Related to Oxidative Stress, Glycoxidation, and Neurodegeneration. Foods 2022; 11:foods11121676. [PMID: 35741873 PMCID: PMC9222775 DOI: 10.3390/foods11121676] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/04/2022] [Accepted: 06/05/2022] [Indexed: 02/01/2023] Open
Abstract
The world is currently undergoing a demographic change towards an increasing number of elderly citizens. Aging is characterized by a temporal decline in physiological capacity, and oxidative stress is a hallmark of aging and age-related disorders. Such an oxidative state is linked to a decrease in the effective mechanisms of cellular repair, the incidence of post-translational protein glycation, mitochondrial dysfunction, and neurodegeneration, just to name some of the markers contributing to the establishment of age-related reduction-oxidation, or redox, imbalance. Currently, there are no prescribed therapies to control oxidative stress; however, there are strategies to elevate antioxidant defenses and overcome related health challenges based on the adoption of nutritional therapies. It is well known that herbal teas such, as hibiscus, rooibos, and yerba mate, are important sources of antioxidants, able to prevent some oxidation-related stresses. These plants produce several bioactive metabolites, have a pleasant taste, and a long-lasting history as safe foods. This paper reviews the literature on hibiscus, rooibos, and yerba mate teas in the context of nutritional strategies for the attenuation of oxidative stress-related glycoxidation and neurodegeneration, and, here, Alzheimer’s Disease is approached as an example. The focus is given to mechanisms of glycation inhibition, as well as neuroprotective in vitro effects, and, in animal studies, to frame interest in these plants as nutraceutical agents related to current health concerns.
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30
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Gu MJ, Hyon JY, Lee HW, Han EH, Kim Y, Cha YS, Ha SK. Glycolaldehyde, an Advanced Glycation End Products Precursor, Induces Apoptosis via ROS-Mediated Mitochondrial Dysfunction in Renal Mesangial Cells. Antioxidants (Basel) 2022; 11:antiox11050934. [PMID: 35624799 PMCID: PMC9137959 DOI: 10.3390/antiox11050934] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/04/2022] [Accepted: 05/04/2022] [Indexed: 02/05/2023] Open
Abstract
Glycolaldehyde (GA) is a reducing sugar and a precursor of advanced glycation end products (AGEs). The role of precursor and precursor-derived AGEs in diabetes and its complications have been actively discussed in the literature. This study aimed to elucidate the mechanism of GA-induced apoptosis in renal cells. Immunoblotting results showed that GA (100 μM) caused cytotoxicity in murine renal glomerular mesangial cells (SV40 MES 13) and induced apoptosis via major modulators, decreasing Bcl-2 and increasing Bax, cytochrome c, and cleaved caspase-3/-9 expression. GA-derived AGE accumulation and receptor for AGE (RAGE) expression increased in mesangial cells; however, cells that were cotreated with aminoguanidine (AG) showed no increase in GA-derived AGE concentration. Furthermore, reactive oxygen species (ROS) production was increased by GA, while AG inhibited AGE formation, leading to a decrease in ROS levels in mesangial cells. We evaluated apoptosis through fluorescence-activated cell sorting, and used TUNEL staining to study DNA fragmentation. Additionally, we measured ATP generation and used MitoTracker staining to access changes in mitochondrial membrane potential. This study showed that GA increased AGE concentration, RAGE expression, and excessive ROS generation, leading to renal mesangial cell damage via GA-induced apoptosis pathway caused by mitochondrial dysfunction.
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Affiliation(s)
- Min Ji Gu
- Division of Food Functionality Research, Korea Food Research Institute, Wanju 55365, Korea; (M.J.G.); (H.-W.L.); (Y.K.)
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Korea;
| | - Ju-Youg Hyon
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Cheongju 28119, Korea; (J.-Y.H.); (E.H.H.)
| | - Hee-Weon Lee
- Division of Food Functionality Research, Korea Food Research Institute, Wanju 55365, Korea; (M.J.G.); (H.-W.L.); (Y.K.)
| | - Eun Hee Han
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Cheongju 28119, Korea; (J.-Y.H.); (E.H.H.)
| | - Yoonsook Kim
- Division of Food Functionality Research, Korea Food Research Institute, Wanju 55365, Korea; (M.J.G.); (H.-W.L.); (Y.K.)
| | - Youn-Soo Cha
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Korea;
| | - Sang Keun Ha
- Division of Food Functionality Research, Korea Food Research Institute, Wanju 55365, Korea; (M.J.G.); (H.-W.L.); (Y.K.)
- Division of Food Biotechnology, University of Science and Technology, Daejeon 34113, Korea
- Correspondence: ; Tel.: +82-63-219-9358
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31
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Baker P, Cooper-Mullin CM, Jimenez AG. Differences in advanced glycation endproducts (AGEs) in plasma from birds and mammals of different body sizes and ages. Comp Biochem Physiol A Mol Integr Physiol 2022; 267:111164. [PMID: 35158049 DOI: 10.1016/j.cbpa.2022.111164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/23/2022] [Accepted: 02/08/2022] [Indexed: 11/24/2022]
Abstract
Birds and mammals provide a physiological paradox: similar-sized mammals live shorter lives than birds; yet, birds have higher blood glucose concentrations than mammals, and higher basal metabolic rates. We have previously shown that oxidative stress patterns between mammals and birds differ, so that birds, generally, have lower blood antioxidant capacity, and lower lipid peroxidation concentration. There is a close association between oxidative stress and the production of carbohydrate-based damaged biomolecules, Advanced Glycation End-products (AGEs). In mammals, AGEs can bind to their receptor (RAGE), which can lead to increases in reactive oxygen species (ROS) production, and can decrease antioxidant capacity. Here, we used plasma from birds and mammals to address whether blood plasma AGE-BSA concentration is associated with body mass and age in these two groups. We found a statistically significantly higher average concentrations of AGE-BSA in birds compared with mammals, and we found a significantly positive correlation between AGE-BSA and age in mammals, though, this correlation disappeared after phylogenetic correction. We propose that the higher AGE concentration in birds is mainly attributable to greater AGE-production due to elevated basal glucose concentrations and decreased AGE-clearance given differences in glomerular filtration rates in birds compared with mammals. Additionally, due to the potential lack of an AGE receptor in birds, AGE accumulation may not be closely linked to oxidative stress and therefore pose a lesser physiological challenge in birds compared to mammals.
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Affiliation(s)
- Peter Baker
- Colgate University, Department of Biology, 13 Oak Dr., Hamilton, NY 13346, United States of America
| | - Clara M Cooper-Mullin
- University of Rhode Island, Natural Resources Science, 1 Greenhouse Drive, Kingston, RI 02881, United States of America
| | - Ana Gabriela Jimenez
- Colgate University, Department of Biology, 13 Oak Dr., Hamilton, NY 13346, United States of America.
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32
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Ray DM, Jennings EQ, Maksimovic I, Chai X, Galligan JJ, David Y, Zheng Q. Chemical Labeling and Enrichment of Histone Glyoxal Adducts. ACS Chem Biol 2022; 17:756-761. [PMID: 35294181 DOI: 10.1021/acschembio.1c00864] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Because of their long half-lives and highly nucleophilic tails, histones are particularly susceptible to accumulating nonenzymatic covalent modifications, such as glycation. The resulting modifications can have profound effects on cellular physiology due to the regulatory role histones play in all DNA-templated processes; however, the complexity of Maillard chemistry on proteins makes tracking and enriching for glycated proteins a challenging task. Here, we characterize glyoxal (GO) modifications on histones using quantitative proteomics and an aniline-derived GO-reactive probe. In addition, we leverage this chemistry to demonstrate that the glycation regulatory proteins DJ-1 and GLO1 reduce levels of histone GO adducts. Finally, we employ a two-round pull-down method to enrich histone H3 GO glycation and map these adducts to specific chromatin regions.
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Affiliation(s)
- Devin M. Ray
- Tri-Institutional MD-PhD Program, New York, New York 10065, United States
- Tri-Institutional PhD Program in Chemical Biology, New York, New York 10065, United States
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
| | - Erin Q. Jennings
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States
| | - Igor Maksimovic
- Tri-Institutional PhD Program in Chemical Biology, New York, New York 10065, United States
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
| | - Xander Chai
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States
| | - James J. Galligan
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States
| | - Yael David
- Tri-Institutional PhD Program in Chemical Biology, New York, New York 10065, United States
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
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Rau R, Glomb MA. Novel Pyridinium Cross-Link Structures Derived from Glycolaldehyde and Glyoxal. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:4434-4444. [PMID: 35348319 DOI: 10.1021/acs.jafc.2c00906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Short-chained α-hydroxycarbonyl compounds such as glycolaldehyde (GA) and its oxidized counterpart glyoxal (GX) are known as potent glycating agents. Here, a novel fluorescent lysine-lysine cross-link 1-(5-amino-5-carboxypentyl)-3-(5-amino-5-carboxy-pentylamino)pyridinium salt (meta-DLP) was synthesized and its structure unequivocally proven by 1H NMR, 13C-NMR attached proton test, and 2D NMR. Further characterization of chemical properties and mechanistic background was obtained in comparison to the known monovalent protein modification 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate (OP-lysine). Identification and quantitation in various sugar incubations with N2-t-Boc-lysine revealed a novel alternative formation pathway for both advanced glycation end products (AGEs) by the interplay of both carbonyl compounds, GA and GX, which was confirmed by isotope labeling experiments. The concentration of pyridinium AGEs was about 1000-fold lower compared to the well-established N6-carboxymethyl lysine. However, pyridinium AGEs were shown to lead to the photosensitized generation of singlet oxygen in irradiation experiments, which was verified by the detection of 3,3'-(naphthalene-1,4-diyl)-dipropionate endoperoxide. Furthermore, meta-DLP was identified in hydrolyzed potato chip proteins by collision-induced dissociation mass spectrometry after HPLC enrichment.
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Affiliation(s)
- Robert Rau
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale 06120, Germany
| | - Marcus A Glomb
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale 06120, Germany
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34
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Differences in kinetics and dynamics of endogenous versus exogenous advanced glycation end products (AGEs) and their precursors. Food Chem Toxicol 2022; 164:112987. [PMID: 35398182 DOI: 10.1016/j.fct.2022.112987] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 03/16/2022] [Accepted: 04/01/2022] [Indexed: 12/31/2022]
Abstract
Advanced glycation end products (AGEs) and their precursors, referred to as glycation products, are a heterogenous group of compounds being associated with adverse health effects. They are formed endogenously and in exogenous sources including food. This review investigates the roles of endogenously versus exogenously formed glycation products in the potential induction of adverse health effects, focusing on differences in toxicokinetics and toxicodynamics, which appeared to differ depending on the molecular mass of the glycation product. Based on the available data, exogenous low molecular mass (LMM) glycation products seem to be bioavailable and to contribute to dicarbonyl stress and protein cross-linking resulting in formation of endogenous AGEs. Bioavailability of exogenous high molecular mass (HMM) glycation products appears limited, while these bind to the AGE receptor (RAGE), initiating adverse health effects. Together, this suggests that RAGE-binding in relevant tissues will more likely result from endogenously formed glycation products. Effects on gut microbiota induced by glycation products is proposed as a third mode of action. Overall, studies which better discriminate between LMM and HMM glycation products and between endogenous and exogenous formation are needed to further elucidate the contributions of these different types and sources of glycation products to the ultimate biological effects.
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Elucidating the degradation mechanism of a self-degradable dextran-based medical adhesive. Carbohydr Polym 2022; 278:118949. [PMID: 34973767 DOI: 10.1016/j.carbpol.2021.118949] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/20/2021] [Accepted: 11/26/2021] [Indexed: 11/20/2022]
Abstract
We developed a self-degradable medical adhesive, LYDEX, consisting of periodate-oxidized aldehyde-functionalized dextran (AD) and succinic anhydride-treated ε-poly-l-lysine (SAPL). After gelation and adhesion of LYDEX by Schiff base bond formation between the AD aldehyde groups and SAPL amino groups, molecular degradation associated with the Maillard reaction is initiated, but the detailed degradation mechanism remains unknown. Herein, we elucidated the degradation mechanism of LYDEX by analyzing the main degradation products under typical solution conditions in vitro. The degradation of the LYDEX gel with a sodium periodate/dextran content of 2.5/20 was observed using gel permeation chromatography and infrared and 1H NMR spectroscopy. The AD ratio in the AD-SAPL mixture increased as the molecular weight decreased with the degradation time. This discovery of LYDEX self-degradability is useful for clarifying other polysaccharide hydrogel degradation mechanisms, and valuable for the use of LYDEX in medical applications, such as hemostatic or sealant materials.
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36
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Impact of Advanced Glycation End products (AGEs) and its receptor (RAGE) on cancer metabolic signaling pathways and its progression. Glycoconj J 2022; 38:717-734. [PMID: 35064413 DOI: 10.1007/s10719-021-10031-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/26/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023]
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Liu L, Liu L, Xie J, Shen M. Formation mechanism of AGEs in Maillard reaction model systems containing ascorbic acid. Food Chem 2022; 378:132108. [PMID: 35032811 DOI: 10.1016/j.foodchem.2022.132108] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 12/22/2021] [Accepted: 01/05/2022] [Indexed: 01/04/2023]
Abstract
The dietary advanced glycation end products (AGEs) contribute to the development of major chronic diseases. Maillard reactions are the main mechanism for AGEs formation but their formation involving ascorbic acid (AA) is far from being fully understood. This study investigated the effect of pH (6-10) and temperature (65, 100 and 120 ℃) on AGEs formation in three model systems: glucose (Glu) + lysine (Lys), AA + Lys and Glu + Lys + AA. In addition, the formation pathway of AGEs in Glu + Lys + AA model system was proposed by carbon module labeling (CAMOLA) technique. The results suggested alkaline environment can promote the production of N-carboxymethyllysine (CML) and N-carboxyethyllysine (CEL), but inhibit the production of pyrraline (Pyr). Meanwhile the high temperature favored AGEs formation. In the U-13C-Glu + Lys + AA model, AA produced glyoxal (GO), methylglyoxal (MGO), CML and CEL, which was significantly higher than with Glu alone. This study provides a theoretical basis for the formation mechanism of AGEs in the Maillard reaction involving AA.
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Affiliation(s)
- Lichun Liu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Lei Liu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Jianhua Xie
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Mingyue Shen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China.
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Poojary MM, Lund MN. Chemical Stability of Proteins in Foods: Oxidation and the Maillard Reaction. Annu Rev Food Sci Technol 2021; 13:35-58. [PMID: 34941384 DOI: 10.1146/annurev-food-052720-104513] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Protein is a major nutrient present in foods along with carbohydrates and lipids. Food proteins undergo a wide range of modifications during food production, processing, and storage. In this review, we discuss two major reactions, oxidation and the Maillard reaction, involved in chemical modifications of food proteins. Protein oxidation in foods is initiated by metal-, enzyme-, or light-induced processes. Food protein oxidation results in the loss of thiol groups and the formation of protein carbonyls and specific oxidation products of cysteine, tyrosine, tryptophan, phenylalanine, and methionine residues, such as disulfides, dityrosine, kynurenine, m-tyrosine, and methionine sulfoxide. The Maillard reaction involves the reaction of nucleophilic amino acid residues with reducing sugars, which yields numerous heterogeneous compounds such as α-dicarbonyls, furans, Strecker aldehydes, advanced glycation end-products, and melanoidins. Both protein oxidation and the Maillard reaction result in the loss of essential amino acids but may positively or negatively impact food structure and flavor. Expected final online publication date for the Annual Review of Food Science and Technology, Volume 13 is March 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Mahesha M Poojary
- Department of Food Science, Faculty of Science, University of Copenhagen, Frederiksberg, Denmark;
| | - Marianne N Lund
- Department of Food Science, Faculty of Science, University of Copenhagen, Frederiksberg, Denmark; .,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;
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Eggen MD, Glomb MA. Analysis of Glyoxal- and Methylglyoxal-Derived Advanced Glycation End Products during Grilling of Porcine Meat. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:15374-15383. [PMID: 34905354 DOI: 10.1021/acs.jafc.1c06835] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The reaction of the N6-amino group of lysine residues and 1,2-dicarbonyl compounds during Maillard processes leads to advanced glycation end products (AGEs). In the present work, we deliver a comprehensive analysis of changes of carbohydrates, dicarbonyl structures, and 11 AGEs during the grilling of porcine meat patties. While raw meat contained mainly glyoxal-derived N6-carboxymethyl lysine (CML), grilling led to an increase of predominantly methylglyoxal-derived AGEs N6-carboxyethyl lysine (CEL), N6-lactoyl lysine, methylglyoxal lysine dimer (MOLD), and methylglyoxal lysine amide (MOLA). Additionally, we identified and quantitated a novel methylglyoxal-derived amidine compound N1,N2-di-(5-amino-5-carboxypentyl)-2-lactoylamidine (methylglyoxal lysine amide, MGLA) in heated meat. Analysis of carbohydrates suggested that approximately 50% of the methylglyoxal stemmed from the fragmentation of triosephosphates during the heat treatment. Surprisingly, N6-lactoyl lysine was the major AGE, and based on model incubations, we propose that approximately 90% must be explained by the nonenzymatic acylation of lysine through S-lactoylglutathione, which was quantitated for the first time in meat herein.
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Affiliation(s)
- Michael D Eggen
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle/Saale, Germany
| | - Marcus A Glomb
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle/Saale, Germany
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40
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Hellwig M, Nitschke J, Henle T. Glycation of N-ε-carboxymethyllysine. Eur Food Res Technol 2021. [DOI: 10.1007/s00217-021-03931-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AbstractThe Maillard reaction is traditionally subdivided into three stages that start consecutively and run in parallel. Here, we show that N-ε-carboxymethyllysine (CML), a compound formed in the late stage of the reaction, can undergo a second glycation event at its secondary amino group leading to a new class of Amadori rearrangement products. When N-α-hippuryl-CML was incubated in the presence of reducing sugars such as glucose, galactose, ribose, xylose, maltose, or lactose in solution for 1 h at 75 °C, the compound was degraded by 6–21%, and N-ε-carboxymethyl-N-ε-deoxyketosyl lysine derivatives were formed. Under the same conditions, lysine was 5–10 times more reactive than CML. N-α-hippuryl-N-ε-carboxymethyl-N-ε-(1-deoxyfructosyl)-l-lysine (hippuryl-CMFL) and N-ε-carboxymethyl-N-ε-(1-deoxyfructosyl)-l-lysine (CMFL) were synthesized, isolated and characterized by MS/MS and NMR experiments. Depending on the reaction conditions, up to 21% of CMFL can be converted to the furosine analogue N-ε-carboxymethyl-N-ε-furoylmethyl-l-lysine (CM-Fur) during standard acid protein hydrolysis with hydrochloric acid. Incubation of bovine serum albumin (BSA) with glucose for up to 9 weeks at 37 °C revealed the formation of CMFL in the protein as assessed by HPLC–MS/MS in the MRM mode. Under these conditions, ca. 13% of lysine residues had been converted to fructosyllysine, and 0.03% had been converted to CMFL. The detection of glycation products of glycated amino acids (heterogeneous multiple glycation) reveals a novel pathway in the Maillard reaction.
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41
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Sroga GE, Vashishth D. Controlled Formation of Carboxymethyllysine in Bone Matrix through Designed Glycation Reaction. JBMR Plus 2021; 5:e10548. [PMID: 34761150 PMCID: PMC8567485 DOI: 10.1002/jbm4.10548] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 08/08/2021] [Accepted: 08/24/2021] [Indexed: 01/15/2023] Open
Abstract
It has been a challenge to establish a link between specific advanced glycation end products (AGEs) as causal agents of different pathologies and age‐related diseases, primarily because of the lack of suitable in vitro experimental strategies facilitating increased formation of a specific AGE, here carboxymethyllysine (CML), over other AGEs under controlled conditions. CML is of considerable importance to various oxidative stress–related diseases, because in vivo formation of this AGE is connected with cellular oxidative/carbonyl metabolism. The mechanistic implications of CML accumulation in bone remain to be elucidated. To facilitate such studies, we developed a new in vitro strategy that allows preferential generation of CML in bone matrix over other AGEs. Using bone samples from human donors of different age (young, middle‐age, and elderly), we show successful in vitro generation of the desired levels of CML and show that they mimic those observed in vivo in several bone disorders. Formation of such physiologically relevant CML levels was achieved by selecting two oxidative/carbonyl stress compounds naturally produced in the human body, glyoxal and glyoxylic acid. Kinetic studies using the two compounds revealed differences not only between their reaction rates but also in the progression and enhanced formation of CML over other AGEs (measured by their collective fluorescence as fluorescent AGEs [fAGEs]) Consequently, through the regulation of reaction time, the levels of CML and fAGEs could be controlled and separated. Given that the developed approach does not fully eliminate the formation of other uncharacterized glycation products, this could be considered as the study limitation. We expect that the concepts of our experimental approach can be used to develop diverse strategies facilitating production of the desired levels of selected AGEs in bone and other tissues, and thus, opens new avenues for investigating the role and mechanistic aspects of specific AGEs, here CML, in bone. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Grażyna E Sroga
- Department of Biomedical Engineering Rensselaer Polytechnic Institute, Center for Biotechnology and Interdisciplinary Studies Troy NY USA
| | - Deepak Vashishth
- Department of Biomedical Engineering Rensselaer Polytechnic Institute, Center for Biotechnology and Interdisciplinary Studies Troy NY USA
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Kitamura K, Hirayama J, Tabuchi Y, Minami T, Matsubara H, Hattori A, Suzuki N. Glyoxal-induced formation of advanced glycation end-products in type 1 collagen decreases both its strength and flexibility in vitro. J Diabetes Investig 2021; 12:1555-1559. [PMID: 33605082 PMCID: PMC8409810 DOI: 10.1111/jdi.13528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 02/05/2021] [Accepted: 02/16/2021] [Indexed: 11/30/2022] Open
Abstract
The high plasma glucose induced in glucose metabolism disorders leads to the non-enzymatic glucose-dependent modification (glycation) of type 1 collagen, which is an essential component of bone tissue. The glycation of proteins induces the formation of advanced glycation end-products, such as carboxymethyl arginine, which is preferentially generated in glycated collagen. However, the effect of advanced glycation end-product formation on the characteristics of type 1 collagen remains unclear due to the lack of suitable in vitro experimental systems analyzing type 1 collagen. Here, we show that the glycation of type 1 collagen can be analyzed in vitro using a goldfish-scale bone model. Our study using these scales provides evidence that the advanced glycation end-product formation in type 1 collagen induced by glyoxal, the carboxymethyl arginine inducer, facilitates the crosslinking of type 1 collagen, decreasing both its strength and flexibility.
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Affiliation(s)
- Kei‐ichiro Kitamura
- Department of Clinical Laboratory ScienceGraduate School of Medical ScienceKanazawa UniversityKanazawaJapan
| | - Jun Hirayama
- Department of Clinical EngineeringFaculty of Health SciencesKomatsu UniversityKomatsuJapan
| | | | - Takao Minami
- Department of Clinical Laboratory ScienceGraduate School of Medical ScienceKanazawa UniversityKanazawaJapan
| | - Hajime Matsubara
- Noto Center for Fisheries Science and TechnologyKanazawa UniversityKanazawaJapan
| | - Atsuhiko Hattori
- Department of BiologyCollege of Liberal Arts and SciencesTokyo Medical and Dental UniversityIchikawaJapan
| | - Nobuo Suzuki
- Noto Marine LaboratoryInstitute of Nature and Environmental TechnologyKanazawa UniversityKanazawaJapan
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43
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Role of saturated and unsaturated fatty acids on dicarbonyl-albumin derived advanced glycation end products in vitro. Amino Acids 2021; 54:721-732. [PMID: 34424383 DOI: 10.1007/s00726-021-03069-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/14/2021] [Indexed: 10/20/2022]
Abstract
Glycation is a non-enzymatic reaction that occurs between the free amino group of proteins and reducing sugars and/or lipids, leading to the formation of advanced glycation end products (AGEs). The reaction also produces reactive oxygen species that have detrimental effects on cellular and extracellular proteins. Aminoguanidine is a known inhibitor of AGEs, and some fatty acids are known to have a beneficial role in vivo by reducing inflammation and oxidative stress. However, the role of fatty acids on AGE formation has not been thoroughly reported. We investigated the role of a range of fatty acids in the formation of AGEs and their reactive intermediates using an in vitro BSA-dicarbonyl model. The model assessed a time-dependent (0-72 h) and dicarbonyl concentration (0-2 mM) -dependent studies for the optimal formation of AGEs. A 72 h time point was found to be optimal for the reaction of BSA with either methylglyoxal (MGO) or glyoxal (GO) to generate AGE-BSA complexes. When arachidonic, eicosapentaenoic or docosahexaenoic acids were included in the reaction, a significant decrease in protein-bound fluorescent AGEs was seen compared to the respective controls. In contrast, saturated and 18 carbon polyunsaturated fatty acids showed no significant activity. Liquid chromatography-mass spectrometry (LC-MS/MS) analysis showed saturated fatty acids significantly decreased the production of Nε-carboxymethyllysine (CML) and Nε-carboxyethyllysine (CEL) from GO and MGO models, respectively, whilst increasing methylglyoxal-derived hydroimidazolone (MG-H1). In contrast, arachidonic, eicosapentaenoic and docosahexaenoic acids did not significantly change either CEL or MG-H1 compared to no treatment controls whilst significantly reducing CML levels.
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Eggen MD, Glomb MA. Novel Amidine Protein Cross-Links Formed by the Reaction of Glyoxal with Lysine. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:7960-7968. [PMID: 34240860 DOI: 10.1021/acs.jafc.1c02792] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
One crucial aspect of the Maillard reaction is the formation of reactive α-dicarbonyl structures like glyoxal, which are prone toward further reactions with proteins, e.g., the N6-amino group of lysine. The initially formed labile glyoxal-imine was previously established as a key intermediate in the formation of the advanced glycation end products N6-carboxymethyl lysine (CML), glyoxal lysine amide (GOLA), glyoxal lysine dimer (GOLD), and N6-glycolyl lysine (GALA). Here, we introduce a novel amidine cross-link structure N1,N2-bis-(5-amino-5-carboxypentyl)-2-hydroxy-acetamidine (glyoxal lysine amidine, GLA), which is formed exclusively from glyoxal through the same isomerization cascade. After independent synthesis of the authentic reference standard, we were able to quantitate this cross-link in incubations of 40 mM N2-t-Boc-lysine with glyoxal and various sugars (40-100 mM) under mild conditions (pH 7.4, 37 °C) using an HPLC-MS/MS method. Furthermore, incubations of proteins (6 mg/mL) with 50 mM glyoxal confirmed the cross-linking by GLA, which was additionally identified in acidic hydrolyzed proteins of butter biscuits after HPLC enrichment.
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Affiliation(s)
- Michael D Eggen
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale 06120, Germany
| | - Marcus A Glomb
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale 06120, Germany
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45
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Dasgupta A, Sori N, Petrova S, Maghdouri-White Y, Thayer N, Kemper N, Polk S, Leathers D, Coughenour K, Dascoli J, Palikonda R, Donahue C, Bulysheva AA, Francis MP. Comprehensive collagen crosslinking comparison of microfluidic wet-extruded microfibers for bioactive surgical suture development. Acta Biomater 2021; 128:186-200. [PMID: 33878472 DOI: 10.1016/j.actbio.2021.04.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/13/2021] [Accepted: 04/13/2021] [Indexed: 12/30/2022]
Abstract
Collagen microfiber-based constructs have garnered considerable attention for ligament, tendon, and other soft tissue repairs, yet with limited clinical translation due to strength, biocompatibility, scalable manufacturing, and other challenges. Crosslinking collagen fibers improves mechanical properties; however, questions remain regarding optimal crosslinking chemistries, biocompatibility, biodegradation, long-term stability, and potential for biotextile assemble at scale, limiting their clinical usefulness. Here, we assessed over 50 different crosslinking chemistries on microfluidic wet-extruded collagen microfibers made with clinically relevant collagen to optimize collagen fibers as a biotextile yarn for suture or other medical device manufacture. The endogenous collagen crosslinker, glyoxal, provides extraordinary fiber ultimate tensile strength near 300MPa, and Young's modulus of over 3GPa while retaining 50% of the initial load-bearing capacity through 6 months as hydrated. Glyoxal crosslinked collagen fibers further proved cytocompatible and biocompatible per ISO 10993-based testing, and further elicits a predominantly M2 macrophage response. Remarkably these strong collagen fibers are amenable to industrial braiding to form strong collagen fiber sutures. Collagen microfluidic wet extrusion with glyoxal crosslinking thus progress bioengineered, strong, and stable collagen microfibers significantly towards clinical use for potentially promoting efficient healing compared to existing suture materials. STATEMENT OF SIGNIFICANCE: Towards improving clinical outcomes for over 1 million ligament and tendon surgeries performed annually, we report an advanced microfluidic extrusion process for type I collagen microfiber manufacturing for biological suture and other biotextile manufacturing. This manuscript reports the most extensive wet-extruded collagen fiber crosslinking compendium published to date, providing a tremendous recourse to the field. Collagen fibers made with clinical-grade collagen and crosslinked with glyoxal, exhibit tensile strength and stability that surpasses all prior reports. This is the first report demonstrating that glyoxal, a native tissue crosslinker, has the extraordinary ability to produce strong, cytocompatible, and biocompatible collagen microfibers. These collagen microfibers are ideal for advanced research and clinical use as surgical suture or other tissue-engineered medical products for sports medicine, orthopedics, and other surgical indications.
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Kobashigawa Y, Ohara T, Morita K, Toyota Y, Nakamura T, Kotani S, Arimori T, Yamauchi S, Liu C, Kitazaki M, Wakeyama-Miyazaki Y, Suwa Y, Uchida-Kamekura M, Fukuda N, Sato T, Nakajima M, Takagi J, Yamagata Y, Morioka H. Molecular recognition of a single-chain Fv antibody specific for GA-pyridine, an advanced glycation end-product (AGE), elucidated using biophysical techniques and synthetic antigen analogues. J Biochem 2021; 170:379-387. [PMID: 34185078 DOI: 10.1093/jb/mvab056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/22/2021] [Indexed: 11/13/2022] Open
Abstract
Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by non-enzymatic reaction between reducing-sugar and Arg/Lys in proteins, and are involved in various diabetic complications. GA-pyridine is derived from glycolaldehyde and is one of the most cytotoxic AGEs. Here, we established a single-chain Fv (scFv) antibody against GA-pyridine, 73MuL9-scFv, and examined the details of its specificity and antigen recognition by using various techniques involving biophysics, chemical biology and structural biology. We also synthesized several compounds that differ slightly in regard to the position and number of GA-pyridine substituent groups, and revealed that GA-pyridine was specifically bound to 73MuL9-scFv. Thermodynamic analysis revealed that the association of GA-pyridine to 73MuL9-scFv was an exothermic and enthalpy driven reaction, and thus that the antigen recognition involved multiple specific interactions. Crystallographic analysis of the Fv fragment of 73MuL9-scFv revealed that several CH-π and hydrogen bond interactions took place between the Fv-fragment and GA-pyridine, which was consistent with the results of thermodynamic analysis. Further studies using 73MuL9-scFv as a tool to clarify the relevance of GA-pyridine to diabetic complications are warranted.
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Affiliation(s)
- Yoshihiro Kobashigawa
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Toshiya Ohara
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Kosuke Morita
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Yuya Toyota
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Teruya Nakamura
- Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.,Priority Organization for Innovation and Excellence, Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto, 860-8555, Japan
| | - Shunsuke Kotani
- Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Takao Arimori
- Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Soichiro Yamauchi
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Chenjiang Liu
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Masaya Kitazaki
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Yukari Wakeyama-Miyazaki
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Yoshiaki Suwa
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Makiyo Uchida-Kamekura
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Natsuki Fukuda
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Takashi Sato
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Makoto Nakajima
- Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Junichi Takagi
- Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuriko Yamagata
- Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
| | - Hiroshi Morioka
- Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan
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Formation of α-dicarbonyl compounds and glycation products in sesame (Sesamum indicum L.) seeds during roasting: a multiresponse kinetic modelling approach. Eur Food Res Technol 2021. [DOI: 10.1007/s00217-021-03787-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Kehm R, Baldensperger T, Raupbach J, Höhn A. Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases. Redox Biol 2021; 42:101901. [PMID: 33744200 PMCID: PMC8113053 DOI: 10.1016/j.redox.2021.101901] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/06/2021] [Accepted: 02/12/2021] [Indexed: 12/16/2022] Open
Abstract
Generation of reactive oxygen species and related oxidants is an inevitable consequence of life. Proteins are major targets for oxidation reactions, because of their rapid reaction rates with oxidants and their high abundance in cells, extracellular tissues, and body fluids. Additionally, oxidative stress is able to degrade lipids and carbohydrates to highly reactive intermediates, which eventually attack proteins at various functional sites. Consequently, a wide variety of distinct posttranslational protein modifications is formed by protein oxidation, glycoxidation, and lipoxidation. Reversible modifications are relevant in physiological processes and constitute signaling mechanisms ("redox signaling"), while non-reversible modifications may contribute to pathological situations and several diseases. A rising number of publications provide evidence for their involvement in the onset and progression of diseases as well as aging processes. Certain protein oxidation products are chemically stable and formed in large quantity, which makes them promising candidates to become biomarkers of oxidative damage. Moreover, progress in the development of detection and quantification methods facilitates analysis time and effort and contributes to their future applicability in clinical routine. The present review outlines the most important classes and selected examples of oxidative protein modifications, elucidates the chemistry beyond their formation and discusses available methods for detection and analysis. Furthermore, the relevance and potential of protein modifications as biomarkers in the context of disease and aging is summarized.
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Affiliation(s)
- Richard Kehm
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558, Nuthetal, Germany.
| | - Tim Baldensperger
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558, Nuthetal, Germany.
| | - Jana Raupbach
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558, Nuthetal, Germany.
| | - Annika Höhn
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, Muenchen-Neuherberg, Germany.
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Xing H, Yaylayan V. Insight into the mechanochemistry of the Maillard reaction: degradation of Schiff bases via 5-oxazolidinone intermediate. Eur Food Res Technol 2021. [DOI: 10.1007/s00217-021-03690-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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50
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Jost T, Henning C, Heymann T, Glomb MA. Comprehensive Analyses of Carbohydrates, 1,2-Dicarbonyl Compounds, and Advanced Glycation End Products in Industrial Bread Making. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:3720-3731. [PMID: 33733759 DOI: 10.1021/acs.jafc.0c07614] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The technology of bread making is characterized by three major steps: dough mixing, proofing, and baking. To follow the course of Maillard processes in an authentic food matrix, the complete manufacturing process of wheat bread rolls was assessed along all production steps with the quantitation of sugars, furfurals, 1,2-dicarbonyl compounds, and advanced glycation end products (AGEs). As a result, the AGE profile was significantly enlarged to more than 12 structures, and comprehensive mechanistic insights were provided. The analyses of five major German bread types including wheat, brown, rye bread, pumpernickel, and crispbreads led to AGE contents of 69-149 mg/kg bread or 984-1857 mg/kg protein. Major lysine protein modifications were carboxymethyl, carboxyethyl, and formyl lysine and pyrraline. Arginine was mainly modified by methylglyoxal (MGO) to give imidazolinones. A major part of MGO was confirmed to stem from microbial metabolism.
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Affiliation(s)
- Tobias Jost
- Institute of Chemistry-Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale D-06120, Germany
| | - Christian Henning
- Institute of Chemistry-Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale D-06120, Germany
| | - Thomas Heymann
- Institute of Chemistry-Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale D-06120, Germany
| | - Marcus A Glomb
- Institute of Chemistry-Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale D-06120, Germany
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