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Zhang M, Li H, Ma J, Yang C, Yang Y, Zhao B, Tie Y, Wang S. Effects of Zinc Combined with Metformin on Zinc Homeostasis, Blood-Epididymal Barrier, and Epididymal Absorption in Male Diabetic Mice. Biol Trace Elem Res 2025; 203:291-304. [PMID: 38589680 DOI: 10.1007/s12011-024-04171-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/01/2024] [Indexed: 04/10/2024]
Abstract
Diabetes increases the likelihood of germ cell damage, hypogonadism, and male infertility. Diabetes leads to lower zinc (Zn) levels, an important micronutrient for maintaining male fertility, and zinc deficiency can lead to decreased male fertility through multiple mechanisms. The aim of this study was to investigate the effect of combined metformin and zinc administration on epididymis in diabetic mice; 10 of 50 male mice were randomly selected as the control group (group C), and the remaining 40 mice were randomly divided into untreated diabetes group (group D), diabetes + zinc group (group Z), diabetes + metformin group (group M), and diabetes + metformin + zinc group (group ZM) with 10 mice each. Diabetic mice in group Z received oral zinc (10 mg/kg) once daily for 4 weeks; diabetic mice in group M received oral metformin (200 mg/kg) once daily for 4 weeks; diabetic mice in group ZM received oral metformin and zinc once daily for 4 weeks; and groups C and D received the same amount of sterile water by gavage. Overnight fasted mice were sacrificed, and blood samples, mouse epididymides, and sperm were collected for further experiments. In group D, fasting blood glucose and insulin resistance index increased significantly, semen quality, serum insulin, and testosterone decreased, and epididymal structure was disordered. In group D, epididymal tissue zinc, free zinc ions in the caput, and cauda of epididymis and zinc transporter (ZnT2) decreased significantly, while ZIP12, metallothionein (MT), and metal transcription factor (MTF1) increased significantly. In addition, the expressions of blood-epididymal barrier (BEB)-related molecules (including ZO-1 β-catenin and N-cadherin) and aquaporins (AQPs, including AQP3, AQP9, and AQP11) in the epididymis of mice in group D were significantly decreased. In addition, compared with groups D, Z, and M, in the ZM group, the expression of BEB-related molecules (including ZO-1, β-catenin, and N-cadherin) and aquaporins (AQP3, AQP9, and AQP11) in epididymis tissue were significantly increased, and sperm motility and serum testosterone were significantly increased. It was concluded that male diabetic mice have a disturbed epididymal structure and decreased semen quality by causing an imbalance in epididymal zinc homeostasis, BEB, and impaired absorptive function. The combination of zinc and metformin is an effective and safe alternative treatment and provides additional benefits over metformin alone.
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Affiliation(s)
- Menghui Zhang
- Graduate School, North China University of Science and Technology, Tangshan, 063210, China
| | - Huanhuan Li
- Hebei Key Laboratory of Reproductive Medicine, Hebei Reproductive Health Hospital, Shijiazhuang, 050071, China
| | - Jing Ma
- Hebei Key Laboratory of Reproductive Medicine, Hebei Reproductive Health Hospital, Shijiazhuang, 050071, China
| | - Chaoju Yang
- Department of Laboratory, Hebei Provincial People's Hospital, Shijiazhuang, 050051, China
| | - Yang Yang
- Hebei Key Laboratory of Reproductive Medicine, Hebei Reproductive Health Hospital, Shijiazhuang, 050071, China
| | - Bangrong Zhao
- Hebei Key Laboratory of Reproductive Medicine, Hebei Reproductive Health Hospital, Shijiazhuang, 050071, China
| | - Yanqing Tie
- Graduate School, North China University of Science and Technology, Tangshan, 063210, China.
- Department of Laboratory, Hebei Provincial People's Hospital, Shijiazhuang, 050051, China.
| | - Shusong Wang
- Hebei Key Laboratory of Reproductive Medicine, Hebei Reproductive Health Hospital, Shijiazhuang, 050071, China.
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Rabbani N, Thornalley PJ. Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications. Front Endocrinol (Lausanne) 2024; 14:1268308. [PMID: 38292764 PMCID: PMC10824962 DOI: 10.3389/fendo.2023.1268308] [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: 07/27/2023] [Accepted: 12/12/2023] [Indexed: 02/01/2024] Open
Abstract
Hyperglycemia is a risk factor for the development of insulin resistance, beta-cell glucotoxicity, and vascular complications of diabetes. We propose the hypothesis, hexokinase-linked glycolytic overload and unscheduled glycolysis, in explanation. Hexokinases (HKs) catalyze the first step of glucose metabolism. Increased flux of glucose metabolism through glycolysis gated by HKs, when occurring without concomitant increased activity of glycolytic enzymes-unscheduled glycolysis-produces increased levels of glycolytic intermediates with overspill into effector pathways of cell dysfunction and pathogenesis. HK1 is saturated with glucose in euglycemia and, where it is the major HK, provides for basal glycolytic flux without glycolytic overload. HK2 has similar saturation characteristics, except that, in persistent hyperglycemia, it is stabilized to proteolysis by high intracellular glucose concentration, increasing HK activity and initiating glycolytic overload and unscheduled glycolysis. This drives the development of vascular complications of diabetes. Similar HK2-linked unscheduled glycolysis in skeletal muscle and adipose tissue in impaired fasting glucose drives the development of peripheral insulin resistance. Glucokinase (GCK or HK4)-linked glycolytic overload and unscheduled glycolysis occurs in persistent hyperglycemia in hepatocytes and beta-cells, contributing to hepatic insulin resistance and beta-cell glucotoxicity, leading to the development of type 2 diabetes. Downstream effector pathways of HK-linked unscheduled glycolysis are mitochondrial dysfunction and increased reactive oxygen species (ROS) formation; activation of hexosamine, protein kinase c, and dicarbonyl stress pathways; and increased Mlx/Mondo A signaling. Mitochondrial dysfunction and increased ROS was proposed as the initiator of metabolic dysfunction in hyperglycemia, but it is rather one of the multiple downstream effector pathways. Correction of HK2 dysregulation is proposed as a novel therapeutic target. Pharmacotherapy addressing it corrected insulin resistance in overweight and obese subjects in clinical trial. Overall, the damaging effects of hyperglycemia are a consequence of HK-gated increased flux of glucose metabolism without increased glycolytic enzyme activities to accommodate it.
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Affiliation(s)
| | - Paul J. Thornalley
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
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Curieses Andrés CM, Pérez de la Lastra JM, Andrés Juan C, Plou FJ, Pérez-Lebeña E. From reactive species to disease development: Effect of oxidants and antioxidants on the cellular biomarkers. J Biochem Mol Toxicol 2023; 37:e23455. [PMID: 37437103 DOI: 10.1002/jbt.23455] [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] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 06/14/2023] [Accepted: 06/29/2023] [Indexed: 07/14/2023]
Abstract
The influence of modern lifestyle, diet, exposure to chemicals such as phytosanitary substances, together with sedentary lifestyles and lack of exercise play an important role in inducing reactive stress (RS) and disease. The imbalance in the production and scavenging of free radicals and the induction of RS (oxidative, nitrosative, and halogenative) plays an essential role in the etiology of various chronic pathologies, such as cardiovascular diseases, diabetes, neurodegenerative diseases, and cancer. The implication of free radicals and reactive species injury in metabolic disturbances and the onset of many diseases have been accumulating for several decades, and are now accepted as a major cause of many chronic diseases. Exposure to elevated levels of free radicals can cause molecular structural impact on proteins, lipids, and DNA, as well as functional alteration of enzyme homeostasis, leading to aberrations in gene expression. Endogenous depletion of antioxidant enzymes can be mitigated using exogenous antioxidants. The current interest in the use of exogenous antioxidants as adjunctive agents for the treatment of human diseases allows a better understanding of these diseases, facilitating the development of new therapeutic agents with antioxidant activity to improve the treatment of various diseases. Here we examine the role that RS play in the initiation of disease and in the reactivity of free radicals and RS in organic and inorganic cellular components.
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Affiliation(s)
| | | | - Celia Andrés Juan
- Department of Organic Chemistry, Cinquima Institute, Faculty of Sciences, Valladolid University, Valladolid, Spain
| | - Francisco J Plou
- Institute of Catalysis and Petrochemistry, CSIC-Spanish Research Council, Madrid, Spain
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4
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Bansal S, Burman A, Tripathi AK. Advanced glycation end products: Key mediator and therapeutic target of cardiovascular complications in diabetes. World J Diabetes 2023; 14:1146-1162. [PMID: 37664478 PMCID: PMC10473940 DOI: 10.4239/wjd.v14.i8.1146] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/21/2023] [Accepted: 05/22/2023] [Indexed: 08/11/2023] Open
Abstract
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a non-homogeneous, chemically diverse group of compounds formed non-enzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Affiliation(s)
- Savita Bansal
- Department of Biochemistry, Institute of Home Sciences, University of Delhi, New Delhi 110016, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi 110016, India
| | - Asok Kumar Tripathi
- Department of Biochemistry, University College of Medical Sciences, University of Delhi, New Delhi 110095, India
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Brembati V, Faustini G, Longhena F, Bellucci A. Alpha synuclein post translational modifications: potential targets for Parkinson's disease therapy? Front Mol Neurosci 2023; 16:1197853. [PMID: 37305556 PMCID: PMC10248004 DOI: 10.3389/fnmol.2023.1197853] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 04/27/2023] [Indexed: 06/13/2023] Open
Abstract
Parkinson's disease (PD) is the most common neurodegenerative disorder with motor symptoms. The neuropathological alterations characterizing the brain of patients with PD include the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies (LB), intraneuronal inclusions that are mainly composed of alpha-synuclein (α-Syn) fibrils. The accumulation of α-Syn in insoluble aggregates is a main neuropathological feature in PD and in other neurodegenerative diseases, including LB dementia (LBD) and multiple system atrophy (MSA), which are therefore defined as synucleinopathies. Compelling evidence supports that α-Syn post translational modifications (PTMs) such as phosphorylation, nitration, acetylation, O-GlcNAcylation, glycation, SUMOylation, ubiquitination and C-terminal cleavage, play important roles in the modulation α-Syn aggregation, solubility, turnover and membrane binding. In particular, PTMs can impact on α-Syn conformational state, thus supporting that their modulation can in turn affect α-Syn aggregation and its ability to seed further soluble α-Syn fibrillation. This review focuses on the importance of α-Syn PTMs in PD pathophysiology but also aims at highlighting their general relevance as possible biomarkers and, more importantly, as innovative therapeutic targets for synucleinopathies. In addition, we call attention to the multiple challenges that we still need to face to enable the development of novel therapeutic approaches modulating α-Syn PTMs.
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Affiliation(s)
| | | | | | - Arianna Bellucci
- Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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6
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Wu HHL, McDonnell T, Chinnadurai R. Physiological Associations between Vitamin B Deficiency and Diabetic Kidney Disease. Biomedicines 2023; 11:biomedicines11041153. [PMID: 37189771 DOI: 10.3390/biomedicines11041153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 03/24/2023] [Accepted: 04/10/2023] [Indexed: 05/17/2023] Open
Abstract
The number of people living with chronic kidney disease (CKD) is growing as our global population continues to expand. With aging, diabetes, and cardiovascular disease being major harbingers of kidney disease, the number of people diagnosed with diabetic kidney disease (DKD) has grown concurrently. Poor clinical outcomes in DKD could be influenced by an array of factors-inadequate glycemic control, obesity, metabolic acidosis, anemia, cellular senescence, infection and inflammation, cognitive impairment, reduced physical exercise threshold, and, importantly, malnutrition contributing to protein-energy wasting, sarcopenia, and frailty. Amongst the various causes of malnutrition in DKD, the metabolic mechanisms of vitamin B (B1 (Thiamine), B2 (Riboflavin), B3 (Niacin/Nicotinamide), B5 (Pantothenic Acid), B6 (Pyridoxine), B8 (Biotin), B9 (Folate), and B12 (Cobalamin)) deficiency and its clinical impact has garnered greater scientific interest over the past decade. There remains extensive debate on the biochemical intricacies of vitamin B metabolic pathways and how their deficiencies may affect the development of CKD, diabetes, and subsequently DKD, and vice-versa. Our article provides a review of updated evidence on the biochemical and physiological properties of the vitamin B sub-forms in normal states, and how vitamin B deficiency and defects in their metabolic pathways may influence CKD/DKD pathophysiology, and in reverse how CKD/DKD progression may affect vitamin B metabolism. We hope our article increases awareness of vitamin B deficiency in DKD and the complex physiological associations that exist between vitamin B deficiency, diabetes, and CKD. Further research efforts are needed going forward to address the knowledge gaps on this topic.
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Affiliation(s)
- Henry H L Wu
- Renal Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, The University of Sydney, Sydney, NSW 2065, Australia
| | - Thomas McDonnell
- Department of Renal Medicine, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, UK
| | - Rajkumar Chinnadurai
- Department of Renal Medicine, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, UK
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M1 7HR, UK
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Shi R, Tao Y, Tang H, Wu C, Fei J, Ge H, Gu HF, Wu J. Abelmoschus Manihot ameliorates the levels of circulating metabolites in diabetic nephropathy by modulating gut microbiota in non-obese diabetes mice. Microb Biotechnol 2023; 16:813-826. [PMID: 36583468 PMCID: PMC10034626 DOI: 10.1111/1751-7915.14200] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 12/12/2022] [Indexed: 12/31/2022] Open
Abstract
Huangkui capsule (HKC), a traditional Chinese medicine, has been used for medication of kidney diseases, including diabetic nephropathy (DN). The current study aimed to evaluate the effects of HKC in the modulation of gut microbiota and the amelioration of metabolite levels by using non-obese diabetes (NOD) mice with DN. The microbiota from three parts of intestines (duodenum, ileum and colon) in NOD mice with and without HKC treatment were analysed using 16S rDNA sequencing techniques. Untargeted metabolomics in plasma of NOD mice were analysed with liquid mass spectrometry. Results showed that HKC administration ameliorated DN in NOD mice and the flora in duodenum were more sensitive to HKC intervention, while the flora in colon had more effects on metabolism. The bacterial genera such as Faecalitalea and Muribaculum significantly increased and negatively correlated with most of the altered metabolites after HKC treatment, while Phyllobacterium, Weissella and Akkermansia showed an opposite trend. The plasma metabolites, mainly including amino acids and fatty acids such as methionine sulfoxide, BCAAs and cis-7-Hexadecenoic acid, exhibited a distinct return to normal after HKC treatment. The current study thereby provides experimental evidence suggesting that HKC may modulate gut microbiota and subsequently ameliorate the metabolite levels in DN.
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Affiliation(s)
- Ruiya Shi
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yingjun Tao
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Haitao Tang
- Suzhong Pharmaceutical Research Institute, Nanjing, China
| | - Chenhua Wu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jingjin Fei
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Haitao Ge
- Suzhong Pharmaceutical Research Institute, Nanjing, China
| | - Harvest F Gu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jie Wu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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8
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Rabbani N, Adaikalakoteswari A, Larkin JR, Panagiotopoulos S, MacIsaac RJ, Yue DK, Fulcher GR, Roberts MA, Thomas M, Ekinci E, Thornalley PJ. Analysis of Serum Advanced Glycation Endproducts Reveals Methylglyoxal-Derived Advanced Glycation MG-H1 Free Adduct Is a Risk Marker in Non-Diabetic and Diabetic Chronic Kidney Disease. Int J Mol Sci 2022; 24:ijms24010152. [PMID: 36613596 PMCID: PMC9820473 DOI: 10.3390/ijms24010152] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022] Open
Abstract
Accumulation of advanced glycation endproducts (AGEs) is linked to decline in renal function, particularly in patients with diabetes. Major forms of AGEs in serum are protein-bound AGEs and AGE free adducts. In this study, we assessed levels of AGEs in subjects with and without diabetes, with normal renal function and stages 2 to 4 chronic kidney disease (CKD), to identify which AGE has the greatest progressive change with decline in renal function and change in diabetes. We performed a cross-sectional study of patients with stages 2-4 CKD, with and without diabetes, and healthy controls (n = 135). Nine protein-bound and free adduct AGEs were quantified in serum. Most protein-bound AGEs increased moderately through stages 2-4 CKD whereas AGE free adducts increased markedly. Methylglyoxal-derived hydroimidazolone MG-H1 free adduct was the AGE most responsive to CKD status, increasing 8-fold and 30-fold in stage 4 CKD in patients without and with diabetes, respectively. MG-H1 Glomerular filtration flux was increased 5-fold in diabetes, likely reflecting increased methylglyoxal glycation status. We conclude that serum MG-H1 free adduct concentration was strongly related to stage of CKD and increased in diabetes status. Serum MG-H1 free adduct is a candidate AGE risk marker of non-diabetic and diabetic CKD.
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Affiliation(s)
- Naila Rabbani
- Department of Basic Medical Science, College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Antonysunil Adaikalakoteswari
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, UK
| | - James R. Larkin
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, UK
| | - Sianna Panagiotopoulos
- Endocrine Centre, Austin Health, The University of Melbourne, West Heidelberg, VIC 3084, Australia
| | - Richard J. MacIsaac
- Department of Endocrinology & Diabetes, St Vincent’s Hospital Melbourne, Fitzroy, VIC 3065, Australia
- Australian Centre for Accelerating Diabetes Innovations, School of Medicine, University of Melbourne, Parkville, VIC 3052, Australia
| | - Dennis K. Yue
- Diabetes Centre, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
| | - Gregory R. Fulcher
- Department of Diabetes, Endocrinology & Metabolism, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Matthew A. Roberts
- Eastern Health Clinical School, Monash University, Box Hill, VIC 3128, Australia
| | - Merlin Thomas
- Department of Diabetes, Monash University, Melbourne, VIC 3004, Australia
| | - Elif Ekinci
- Endocrine Centre, Austin Health, The University of Melbourne, West Heidelberg, VIC 3084, Australia
- Australian Centre for Accelerating Diabetes Innovations, School of Medicine, University of Melbourne, Parkville, VIC 3052, Australia
| | - Paul J. Thornalley
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, UK
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar
- Correspondence: ; Tel.: +974-7090-1635
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Impact of Reactive Species on Amino Acids-Biological Relevance in Proteins and Induced Pathologies. Int J Mol Sci 2022; 23:ijms232214049. [PMID: 36430532 PMCID: PMC9692786 DOI: 10.3390/ijms232214049] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
This review examines the impact of reactive species RS (of oxygen ROS, nitrogen RNS and halogens RHS) on various amino acids, analyzed from a reactive point of view of how during these reactions, the molecules are hydroxylated, nitrated, or halogenated such that they can lose their capacity to form part of the proteins or peptides, and can lose their function. The reactions of the RS with several amino acids are described, and an attempt was made to review and explain the chemical mechanisms of the formation of the hydroxylated, nitrated, and halogenated derivatives. One aim of this work is to provide a theoretical analysis of the amino acids and derivatives compounds in the possible positions. Tyrosine, methionine, cysteine, and tryptophan can react with the harmful peroxynitrite or •OH and •NO2 radicals and glycine, serine, alanine, valine, arginine, lysine, tyrosine, histidine, cysteine, methionine, cystine, tryptophan, glutamine and asparagine can react with hypochlorous acid HOCl. These theoretical results may help to explain the loss of function of proteins subjected to these three types of reactive stresses. We hope that this work can help to assess the potential damage that reactive species can cause to free amino acids or the corresponding residues when they are part of peptides and proteins.
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Methylglyoxal and glyoxalase 1-a metabolic stress pathway-linking hyperglycemia to the unfolded protein response and vascular complications of diabetes. Clin Sci (Lond) 2022; 136:819-824. [PMID: 35635155 PMCID: PMC9152679 DOI: 10.1042/cs20220099] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 11/23/2022]
Abstract
The study of the glyoxalase system by Thornalley and co-workers in clinical diabetes mellitus and correlation with diabetic complications revealed increased exposure of patients with diabetes to the reactive, dicarbonyl metabolite methylglyoxal (MG). Twenty-eight years later, extended and built on by Thornalley and co-workers and others, the glyoxalase system is an important pathway contributing to the development of insulin resistance and vascular complications of diabetes. Other related advances have been: characterization of a new kind of metabolic stress—‘dicarbonyl stress’; identification of the major physiological advanced glycation endproduct (AGE), MG-H1; physiological substrates of the unfolded protein response (UPR); new therapeutic agents—‘glyoxalase 1 (Glo1) inducers’; and a refined mechanism underlying the link of dysglycemia to the development of insulin resistance and vascular complications of diabetes.
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11
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Therapeutic potential of vitamin B 1 derivative benfotiamine from diabetes to COVID-19. Future Med Chem 2022; 14:809-826. [PMID: 35535731 DOI: 10.4155/fmc-2022-0040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Benfotiamine (S-benzoylthiamine-O-monophosphate), a unique, lipid-soluble derivative of thiamine, is the most potent allithiamine found in roasted garlic, as well as in other herbs of the genus Allium. In addition to potent antioxidative properties, benfotiamine has also been shown to be a strong anti-inflammatory agent with therapeutic significance to several pathological complications. Specifically, over the past decade or so, benfotiamine has been shown to prevent not only various secondary diabetic complications but also several inflammatory complications such as uveitis and endotoxemia. Recent studies also demonstrate that this compound could be used to prevent the symptoms associated with various infectious diseases such as HIV and COVID-19. In this review article, the authors discuss the significance of benfotiamine in the prevention of various pathological complications.
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Patel J, Torrealba JR, Poggio ED, Bebiak J, Alpers CE, Grewenow SM, Toto RD, Eadon MT. Molecular Signatures of Diabetic Kidney Disease Hiding in a Patient with Hypertension-Related Kidney Disease: A Clinical Pathologic Molecular Correlation. Clin J Am Soc Nephrol 2022; 17:594-601. [PMID: 34911732 PMCID: PMC8993486 DOI: 10.2215/cjn.10350721] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The Kidney Precision Medicine Project (KPMP) seeks to establish a molecular atlas of the kidney in health and disease and improve our understanding of the molecular drivers of CKD and AKI. Herein, we describe the case of a 66-year-old woman with CKD who underwent a protocol KPMP kidney biopsy. Her clinical history included well-controlled diabetes mellitus, hypertension, and proteinuria. The patient's histopathology was consistent with modest hypertension-related kidney injury, without overt diabetic kidney disease. Transcriptomic signatures of the glomerulus, interstitium, and tubular subsegments were obtained from laser microdissected tissue. The molecular signatures that were uncovered revealed evidence of early diabetic kidney disease adaptation and ongoing active tubular injury with enriched pathways related to mesangial cell hypertrophy, glycosaminoglycan biosynthesis, and apoptosis. Molecular evidence of diabetic kidney disease was found across the nephron. Novel molecular assays can supplement and enrich the histopathologic diagnosis obtained from a kidney biopsy.
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Affiliation(s)
- Jiten Patel
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, Texas
| | - Jose R. Torrealba
- Department of Pathology, University of Texas Southwestern, Dallas, Texas
| | - Emilio D. Poggio
- Department of Nephrology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
| | - Jack Bebiak
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Charles E. Alpers
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
| | - Stephanie M. Grewenow
- Kidney Research Institute and Division of Nephrology, University of Washington, Seattle, Washington
| | - Robert D. Toto
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, Texas
| | - Michael T. Eadon
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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Koska J, Gerstein HC, Beisswenger PJ, Reaven PD. Advanced Glycation End Products Predict Loss of Renal Function and High-Risk Chronic Kidney Disease in Type 2 Diabetes. Diabetes Care 2022; 45:684-691. [PMID: 35051276 PMCID: PMC8918197 DOI: 10.2337/dc21-2196] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/18/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To evaluate the association of a multicomponent advanced glycation end product (AGE) panel with decline in kidney function and its utility in predicting renal function loss (RFL) when added to routine clinical measures in type 2 diabetes. RESEARCH DESIGN AND METHODS Carboxymethyl and carboxyethyl lysine and methylglyoxal, 3-deoxyglucosone, and glyoxal hydroimidazolones were measured in baseline serum and plasma samples, respectively, from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (n = 1,150) and Veterans Affairs Diabetes Trial (VADT) (n = 447) participants. A composite AGE score was calculated from individual AGE z scores. The primary outcome was a sustained 30% decline in estimated glomerular filtration rate (eGFR) (30% RFL in both cohorts). Secondary outcomes (in ACCORD) were 40% RFL, macroalbuminuria, and high-risk chronic kidney disease (hrCKD). RESULTS After adjustment for baseline and follow-up HbA1c and other risk factors in ACCORD, the AGE score was associated with reduction in eGFR (β-estimate -0.66 mL/min ⋅ 1.73 m2 per year; P = 0.001), 30% RFL (hazard ratio 1.42 [95% CI 1.13-1.78]; P = 0.003), 40% RFL (1.40 [1.13-1.74]; P = 0.003), macroalbuminuria (1.53 [1.13-2.06]; P = 0.006), and hrCKD (1.88 [1.37-2.57]; P < 0.0001). AGE score improved net reclassification (NRI) and relative integrated discrimination (IDI) for 30% RFL (NRI 23%; P = 0.02) (relative IDI 7%; P = 0.009). In VADT, the AGE score calculated by the ACCORD-derived coefficients was associated with 30% RFL (1.37 [1.03-1.82); P = 0.03) and improved NRI (24%; P = 0.03) but not IDI (P = 0.18). CONCLUSIONS These data provide further support for a causal role of AGEs in diabetic nephropathy independently of glycemic control and suggest utility of the composite AGE panel in predicting long-term decline in renal function.
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Affiliation(s)
- Juraj Koska
- Phoenix Veterans Affairs Health Care System, Phoenix, AZ
| | | | | | - Peter D Reaven
- Phoenix Veterans Affairs Health Care System, Phoenix, AZ.,University of Arizona College of Medicine-Phoenix, Phoenix, AZ
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14
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Rabbani N, Xue M, Thornalley PJ. Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis-Driver of Insulin Resistance and Development of Vascular Complications of Diabetes. Int J Mol Sci 2022; 23:ijms23042165. [PMID: 35216280 PMCID: PMC8877341 DOI: 10.3390/ijms23042165] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/01/2022] [Accepted: 02/14/2022] [Indexed: 12/11/2022] Open
Abstract
The recent discovery of the glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis in cell dysfunction in model hyperglycemia has revealed a likely key initiating factor contributing to the development of insulin resistance and vascular complications in diabetes. Consequently, the increased flux of glucose metabolism without a change in the expression and activity of glycolytic enzymes produces a wave of increased glycolytic intermediates driving mitochondrial dysfunction and increased reactive oxygen species (ROS) formation, the activation of hexosamine and protein kinase C pathways, the increased formation of methylglyoxal-producing dicarbonyl stress, and the activation of the unfolded protein response. This is called HK2-linked glycolytic overload and unscheduled glycolysis. The conditions required to sustain this are GLUT1 and/or GLUT3 glucose uptake and the expression of HK2. A metabolic biomarker of its occurrence is the abnormally increased deposition of glycogen, which is produced by metabolic channeling when HK2 becomes detached from mitochondria. These conditions and metabolic consequences are found in the vasculature, kidneys, retina, peripheral nerves, and early-stage embryo development in diabetes and likely sustain the development of diabetic vascular complications and embryopathy. In insulin resistance, HK2-linked unscheduled glycolysis may also be established in skeletal muscle and adipose tissue. This may explain the increased glucose disposal by skeletal uptake in the fasting phase in patients with type 2 diabetes mellitus, compared to healthy controls, and the presence of insulin resistance in patients with type 1 diabetes mellitus. Importantly, glyoxalase 1 inducer—trans-resveratrol and hesperetin in combination (tRES-HESP)—corrected HK2-linked glycolytic overload and unscheduled glycolysis and reversed insulin resistance and improved vascular inflammation in overweight and obese subjects in clinical trial. Further studies are now required to evaluate tRES-HESP for the prevention and reversal of early-stage type 2 diabetes and for the treatment of the vascular complications of diabetes.
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Affiliation(s)
- Naila Rabbani
- Department of Basic Medical Science, College of Medicine, Qatar University Health, Qatar University, Doha P.O. Box 2713, Qatar
- Correspondence: (N.R.); (P.J.T.); Tel.: +974-7479-5649 (N.R.); +974-7090-1635 (P.J.T.)
| | - Mingzhan Xue
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
| | - Paul J. Thornalley
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
- Correspondence: (N.R.); (P.J.T.); Tel.: +974-7479-5649 (N.R.); +974-7090-1635 (P.J.T.)
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15
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Khorasani MK, Ahangarpour A, Khorsandi L. Effects of crocin and metformin on methylglyoxal-induced reproductive system dysfunction in diabetic male mice. Clin Exp Reprod Med 2021; 48:221-228. [PMID: 34488286 PMCID: PMC8421661 DOI: 10.5653/cerm.2020.04259] [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: 11/21/2020] [Accepted: 03/16/2021] [Indexed: 11/17/2022] Open
Abstract
Objective This study investigated the effect of crocin in methylglyoxal (MGO)-induced diabetic male mice. Methods Seventy 1-month-old male NMRI mice weighing 20–25 g were divided into seven groups (n=10): sham, MGO (600 mg/kg/day), MGO+crocin (15, 30, and 60 mg/kg/day), MGO+metformin (150 mg/kg/day), and crocin (60 mg/kg/day). MGO was administered orally for 30 days. Starting on day 14, after confirming hyperglycemia, metformin and crocin were administered orally. On day 31, plasma and tissue samples were prepared for experimental assessments. Results Blood glucose and insulin levels in the MGO group were higher than those in the sham group (p<0.001), and decreased in response to metformin (p<0.001) and crocin treatment (not at all doses). Testis width and volume decreased in the MGO mice and improved in the crocin-treated mice (p<0.05), but not in the metformin group. Superoxide dismutase levels decreased in diabetic mice (p<0.05) and malondialdehyde levels increased (p<0.001). Crocin and metformin improved malondialdehyde and superoxide dismutase. Testosterone (p<0.001) and sperm count (p<0.05) decreased in the diabetic mice, and treatment with metformin and crocin recovered these variables. Luteinizing hormone levels increased in diabetic mice (p<0.001) and crocin treatment (but not metformin) attenuated this increase. Seminiferous diameter and height decreased in the diabetic mice and increased in the treatment groups. Vacuoles and ruptures were seen in diabetic testicular tissue, and crocin improved testicular morphology (p<0.01). Conclusion MGO increased oxidative stress, reduced sex hormones, and induced histological problems in male reproductive organs. Crocin and metformin improved the reproductive damage caused by MGO-induced diabetes.
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Affiliation(s)
- Maryam Kheirollahi Khorasani
- Department of Physiology, Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Akram Ahangarpour
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Layasadat Khorsandi
- Department of Anatomical Sciences, Faculty of Medicine, Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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16
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Piazza M, Hanssen NMJ, Persson F, Scheijen JL, van de Waarenburg MPH, van Greevenbroek MMJ, Rossing P, Hovind P, Stehouwer CDA, Parving H, Schalkwijk CG. Irbesartan treatment does not influence plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone in participants with type 2 diabetes and microalbuminuria: An IRMA2 sub-study. Diabet Med 2021; 38:e14405. [PMID: 32961617 PMCID: PMC8451908 DOI: 10.1111/dme.14405] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/18/2020] [Accepted: 09/11/2020] [Indexed: 12/13/2022]
Abstract
AIM Angiotensin receptor blockers (ARBs) reduce vascular complications in diabetes independently of blood pressure. Experimental studies suggested that ARBs may restore the detoxifying enzyme glyoxalase 1, thereby lowering dicarbonyls such as methylglyoxal. Human data on the effects of ARBs on plasma dicarbonyl levels are lacking. We investigated, in individuals with type 2 diabetes, whether irbesartan lowered plasma levels of the dicarbonyls methylglyoxal, glyoxal, 3-deoxyglucosone and their derived advanced glycation end products (AGEs), and increased d-lactate, reflecting greater methylglyoxal flux. METHODS We analysed a subset of the Irbesartan in Patients with T2D and Microalbuminuria (IRMA2) study. We measured plasma dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs and d-lactate using ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) in the treatment arm receiving 300 mg irbesartan (n = 121) and a placebo group (n = 101) at baseline and after 1 and 2 years. Effect of treatment was analysed with repeated measurements ANOVA. RESULTS There was a slight, but significant difference in baseline median methylglyoxal levels [placebo 1119 (907-1509) nmol/l vs. irbesartan 300 mg 1053 (820-1427) nmol/l], but no significant changes were observed in any of the plasma dicarbonyls over time in either group and there was no effect of irbesartan treatment on plasma free AGEs or d-lactate levels at either 1 or 2 years. CONCLUSION Irbesartan treatment does not change plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs or d-lactate in type 2 diabetes. This indicates that increased dicarbonyls in type 2 diabetes are not targetable by ARBs, and other approaches to lower systemic dicarbonyls are needed in type 2 diabetes. (Clinical Trial Registry No: #NCT00317915).
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Affiliation(s)
- M. Piazza
- Internal MedicineMaastricht University Medical CentreMaastrichtthe Netherlands
- Cardiovascular Research Institute Maastricht (CARIM)Maastrichtthe Netherlands
- Department of Medicine‐DIMED University of PaduaItaly
| | - N. M. J. Hanssen
- Internal MedicineMaastricht University Medical CentreMaastrichtthe Netherlands
- Cardiovascular Research Institute Maastricht (CARIM)Maastrichtthe Netherlands
| | - F. Persson
- Steno Diabetes Center CopenhagenCopenhagenDenmark
| | - J. L. Scheijen
- Internal MedicineMaastricht University Medical CentreMaastrichtthe Netherlands
- Cardiovascular Research Institute Maastricht (CARIM)Maastrichtthe Netherlands
| | - M. P. H. van de Waarenburg
- Internal MedicineMaastricht University Medical CentreMaastrichtthe Netherlands
- Cardiovascular Research Institute Maastricht (CARIM)Maastrichtthe Netherlands
| | - M. M. J. van Greevenbroek
- Internal MedicineMaastricht University Medical CentreMaastrichtthe Netherlands
- Cardiovascular Research Institute Maastricht (CARIM)Maastrichtthe Netherlands
| | - P. Rossing
- Steno Diabetes Center CopenhagenCopenhagenDenmark
- Department of Clinical MedicineUniversity of CopenhagenCopenhagenDenmark
| | - P. Hovind
- Steno Diabetes Center CopenhagenCopenhagenDenmark
- Clinical Physiology and Nuclear MedicineBispebjerg HospitalCopenhagenDenmark
| | - C. D. A. Stehouwer
- Internal MedicineMaastricht University Medical CentreMaastrichtthe Netherlands
- Cardiovascular Research Institute Maastricht (CARIM)Maastrichtthe Netherlands
| | - H‐H. Parving
- Medical EndocrinologyUniversity Hospital of CopenhagenCopenhagenDenmark
| | - C. G. Schalkwijk
- Internal MedicineMaastricht University Medical CentreMaastrichtthe Netherlands
- Cardiovascular Research Institute Maastricht (CARIM)Maastrichtthe Netherlands
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17
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The Glyoxalase System in Age-Related Diseases: Nutritional Intervention as Anti-Ageing Strategy. Cells 2021; 10:cells10081852. [PMID: 34440621 PMCID: PMC8393707 DOI: 10.3390/cells10081852] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/09/2021] [Accepted: 07/15/2021] [Indexed: 12/19/2022] Open
Abstract
The glyoxalase system is critical for the detoxification of advanced glycation end-products (AGEs). AGEs are toxic compounds resulting from the non-enzymatic modification of biomolecules by sugars or their metabolites through a process called glycation. AGEs have adverse effects on many tissues, playing a pathogenic role in the progression of molecular and cellular aging. Due to the age-related decline in different anti-AGE mechanisms, including detoxifying mechanisms and proteolytic capacities, glycated biomolecules are accumulated during normal aging in our body in a tissue-dependent manner. Viewed in this way, anti-AGE detoxifying systems are proposed as therapeutic targets to fight pathological dysfunction associated with AGE accumulation and cytotoxicity. Here, we summarize the current state of knowledge related to the protective mechanisms against glycative stress, with a special emphasis on the glyoxalase system as the primary mechanism for detoxifying the reactive intermediates of glycation. This review focuses on glyoxalase 1 (GLO1), the first enzyme of the glyoxalase system, and the rate-limiting enzyme of this catalytic process. Although GLO1 is ubiquitously expressed, protein levels and activities are regulated in a tissue-dependent manner. We provide a comparative analysis of GLO1 protein in different tissues. Our findings indicate a role for the glyoxalase system in homeostasis in the eye retina, a highly oxygenated tissue with rapid protein turnover. We also describe modulation of the glyoxalase system as a therapeutic target to delay the development of age-related diseases and summarize the literature that describes the current knowledge about nutritional compounds with properties to modulate the glyoxalase system.
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18
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Kalyesubula M, Mopuri R, Asiku J, Rosov A, Yosefi S, Edery N, Bocobza S, Moallem U, Dvir H. High-dose vitamin B1 therapy prevents the development of experimental fatty liver driven by overnutrition. Dis Model Mech 2021; 14:dmm.048355. [PMID: 33608323 PMCID: PMC7988776 DOI: 10.1242/dmm.048355] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/11/2021] [Indexed: 12/16/2022] Open
Abstract
Fatty liver is an abnormal metabolic condition of excess intrahepatic fat. This condition, referred to as hepatic steatosis, is tightly associated with chronic liver disease and systemic metabolic morbidity. The most prevalent form in humans, i.e. non-alcoholic fatty liver, generally develops due to overnutrition and sedentary lifestyle, and has as yet no approved drug therapy. Previously, we have developed a relevant large-animal model in which overnourished sheep raised on a high-calorie carbohydrate-rich diet develop hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. Here, we tested the hypothesis that treatment with thiamine (vitamin B1) can counter the development of hepatic steatosis driven by overnutrition. Remarkably, the thiamine-treated animals presented with completely normal levels of intrahepatic fat, despite consuming the same amount of liver-fattening diet. Thiamine treatment also decreased hyperglycemia and increased the glycogen content of the liver, but it did not improve insulin sensitivity, suggesting that steatosis can be addressed independently of targeting insulin resistance. Thiamine increased the catalytic capacity for hepatic oxidation of carbohydrates and fatty acids. However, at gene-expression levels, more-pronounced effects were observed on lipid-droplet formation and lipidation of very-low-density lipoprotein, suggesting that thiamine affects lipid metabolism not only through its known classic coenzyme roles. This discovery of the potent anti-steatotic effect of thiamine may prove clinically useful in managing fatty liver-related disorders.This article has an associated First Person interview with the joint first authors of the paper.
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Affiliation(s)
- Mugagga Kalyesubula
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel.,Department of Animal Science, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
| | - Ramgopal Mopuri
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
| | - Jimmy Asiku
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel.,Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
| | - Alexander Rosov
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
| | - Sara Yosefi
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
| | - Nir Edery
- Pathology Laboratory, Kimron Veterinary Institute, Veterinary Services, Rishon LeZion 50250, Israel
| | - Samuel Bocobza
- Institute of Plant Sciences, Volcani Center - ARO, Rishon LeZion 7528809, Israel
| | - Uzi Moallem
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
| | - Hay Dvir
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
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19
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Lee DY, Lin YC, Chang GD. Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling. Antioxidants (Basel) 2021; 10:antiox10020326. [PMID: 33671767 PMCID: PMC7926409 DOI: 10.3390/antiox10020326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 11/18/2022] Open
Abstract
Methylglyoxal (MG) is a reactive glycation metabolite and potentially induces dicarbonyl stress. The production of MG in cells is increased along with an increase in carbohydrate metabolism. The efficiency of the glyoxalase system, consisting of glyoxalase 1 (GlxI) and glyoxalase 2 (GlxII), is crucial for turning the accumulated MG into nontoxic metabolites. Converting MG-glutathione hemithioacetal to S-d-lactoylglutathione by GlxI is the rate-determining step of the enzyme system. In this study, we found lactic acid accumulated during insulin stimulation in cells, however, cellular MG and S-d-lactoylglutathione also increased due to the massive flux of glycolytic intermediates. The insulin-induced accumulation of MG and S-d-lactoylglutathione were efficiently removed by the treatment of metformin, possibly via affecting the glyoxalase system. With the application of isotopic 13C3-MG, the flux of MG from extracellular and intracellular origins was dissected. While insulin induced an influx of extracellular MG, metformin inhibited the trafficking of MG across the plasma membrane. Therefore, metformin could maintain the extracellular MG by means of reducing the secretion of MG rather than facilitating the scavenging. In addition, metformin may affect the glyoxalase system by controlling the cellular redox state through replenishing reduced glutathione. Overall, alternative biochemical regulation of the glyoxalase system mediated by insulin signaling or molecules like biguanides may control cellular MG homeostasis.
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Affiliation(s)
- Der-Yen Lee
- Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
- Correspondence: (D.-Y.L.); (G.-D.C.); Tel.: +886-4-22053366#3505 (D.-Y.L.); +886-2-33664071 (G.-D.C.); Fax: +886-2-22037690 (D.-Y.L.); +886-2-23635038 (G.-D.C.)
| | - Yu-Chin Lin
- Ph.D. Program for Health Science and Industry, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan;
| | - Geen-Dong Chang
- Graduate Institute of Biochemical Sciences, National Taiwan University, No.1, Section 4, Roosevelt Road, Taipei 106, Taiwan
- Correspondence: (D.-Y.L.); (G.-D.C.); Tel.: +886-4-22053366#3505 (D.-Y.L.); +886-2-33664071 (G.-D.C.); Fax: +886-2-22037690 (D.-Y.L.); +886-2-23635038 (G.-D.C.)
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20
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Nwadiugwu MC. Inflammatory Activities in Type 2 Diabetes Patients With Co-morbid Angiopathies and Exploring Beneficial Interventions: A Systematic Review. Front Public Health 2021; 8:600427. [PMID: 33569370 PMCID: PMC7868423 DOI: 10.3389/fpubh.2020.600427] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 12/14/2020] [Indexed: 12/19/2022] Open
Abstract
Background: Diabetes is a long-term condition that can be treated and controlled but do not yet have a cure; it could be induced by inflammation and the goal of managing it is to prevent additional co-morbidities and reduce glycemic fluctuations. There is a need to examine inflammatory activities in diabetes-related angiopathies and explore interventions that could reduce the risk for future outcome or ameliorate its effects to provide insights for improved care and management strategies. Method: The study was conducted in Embase (1946–2020), Ovid Medline (1950–2020), and PubMed databases (1960–2020) using the PICO framework. Primary studies (randomized controlled trials) on type 2 diabetes mellitus and inflammatory activities in diabetes-related angiopathies were included. Terms for the review were retrieved from the Cochrane library and from PROSPERO using its MeSH thesaurus qualifiers. Nine articles out of 454 total hits met the eligibility criteria. The quality assessment for the selected study was done using the Center for Evidence-Based Medicine Critical Appraisal Sheet. Results: Data analysis showed that elevated CRP, TNF-α, and IL-6 were the most commonly found inflammatory indicator in diabetes-related angiopathies, while increased IL-10 and soluble RAGE was an indicator for better outcome. Use of drugs such as salsalate, pioglitazone, simvastatin, and fenofibrate but not glimepiride or benfotiamine reported a significant decrease in inflammatory events. Regular exercise and consumption of dietary supplements such as ginger, hesperidin which have anti-inflammatory properties, and those containing prebiotic fibers (e.g., raspberries) revealed a consistent significant (p < 0.05) reduction in inflammatory activities. Conclusion: Inflammatory activities are implicated in diabetes-related angiopathies; regular exercise, the intake of healthy dietary supplements, and medications with anti-inflammatory properties could result in improved protective risk outcome for diabetes patients by suppressing inflammatory activities and elevating anti-inflammatory events.
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Affiliation(s)
- Martin C Nwadiugwu
- Faculty of Health and Sports, University of Stirling, Stirling, United Kingdom
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21
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Reading patterns of proteome damage by glycation, oxidation and nitration: quantitation by stable isotopic dilution analysis LC-MS/MS. Essays Biochem 2020; 64:169-183. [PMID: 32065835 DOI: 10.1042/ebc20190047] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 01/08/2020] [Accepted: 01/13/2020] [Indexed: 12/25/2022]
Abstract
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides a high sensitivity, high specificity multiplexed method for concurrent detection of adducts formed by protein glycation, oxidation and nitration, also called AGEomics. Combined with stable isotopic dilution analysis, it provides for robust quantitation of protein glycation, oxidation and nitration adduct analytes. It is the reference method for such measurements. LC-MS/MS has been used to measure glycated, oxidized and nitrated amino acids - also called glycation, oxidation and nitration free adducts, with a concurrent quantitation of the amino acid metabolome in physiological fluids. Similar adduct residues in proteins may be quantitated with prior exhaustive enzymatic hydrolysis. It has also been applied to quantitation of other post-translation modifications, such as citrullination and formation of Nε-(γ-glutamyl)lysine crosslink by transglutaminases. Application to cellular and extracellular proteins gives estimates of the steady-state levels of protein modification by glycation, oxidation and nitration, and measurement of the accumulation of glycation, oxidation and nitration adducts in cell culture medium and urinary excretion gives an indication of flux of adduct formation. Measurement of glycation, oxidation and nitration free adducts in plasma and urine provides for estimates of renal clearance of free adducts. Diagnostic potential in clinical studies has been enhanced by the combination of estimates of multiple adducts in optimized diagnostic algorithms by machine learning. Recent applications have been in early-stage detection of metabolic, vascular and renal disease, and arthritis, metabolic control and risk of developing vascular complication in diabetes, and a blood test for autism.
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22
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Tessier FJ, Boulanger E, Howsam M. Metabolic transit of dietary advanced glycation end-products - the case of N Ɛ-carboxymethyllysine. Glycoconj J 2020; 38:311-317. [PMID: 32990827 DOI: 10.1007/s10719-020-09950-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 08/31/2020] [Accepted: 09/25/2020] [Indexed: 11/27/2022]
Abstract
The Maillard reaction, also called glycation, is one of the major chemical reactions responsible for most yellow-to-brown colors and aromas in cooked foods. This reaction between reducing sugars and amino functions on proteins affects not only the flavor of food, but also leads to the formation of an heterogenous group of structurally-modified amino acids. Some of these, known as "advanced glycation end products" (AGEs), have been found in both foods and human biological fluids, tissues and organs. Except for those that are formed over long periods in vivo at 37 °C, AGEs in the body originate from the digestion and absorption of dietary sources. A high or chronic exposure to dietary AGEs (dAGEs) is suspected as potentially detrimental to human health and studies in the field of food safety have begun to focus their attention on the metabolic transit of dAGEs. This review presents some important findings in this field, with a focus on NƐ-carboxymethyllysine, and presents the evidence for and against an association between intake of dAGEs and their presence in the body. New and promising avenues of research are described, and some future directions outlined.
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Affiliation(s)
- Frederic J Tessier
- Inserm, CHU Lille, Pasteur Institute of Lille, University of Lille, U1167 - RID-AGE, F-59000, Lille, France.
| | - Eric Boulanger
- Inserm, CHU Lille, Pasteur Institute of Lille, University of Lille, U1167 - RID-AGE, F-59000, Lille, France
| | - Michael Howsam
- Inserm, CHU Lille, Pasteur Institute of Lille, University of Lille, U1167 - RID-AGE, F-59000, Lille, France
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23
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Perkins BA, Rabbani N, Weston A, Adaikalakoteswari A, Lee JA, Lovblom LE, Cardinez N, Thornalley PJ. High fractional excretion of glycation adducts is associated with subsequent early decline in renal function in type 1 diabetes. Sci Rep 2020; 10:12709. [PMID: 32728119 PMCID: PMC7391737 DOI: 10.1038/s41598-020-69350-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 06/10/2020] [Indexed: 12/18/2022] Open
Abstract
Increased protein glycation, oxidation and nitration is linked to the development of diabetic nephropathy. We reported levels of serum protein glycation, oxidation and nitration and related hydrolysis products, glycation, oxidation and nitration free adducts in patients with type 1 diabetes (T1DM) during onset of microalbuminuria (MA) from the First Joslin Kidney Study, a prospective case-control study of patients with T1DM with and without early decline in GFR. Herein we report urinary excretion of the latter analytes and related fractional excretion values, exploring the link to MA and early decline in GFR. We recruited patients with T1DM and normoalbuminuria (NA) (n = 30) or new onset MA with and without early GFR decline (n = 22 and 33, respectively) for this study. We determined urinary protein glycation, oxidation and nitration free adducts by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry (LC-MS/MS) and deduced fractional excretion using reported plasma levels and urinary and plasma creatinine estimates. We found urinary excretion of pentosidine was increased ca. twofold in patients with MA, compared to normoalbuminuria (0.0442 vs 0.0103 nmol/mg creatinine, P < 0.0001), and increased ca. threefold in patients with early decline in GFR, compared to patients with stable GFR (0.0561 vs 0.0176 nmol/mg creatinine, P < 0.01). Urinary excretion of all other analytes was unchanged between the study groups. Remarkably, fractional excretions of 6 lysine and arginine-derived glycation free adducts were higher in patients with early decline in GFR, compared to those with stable GFR. Impaired tubular reuptake of glycation free adducts by lysine and arginine transporter proteins in patients with early GFR decline is likely involved. We conclude that higher fractional excretions of glycation adducts are potential biomarkers for early GFR decline in T1DM and MA. Measurement of these analytes could provide the basis for identifying patients at risk of early decline in renal function to target and intensify renoprotective treatment.
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Affiliation(s)
- Bruce A Perkins
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Mount Sinai Hospital, Toronto, ON, Canada
| | - Naila Rabbani
- Department of Basic Medical Science, College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Andrew Weston
- Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry, UK.,University College London School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Antonysunil Adaikalakoteswari
- Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry, UK.,School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK
| | - Justin A Lee
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Mount Sinai Hospital, Toronto, ON, Canada
| | - Leif E Lovblom
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Mount Sinai Hospital, Toronto, ON, Canada
| | - Nancy Cardinez
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Mount Sinai Hospital, Toronto, ON, Canada
| | - Paul J Thornalley
- Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry, UK. .,Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, P.O. Box 34110, Doha, Qatar.
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Evaluation of metabolic changes in liver and serum of streptozotocin-induced diabetic rats after Mango diet supplementation. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103695] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Schalkwijk CG, Stehouwer CDA. Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases. Physiol Rev 2020; 100:407-461. [DOI: 10.1152/physrev.00001.2019] [Citation(s) in RCA: 368] [Impact Index Per Article: 73.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The formation and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of type 2 diabetes, vascular complications of diabetes, and several other age-related chronic inflammatory diseases such as cardiovascular disease, cancer, and disorders of the central nervous system. MGO is mainly formed as a byproduct of glycolysis and, under physiological circumstances, detoxified by the glyoxalase system. MGO is the major precursor of nonenzymatic glycation of proteins and DNA, subsequently leading to the formation of advanced glycation end products (AGEs). MGO and MGO-derived AGEs can impact on organs and tissues affecting their functions and structure. In this review we summarize the formation of MGO, the detoxification of MGO by the glyoxalase system, and the biochemical pathways through which MGO is linked to the development of diabetes, vascular complications of diabetes, and other age-related diseases. Although interventions to treat MGO-associated complications are not yet available in the clinical setting, several strategies to lower MGO have been developed over the years. We will summarize several new directions to target MGO stress including glyoxalase inducers and MGO scavengers. Targeting MGO burden may provide new therapeutic applications to mitigate diseases in which MGO plays a crucial role.
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Affiliation(s)
- C. G. Schalkwijk
- CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands; and Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - C. D. A. Stehouwer
- CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands; and Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
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26
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Gonçalves ÁDC, Moreira EJS, Portari GV. Benfotiamine supplementation prevents oxidative stress in anterior tibialis muscle and heart. JOURNAL OF INTEGRATIVE MEDICINE-JIM 2019; 17:423-429. [PMID: 31395444 DOI: 10.1016/j.joim.2019.07.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 05/21/2019] [Indexed: 10/26/2022]
Abstract
OBJECTIVE This study aimed to evaluate the influence of oral supplementation with benfotiamine on oxidative stress in the liver, heart and muscles of endurance-trained mice. METHODS Twenty-five male BALB/c mice were allocated to the following treatment groups: standard diet and sedentary activity (Sta-Sed), benfotiamine-supplemented diet and sedentary activity (Ben-Sed), standard diet and training activity (Sta-Tr) and benfotiamine-supplemented diet and training activity (Ben-Tr). The training comprised 6 weeks of endurance swimming training. The concentration of thiobarbituric acid reactive substances (TBARS), carbonylated proteins, total thiols and non-protein thiols was analyzed in the liver, heart and tibialis anterior muscle. RESULTS In the muscle, TBARS concentration in the Sta-Sed group was higher than that in other groups; in the heart, TBARS concentration in the Sta-Sed and Ben-Tr groups was higher than that in the Ben-Sed group. The carbonyl content of the muscle tissues was higher in the Sta-Sed group than in both supplemented groups. In liver, the carbonyl content was lower in the Ben-Sed group than in the Sta-Sed group. The level of total thiols was lower in the Ben-Sed group than in the Sta-Tr group. In the heart, the level of total thiols was higher in the Ben-Sed group than in the Ben-Tr group. The concentration of non-protein thiols in the muscle was higher in the Ben-Sed group than in the Ben-Tr group, whereas in the heart, concentration of non-protein thiols of Sta-Tr group was lower than that of Sta-Sed group. CONCLUSION The results show that benfotiamine is an efficient antioxidant for the anterior tibialis muscle and heart; however, swimming training did not alter redox status.
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Affiliation(s)
- Álisson de Carvalho Gonçalves
- Laboratory of Experimental Nutrition, Health Sciences Institute, Federal University of Triangulo Mineiro, Uberaba, MG 38025-440, Brazil
| | - Einy Jéssika Siqueira Moreira
- Laboratory of Experimental Nutrition, Health Sciences Institute, Federal University of Triangulo Mineiro, Uberaba, MG 38025-440, Brazil
| | - Guilherme Vannucchi Portari
- Department of Nutrition, Health Sciences Institute, Federal University of Triangulo Mineiro, Uberaba, MG 38025-440, Brazil.
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Rabbani N, Thornalley PJ. Hexokinase-2 Glycolytic Overload in Diabetes and Ischemia-Reperfusion Injury. Trends Endocrinol Metab 2019; 30:419-431. [PMID: 31221272 DOI: 10.1016/j.tem.2019.04.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/21/2019] [Accepted: 04/25/2019] [Indexed: 01/12/2023]
Abstract
Hexokinase-2 (HK2) was recently found to produce increased metabolic flux through glycolysis in hyperglycemia without concurrent transcriptional or other functional regulation. Rather, stabilization to proteolysis by increased glucose substrate binding produced unscheduled increased glucose metabolism in response to high cytosolic glucose concentration. This produces abnormal increases in glycolytic intermediates or glycolytic overload, driving cell dysfunction and vulnerability to the damaging effects of hyperglycemia in diabetes, explaining tissue-specific pathogenesis. Glycolytic overload is also activated in ischemia-reperfusion injury and cell senescence. A further key feature is HK2 displacement from mitochondria by increased glucose-6-phosphate concentration, inducing mitochondrial dysfunction and oxidative stress. This pathogenic mechanism suggested new targets for therapeutics development that gave promising outcomes in initial clinical evaluation.
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Affiliation(s)
- Naila Rabbani
- Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, UK
| | - Paul J Thornalley
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, P.O. Box 34110, Doha, Qatar.
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Wang Y, Hall LM, Kujawa M, Li H, Zhang X, O'Meara M, Ichinose T, Wang JM. Methylglyoxal triggers human aortic endothelial cell dysfunction via modulation of the K ATP/MAPK pathway. Am J Physiol Cell Physiol 2019; 317:C68-C81. [PMID: 30995106 DOI: 10.1152/ajpcell.00117.2018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Endothelial dysfunction is a key risk factor in diabetes-related multiorgan damage. Methylglyoxal (MGO), a highly reactive dicarbonyl generated primarily as a by-product of glycolysis, is increased in both type 1 and type 2 diabetic patients. MGO can rapidly bind with proteins, nucleic acids, and lipids, resulting in structural and functional changes. MGO can also form advanced glycation end products (AGEs). How MGO causes endothelial cell dysfunction, however, is not clear. Human aortic endothelial cells (HAECs) from healthy (H-HAECs) and type 2 diabetic (D-HAECs) donors were cultured in endothelial growth medium (EGM-2). D-HAECs demonstrated impaired network formation (on Matrigel) and proliferation (MTT assay), as well as increased apoptosis (caspase-3/7 activity and TUNEL staining), compared with H-HAECs. High glucose (25 mM) or AGEs (200 ng/ml) did not induce such immediate, detrimental effects as MGO (10 µM). H-HAECs were treated with MGO (10 µM) for 24 h with or without the ATP-sensitive potassium (KATP) channel antagonist glibenclamide (1 µM). MGO significantly impaired H-HAEC network formation and proliferation and induced cell apoptosis, which was reversed by glibenclamide. Furthermore, siRNA against the KATP channel protein Kir6.1 significantly inhibited endothelial cell function at basal status but rescued impaired endothelial cell function upon MGO exposure. Meanwhile, activation of MAPK pathways p38 kinase, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) (determined by Western blot analyses of their phosphorylated forms, p-JNK, p-p38, and p-ERK) in D-HAECs were significantly enhanced compared with those in H-HAECs. MGO exposure enhanced the activation of all three MAPK pathways in H-HAECs, whereas glibenclamide reversed the activation of p-stress-activated protein kinase/JNK induced by MGO. Glyoxalase-1 (GLO1) is the endogenous MGO-detoxifying enzyme. In healthy mice that received an inhibitor of GLO1, MGO deposition in aortic wall was enhanced and endothelial cell sprouting from isolated aortic segment was significantly inhibited. Our data suggest that MGO triggers endothelial cell dysfunction by activating the JNK/p38 MAPK pathway. This effect arises partly through activation of KATP channels. By understanding how MGO induces endothelial dysfunction, our study may provide useful information for developing MGO-targeted interventions to treat vascular disorders in diabetes.
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Affiliation(s)
- Yihan Wang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan
| | - Leo M Hall
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University , Detroit, Michigan
| | - Marisa Kujawa
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan
| | - Hainan Li
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan
| | - Xiang Zhang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan
| | - Megan O'Meara
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan
| | - Tomomi Ichinose
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University , Detroit, Michigan
| | - Jie-Mei Wang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan.,Centers for Molecular Medicine and Genetics, Wayne State University , Detroit, Michigan.,Cardiovascular Research Institute, Wayne State University, Detroit, Michigan
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Guilbaud A, Howsam M, Niquet-Léridon C, Delguste F, Boulanger E, Tessier FJ. The LepR db/db mice model for studying glycation in the context of diabetes. Diabetes Metab Res Rev 2019; 35:e3103. [PMID: 30467969 DOI: 10.1002/dmrr.3103] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 11/16/2018] [Accepted: 11/20/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Early (furosine) and advanced (carboxymethyllysine, CML) products of glycation (AGEs) have been reported as increased in plasma, tissues, and organs of diabetic people, indicating a direct link between glycation and type 2 diabetes (T2D). While murine models present some of the characteristics observed in diabetic humans, their pertinence as models of glycation, particularly for T2D, remains poorly described. The aim of this study was to characterize and compare glycation in several organs of two commonly studied murine models of T2D using stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS). METHODS Defining parameters of type 2 diabetes including body weight, fasting glycaemia, and glucose intolerance were measured in three different C57BL6 mouse models of T2D-the genetic LepRdb/db (db/db) model and two diet-induced obesity (DIO) models-and their respective controls. Furosine, free, and protein-bound CML were quantified in kidneys, lungs, heart, and liver by LC-MS/MS. RESULTS The obesity, hyperglycaemia, and glucose intolerance in db/db mice was accompanied by an increase of furosine and protein-bound CML levels in all organs relative to controls. The DIO models took several months to become obese, exhibited less severe hyperglycaemia and glucose intolerance, while glycation products were not significantly different between these groups (with the exception of furosine in liver and CML in lungs). CONCLUSIONS The db/db model better reflected the characteristics of human T2D compared with the DIO models and exhibited greater formation and accumulation of both furosine and protein-bound CML in all of the organs tested here.
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Affiliation(s)
- Axel Guilbaud
- U995-LIRIC-Lille Inflammation Research International Center, University Lille, Inserm, CHU Lille, Lille, France
- VF Bioscience SAS, Loos-lez-Lille, France
| | - Michael Howsam
- U995-LIRIC-Lille Inflammation Research International Center, University Lille, Inserm, CHU Lille, Lille, France
| | - Céline Niquet-Léridon
- Transformations & Agroresources Unit, Institut Polytechnique UniLaSalle, Beauvais, France
| | - Florian Delguste
- U995-LIRIC-Lille Inflammation Research International Center, University Lille, Inserm, CHU Lille, Lille, France
| | - Eric Boulanger
- U995-LIRIC-Lille Inflammation Research International Center, University Lille, Inserm, CHU Lille, Lille, France
| | - Frédéric J Tessier
- U995-LIRIC-Lille Inflammation Research International Center, University Lille, Inserm, CHU Lille, Lille, France
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Abstract
Significance: Obesity and type 2 diabetes mellitus are increasing globally. There is also increasing associated complications, such as non-alcoholic fatty liver disease (NAFLD) and vascular complications of diabetes. There is currently no licensed treatment for NAFLD and no recent treatments for diabetic complications. New approaches are required, particularly those addressing mechanism-based risk factors for health decline and disease progression. Recent Advances: Dicarbonyl stress is the abnormal accumulation of reactive dicarbonyl metabolites such as methylglyoxal (MG) leading to cell and tissue dysfunction. It is a potential driver of obesity, diabetes, and related complications that are unaddressed by current treatments. Increased formation of MG is linked to increased glyceroneogenesis and hyperglycemia in obesity and diabetes and also down-regulation of glyoxalase 1 (Glo1)-which provides the main enzymatic detoxification of MG. Glo1 functional genomics studies suggest that increasing Glo1 expression and activity alleviates dicarbonyl stress; slows development of obesity, related insulin resistance; and prevents development of diabetic nephropathy and other microvascular complications of diabetes. A new therapeutic approach constitutes small-molecule inducers of Glo1 expression-Glo1 inducers-exploiting a regulatory antioxidant response element in the GLO1 gene. A prototype Glo1 inducer, trans-resveratrol (tRES)-hesperetin (HESP) combination, in corrected insulin resistance, improved glycemic control and vascular inflammation in healthy overweight and obese subjects in clinical trial. Critical Issues: tRES and HESP synergize pharmacologically, and HESP likely overcomes the low bioavailability of tRES by inhibition of intestinal glucuronosyltransferases. Future Directions: Glo1 inducers may now be evaluated in Phase 2 clinical trials for treatment of NAFLD and vascular complications of diabetes.
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Affiliation(s)
- Naila Rabbani
- 1 Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital , Coventry, United Kingdom .,2 Warwick Systems Biology Centre, Senate House, University of Warwick , Coventry, United Kingdom
| | - Paul J Thornalley
- 1 Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital , Coventry, United Kingdom .,2 Warwick Systems Biology Centre, Senate House, University of Warwick , Coventry, United Kingdom
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Kim M, Basharat A, Santosh R, Mehdi SF, Razvi Z, Yoo SK, Lowell B, Kumar A, Brima W, Danoff A, Dankner R, Bergman M, Pavlov VA, Yang H, Roth J. Reuniting overnutrition and undernutrition, macronutrients, and micronutrients. Diabetes Metab Res Rev 2019; 35:e3072. [PMID: 30171821 DOI: 10.1002/dmrr.3072] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/20/2018] [Accepted: 08/26/2018] [Indexed: 12/15/2022]
Abstract
Over-nutrition and its late consequences are a dominant theme in medicine today. In addition to the health hazards brought on by over-nutrition, the medical community has recently accumulated a roster of health benefits with obesity, grouped under "obesity paradox." Throughout the world and throughout history until the 20th century, under-nutrition was a dominant evolutionary force. Under-nutrition brings with it a mix of benefits and detriments that are opposite to and continuous with those of over-nutrition. This continuum yields J-shaped or U-shaped curves relating body mass index to mortality. The overweight have an elevated risk of dying in middle age of degenerative diseases while the underweight are at increased risk of premature death from infectious conditions. Micronutrient deficiencies, major concerns of nutritional science in the 20th century, are being neglected. This "hidden hunger" is now surprisingly prevalent in all weight groups, even among the overweight. Because micronutrient replacement is safe, inexpensive, and predictably effective, it is now an exceptionally attractive target for therapy across the spectrum of weight and age. Nutrition-related conditions worthy of special attention from caregivers include excess vitamin A, excess vitamin D, and deficiency of magnesium.
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Affiliation(s)
- Miji Kim
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Anam Basharat
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Ramchandani Santosh
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Syed F Mehdi
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Zanali Razvi
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Sun K Yoo
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Barbara Lowell
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Amrat Kumar
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Wunnie Brima
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, USA
| | - Ann Danoff
- Department of Medicine, Cpl. Michael J Crescenz Veterans Administration Medical Center, Philadelphia, PA, USA
| | - Rachel Dankner
- Department of Epidemiology and Preventive Medicine, School of Public Health, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michael Bergman
- Department of Medicine, Division of Endocrinology, NYU School of Medicine, New York, NY, USA
| | - Valentin A Pavlov
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
- Center for Biomedical Science and Center for Bioelectric Medicine, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Huan Yang
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
- Center for Biomedical Science and Center for Bioelectric Medicine, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Jesse Roth
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, USA
- Center for Biomedical Science and Center for Bioelectric Medicine, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
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Schumacher D, Morgenstern J, Oguchi Y, Volk N, Kopf S, Groener JB, Nawroth PP, Fleming T, Freichel M. Compensatory mechanisms for methylglyoxal detoxification in experimental & clinical diabetes. Mol Metab 2018; 18:143-152. [PMID: 30287091 PMCID: PMC6308908 DOI: 10.1016/j.molmet.2018.09.005] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 09/10/2018] [Accepted: 09/14/2018] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVES The deficit of Glyoxalase I (Glo1) and the subsequent increase in methylglyoxal (MG) has been reported to be one the five mechanisms by which hyperglycemia causes diabetic late complications. Aldo-keto reductases (AKR) have been shown to metabolize MG; however, the relative contribution of this superfamily to the detoxification of MG in vivo, particularly within the diabetic state, remains unknown. METHODS CRISPR/Cas9-mediated genome editing was used to generate a Glo1 knock-out (Glo1-/-) mouse line. Streptozotocin was then applied to investigate metabolic changes under hyperglycemic conditions. RESULTS Glo1-/- mice were viable and showed no elevated MG or MG-H1 levels under hyperglycemic conditions. It was subsequently found that the enzymatic efficiency of various oxidoreductases in the liver and kidney towards MG were increased in the Glo1-/- mice. The functional relevance of this was supported by the altered distribution of alternative detoxification products. Furthermore, it was shown that MG-dependent AKR activity is a potentially clinical relevant pathway in human patients suffering from diabetes. CONCLUSIONS These data suggest that in the absence of GLO1, AKR can effectively compensate to prevent the accumulation of MG. The combination of metabolic, enzymatic, and genetic factors, therefore, may provide a better means of identifying patients who are at risk for the development of late complications caused by elevated levels of MG.
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Affiliation(s)
- Dagmar Schumacher
- Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany
| | - Jakob Morgenstern
- Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Yoko Oguchi
- Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany
| | - Nadine Volk
- Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
| | - Stefan Kopf
- Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jan Benedikt Groener
- Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Peter Paul Nawroth
- Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ), Heidelberg Center for Molecular Biology (ZMBH), Heidelberg, Germany; University Hospital Heidelberg University, Heidelberg, Germany; Germany Institute for Diabetes, Neuherberg, Germany; Cancer IDC Helmholtz Center Munich, Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany
| | - Thomas Fleming
- Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Marc Freichel
- Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany.
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Immunochemical studies on native and glycated LDL – An approach to uncover the structural perturbations. Int J Biol Macromol 2018; 115:287-299. [DOI: 10.1016/j.ijbiomac.2018.04.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 03/20/2018] [Accepted: 04/04/2018] [Indexed: 01/27/2023]
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Zhu X, Cheng YQ, Lu Q, Du L, Yin XX, Liu YW. Enhancement of glyoxalase 1, a polyfunctional defense enzyme, by quercetin in the brain in streptozotocin-induced diabetic rats. Naunyn Schmiedebergs Arch Pharmacol 2018; 391:1237-1245. [DOI: 10.1007/s00210-018-1543-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 07/18/2018] [Indexed: 12/14/2022]
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Study on Tissue Distribution of A Variety of Endogenous Metabolites By Air Flow Assisted Ionization-Ultra High Resolution Mass Spectrometry Imaging. CHINESE JOURNAL OF ANALYTICAL CHEMISTRY 2018. [DOI: 10.1016/s1872-2040(17)61074-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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König A, Vicente Miranda H, Outeiro TF. Alpha-Synuclein Glycation and the Action of Anti-Diabetic Agents in Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2018; 8:33-43. [PMID: 29480231 PMCID: PMC5842785 DOI: 10.3233/jpd-171285] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 01/17/2018] [Indexed: 12/21/2022]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology and variable pathology. While a subset of cases is associated with single-gene mutations, the majority originates from a combination of factors we do not fully understand. Thus, understanding the underlying causes of PD is indispensable for the development of novel therapeutics. Glycation, the non-enzymatic reaction between reactive dicarbonyls and amino groups, gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). AGEs accumulate over a proteins life-time, and increased levels of glycation reaction products play a role in diabetic complications. It is now also becoming evident that PD patients also display perturbed sugar metabolism and protein glycation, including that of alpha-synuclein, a key player in PD. Here, we hypothesize that anti-diabetic drugs targeting the levels of glycation precursors, or promoting the clearance of glycated proteins may also prove beneficial for PD patients.
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Affiliation(s)
- Annekatrin König
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany
| | - Hugo Vicente Miranda
- CEDOC, Chronic Diseases Research Center, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal
| | - Tiago Fleming Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany
- CEDOC, Chronic Diseases Research Center, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal
- Max Planck Institute for Experimental Medicine, Göttingen, Germany
- Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle Upon Tyne, UK
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Xue M, Shafie A, Qaiser T, Rajpoot NM, Kaltsas G, James S, Gopalakrishnan K, Fisk A, Dimitriadis GK, Grammatopoulos DK, Rabbani N, Thornalley PJ, Weickert MO. Glyoxalase 1 copy number variation in patients with well differentiated gastro-entero-pancreatic neuroendocrine tumours (GEP-NET). Oncotarget 2017; 8:76961-76973. [PMID: 29100361 PMCID: PMC5652755 DOI: 10.18632/oncotarget.20290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 06/27/2017] [Indexed: 11/25/2022] Open
Abstract
Background The glyoxalase-1 gene (GLO1) is a hotspot for copy-number variation (CNV) in human genomes. Increased GLO1 copy-number is associated with multidrug resistance in tumour chemotherapy, but prevalence of GLO1 CNV in gastro-entero-pancreatic neuroendocrine tumours (GEP-NET) is unknown. Methods GLO1 copy-number variation was measured in 39 patients with GEP-NET (midgut NET, n = 25; pancreatic NET, n = 14) after curative or debulking surgical treatment. Primary tumour tissue, surrounding healthy tissue and, where applicable, additional metastatic tumour tissue were analysed, using real time qPCR. Progression and survival following surgical treatment were monitored over 4.2 ± 0.5 years. Results In the pooled GEP-NET cohort, GLO1 copy-number in healthy tissue was 2.0 in all samples but significantly increased in primary tumour tissue in 43% of patients with pancreatic NET and in 72% of patients with midgut NET, mainly driven by significantly higher GLO1 copy-number in midgut NET. In tissue from additional metastases resection (18 midgut NET and one pancreatic NET), GLO1 copy number was also increased, compared with healthy tissue; but was not significantly different compared with primary tumour tissue. During mean 3 - 5 years follow-up, 8 patients died and 16 patients showed radiological progression. In midgut NET, a high GLO1 copy-number was associated with earlier progression. In NETs with increased GLO1 copy number, there was increased Glo1 protein expression compared to non-malignant tissue. Conclusions GLO1 copy-number was increased in a large percentage of patients with GEP-NET and correlated positively with increased Glo1 protein in tumour tissue. Analysis of GLO1 copy-number variation particularly in patients with midgut NET could be a novel prognostic marker for tumour progression.
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Affiliation(s)
- Mingzhan Xue
- Division of Translational Medicine, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K
| | - Alaa Shafie
- Division of Translational Medicine, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.,Faculty of Applied Medical Sciences, Taif University, Taif, Kingdom of Saudi Arabia
| | - Talha Qaiser
- Department of Computer Sciences, University of Warwick, Coventry, U.K
| | - Nasir M Rajpoot
- Department of Computer Sciences, University of Warwick, Coventry, U.K
| | - Gregory Kaltsas
- University Hospitals Coventry & Warwickshire NHS Trust, The ARDEN NET Centre, ENETS CoE, Coventry, U.K
| | - Sean James
- University Hospitals Coventry & Warwickshire NHS Trust, The ARDEN NET Centre, ENETS CoE, Coventry, U.K
| | - Kishore Gopalakrishnan
- University Hospitals Coventry & Warwickshire NHS Trust, The ARDEN NET Centre, ENETS CoE, Coventry, U.K
| | - Adrian Fisk
- University Hospitals Coventry & Warwickshire NHS Trust, The ARDEN NET Centre, ENETS CoE, Coventry, U.K
| | - Georgios K Dimitriadis
- Division of Translational Medicine, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.,University Hospitals Coventry & Warwickshire NHS Trust, The ARDEN NET Centre, ENETS CoE, Coventry, U.K.,Coventry University, Centre for Applied Biological & Exercise Sciences, Coventry, U.K
| | - Dimitris K Grammatopoulos
- Division of Translational Medicine, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.,University Hospitals Coventry & Warwickshire NHS Trust, The ARDEN NET Centre, ENETS CoE, Coventry, U.K
| | - Naila Rabbani
- Division of Translational Medicine, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.,Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry, U.K
| | - Paul J Thornalley
- Division of Translational Medicine, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.,Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry, U.K
| | - Martin O Weickert
- Division of Translational Medicine, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.,University Hospitals Coventry & Warwickshire NHS Trust, The ARDEN NET Centre, ENETS CoE, Coventry, U.K.,Coventry University, Centre for Applied Biological & Exercise Sciences, Coventry, U.K
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Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments. Clin Sci (Lond) 2017; 130:1677-96. [PMID: 27555612 DOI: 10.1042/cs20160025] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 06/03/2016] [Indexed: 12/20/2022]
Abstract
Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in aging and disease. It is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites. MG (methylglyoxal) is a dicarbonyl metabolite of relatively high flux of formation and precursor of the most quantitatively and functionally important spontaneous modifications of protein and DNA clinically. Major MG-derived adducts are arginine-derived hydroimidazolones of protein and deoxyguanosine-derived imidazopurinones of DNA. These are formed non-oxidatively. The glyoxalase system provides an efficient and essential basal and stress-response-inducible enzymatic defence against dicarbonyl stress by the reduced glutathione-dependent metabolism of methylglyoxal by glyoxalase 1. The GLO1 gene encoding glyoxalase 1 has low prevalence duplication and high prevalence amplification in some tumours. Dicarbonyl stress contributes to aging, disease and activity of cytotoxic chemotherapeutic agents. It is found at a low, moderate and severe level in obesity, diabetes and renal failure respectively, where it contributes to the development of metabolic and vascular complications. Increased glyoxalase 1 expression confers multidrug resistance to cancer chemotherapy and has relatively high prevalence in liver, lung and breast cancers. Studies of dicarbonyl stress are providing improved understanding of aging and disease and the basis for rational design of novel pharmaceuticals: glyoxalase 1 inducers for obesity, diabetes and cardiovascular disease and glyoxalase 1 inhibitors for multidrug-resistant tumours. The first clinical trial of a glyoxalase 1 inducer in overweight and obese subjects showed improved glycaemic control, insulin resistance and vascular function.
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Guilbaud A, Niquet-Leridon C, Boulanger E, Tessier FJ. How Can Diet Affect the Accumulation of Advanced Glycation End-Products in the Human Body? Foods 2016; 5:foods5040084. [PMID: 28231179 PMCID: PMC5302422 DOI: 10.3390/foods5040084] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 11/29/2016] [Accepted: 11/30/2016] [Indexed: 02/07/2023] Open
Abstract
The accumulation of advanced glycation end products (AGEs) is associated with the complications of diabetes, kidney disease, metabolic disorders and degenerative diseases. It is recognized that the pool of glycation products found in the human body comes not only from an endogenous formation, but also from a dietary exposure to exogenous AGEs. In recent years, the development of pharmacologically-active ingredients aimed at inhibiting endogenous glycation has not been successful. Since the accumulation of AGEs in the human body appears to be progressive throughout life, an early preventive action against glycation could be effective through dietary adjustments or supplementation with purified micronutrients. The present article provides an overview of current dietary strategies tested either in vitro, in vivo or both to reduce the endogenous formation of AGEs and to limit exposure to food AGEs.
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Affiliation(s)
- Axel Guilbaud
- University Lille, Inserm, CHU Lille, U995-LIRIC-Lille Inflammation Research International Center, F-59000 Lille, France.
| | | | - Eric Boulanger
- University Lille, Inserm, CHU Lille, U995-LIRIC-Lille Inflammation Research International Center, F-59000 Lille, France.
| | - Frederic J Tessier
- University Lille, Inserm, CHU Lille, U995-LIRIC-Lille Inflammation Research International Center, F-59000 Lille, France.
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40
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Glyoxalase 1-knockdown in human aortic endothelial cells - effect on the proteome and endothelial function estimates. Sci Rep 2016; 6:37737. [PMID: 27898103 PMCID: PMC5127188 DOI: 10.1038/srep37737] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 11/01/2016] [Indexed: 11/08/2022] Open
Abstract
Methylglyoxal (MG), an arginine-directed glycating agent, is implicated in diabetic late complications. MG is detoxified by glyoxalase 1 (GLO1) of the cytosolic glyoxalase system. The aim was to investigate the effects of MG accumulation by GLO1-knockdown under hyperglycaemic conditions in human aortic endothelial cells (HAECs) hypothesizing that the accumulation of MG accounts for the deleterious effects on vascular function. SiRNA-mediated knockdown of GLO1 was performed and MG concentrations were determined. The impact of MG on the cell proteome and targets of MG glycation was analysed, and confirmed by Western blotting. Markers of endothelial function and apoptosis were assessed. Collagen content was assayed in cell culture supernatant. GLO1-knockdown increased MG concentration in cells and culture medium. This was associated with a differential abundance of cytoskeleton stabilisation proteins, intermediate filaments and proteins involved in posttranslational modification of collagen. An increase in fibrillar collagens 1 and 5 was detected. The extracellular concentration of endothelin-1 was increased following GLO1-knockdown, whereas the phosphorylation and amount of eNOS was not influenced by GLO1-knockdown. The expression of ICAM-1, VCAM-1 and of MCP-1 was elevated and apoptosis was increased. MG accumulation by GLO1-knockdown provoked collagen expression, endothelial inflammation and dysfunction and apoptosis which might contribute to vascular damage.
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41
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Yeh WJ, Yang HY, Pai MH, Wu CH, Chen JR. Long-term administration of advanced glycation end-product stimulates the activation of NLRP3 inflammasome and sparking the development of renal injury. J Nutr Biochem 2016; 39:68-76. [PMID: 27816762 DOI: 10.1016/j.jnutbio.2016.09.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Revised: 06/20/2016] [Accepted: 09/02/2016] [Indexed: 01/13/2023]
Abstract
The accumulation of advanced glycation end-products (AGEs) and the enhanced interaction of AGE with their cellular receptor (RAGE) have been implicated in the progression of chronic kidney disease. The purpose of this study was to examine whether the AGE/RAGE-induced nephrotoxic effects are associated with inflammasome activation and endothelial dysfunction. Chronic renal injury was examined in BALB/c mice by the long-term administration of carbonyl-AGE for 16 weeks. Endothelial dysfunction was detected by measuring the number of circulating endothelial progenitor cells (EPCs) and the levels of nitric oxide synthase (eNOS) and nitric oxide (NO) in kidneys. Results showed that administration of methylglyoxal-bovine serum albumin (MG-BSA) AGE accelerated renal MG, carboxyethyl lysine, carboxymethyl lysine and malondialdehyde formation and, in parallel, the levels of serum creatinine and blood urea nitrogen (BUN) were significantly increased. Expression of RAGE and NLRP3 inflammasome-related proteins (TXNIP, NLRP3, procaspase-1 and caspase-1) and IL (interleukin)-1β secretion were upregulated, whereas the levels of EPCs, eNOS and NO were lower in MG-BSA-treated mice. This induction by MG-BSA was significantly inhibited by RAGE antagonist. Our results firstly reveal a possible mechanism of AGE-mediated renal dysfunction upon NLRP3 inflammasome activation. Therapeutic blockade of RAGE may ameliorate renal and endothelial functions in subjects under high AGE burden.
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Affiliation(s)
- Wan-Ju Yeh
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan
| | - Hsin-Yi Yang
- Department of Nutrition, I-Shou University, Kaohsiung, Taiwan
| | - Man-Hui Pai
- Department of Anatomy and Cell Biology, School of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chi-Hao Wu
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan
| | - Jiun-Rong Chen
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan; Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
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42
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Sadowska-Bartosz I, Bartosz G. Effect of glycation inhibitors on aging and age-related diseases. Mech Ageing Dev 2016; 160:1-18. [PMID: 27671971 DOI: 10.1016/j.mad.2016.09.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 06/30/2016] [Accepted: 09/21/2016] [Indexed: 02/07/2023]
Abstract
Vast evidence supports the view that glycation of proteins is one of the main factors contributing to aging and is an important element of etiopathology of age-related diseases, especially type 2 diabetes mellitus, cataract and neurodegenerative diseases. Counteracting glycation can therefore be a means of increasing both the lifespan and healthspan. In this review, accumulation of glycation products during aging is presented, pathophysiological effects of glycation are discussed and ways of attenuation of the effects of glycation are described, concentrating on prevention of glycation. The effects of glycation and glycation inhibitors on the course of selected age-related diseases, such as Alzheimer's disease, Parkinson's disease and cataract are also reviewed.
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Affiliation(s)
- Izabela Sadowska-Bartosz
- Department of Biochemistry and Cell Biology, Faculty of Biology and Agriculture, University of Rzeszow, Zelwerowicza St. 4, 35-604 Rzeszów, Poland.
| | - Grzegorz Bartosz
- Department of Biochemistry and Cell Biology, Faculty of Biology and Agriculture, University of Rzeszow, Zelwerowicza St. 4, 35-604 Rzeszów, Poland; Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
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Tessier FJ, Niquet-Léridon C, Jacolot P, Jouquand C, Genin M, Schmidt AM, Grossin N, Boulanger E. Quantitative assessment of organ distribution of dietary protein-bound 13 C-labeled N ɛ -carboxymethyllysine after a chronic oral exposure in mice. Mol Nutr Food Res 2016; 60:2446-2456. [PMID: 27393741 DOI: 10.1002/mnfr.201600140] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 06/15/2016] [Accepted: 06/17/2016] [Indexed: 12/28/2022]
Abstract
SCOPE Nɛ -Carboxymethyl-lysine (CML) is a prominent advanced glycation end-product which is not only found in vivo but also in food. It is known that a percentage of the dietary CML (dCML) is absorbed into the circulation and only partly excreted in the urine. Several studies have tried to measure how much dCML remains in tissues. However obstacles to interpreting the data have been found. METHODS AND RESULTS A new protocol which discriminates dCML from native CML (nCML) has been developed. Three CML isotopes with different mass-to-charge ratios were used: nCML Nε -carboxymethyl-L-lysine, dCML Nε -[13 C]carboxy[13 C]methyl-L-lysine and internal standard Nε -carboxymethyl-L-[4,4,5,5-2 H4 ]lysine. Wild-type (n = 7) and RAGE-/- (n = 8) mice were fed for 30 days with either a control, or a BSA-bound dCML-enriched diet. Organs were analyzed for nCML and dCML using liquid chromatography-tandem mass spectrometry. Mice exposed to dCML showed an accumulation in all tissues tested except fat. The rate of deposition was high (81-320 μgdCML /g dry matter) in kidneys, intestine, and lungs and low (<5 μg/g) in heart, muscle, and liver. This accumulation was not RAGE dependent. CONCLUSION The kidney is not the only organ affected by the accumulation of dCML. Its high accumulation in other tissues and organs may also, however, have important physiological consequences.
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Affiliation(s)
- Frédéric J Tessier
- Univ. Lille, Inserm, CHU Lille, U995 - LIRIC - Lille Inflammation Research International Center, Lille, France.,Institut Polytechnique LaSalle Beauvais, EGEAL Unit, Beauvais, France
| | | | - Philippe Jacolot
- Institut Polytechnique LaSalle Beauvais, EGEAL Unit, Beauvais, France
| | - Céline Jouquand
- Institut Polytechnique LaSalle Beauvais, EGEAL Unit, Beauvais, France
| | - Michaël Genin
- Univ. Lille, EA 2694-Santé publique: épidémiologie et qualité des soins, Lille, France
| | - Ann-Marie Schmidt
- Diabetes Research Center, Department of Medicine, NYU Langone Medical Center, New York, NY, USA
| | - Nicolas Grossin
- Univ. Lille, Inserm, CHU Lille, U995 - LIRIC - Lille Inflammation Research International Center, Lille, France
| | - Eric Boulanger
- Univ. Lille, Inserm, CHU Lille, U995 - LIRIC - Lille Inflammation Research International Center, Lille, France
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Rabbani N, Xue M, Thornalley PJ. Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics. Glycoconj J 2016; 33:513-25. [PMID: 27406712 PMCID: PMC4975768 DOI: 10.1007/s10719-016-9705-z] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 06/06/2016] [Accepted: 06/09/2016] [Indexed: 12/15/2022]
Abstract
The reactive dicarbonyl metabolite methylglyoxal (MG) is the precursor of the major quantitative advanced glycation endproducts (AGEs) in physiological systems - arginine-derived hydroimidazolones and deoxyguanosine-derived imidazopurinones. The glyoxalase system in the cytoplasm of cells provides the primary defence against dicarbonyl glycation by catalysing the metabolism of MG and related reactive dicarbonyls. Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in ageing and disease. It is produced endogenously by increased formation and/or decreased metabolism of dicarbonyl metabolites. Dicarbonyl stress contributes to ageing, disease and activity of cytotoxic chemotherapeutic agents. It contributes to ageing through age-related decline in glyoxalase 1 (Glo-1) activity. Glo-1 has a dual role in cancer as a tumour suppressor protein prior to tumour development and mediator of multi-drug resistance in cancer treatment, implicating dicarbonyl glycation of DNA in carcinogenesis and dicarbonyl-driven cytotoxicity in mechanism of action of anticancer drugs. Glo-1 is a driver of cardiovascular disease, likely through dicarbonyl stress-driven dyslipidemia and vascular cell dysfunction. Dicarbonyl stress is also a contributing mediator of obesity and vascular complications of diabetes. There are also emerging roles in neurological disorders. Glo-1 responds to dicarbonyl stress to enhance cytoprotection at the transcriptional level through stress-responsive increase of Glo-1 expression. Small molecule Glo-1 inducers are in clinical development for improved metabolic, vascular and renal health and Glo-1 inhibitors in preclinical development for multidrug resistant cancer chemotherapy.
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Affiliation(s)
- Naila Rabbani
- Warwick Systems Biology Centre, Coventry House, University of Warwick, Coventry, CV4 7AL, UK
| | - Mingzhan Xue
- Glyoxalase Research Group, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, CV2 2DX, UK
| | - Paul J Thornalley
- Warwick Systems Biology Centre, Coventry House, University of Warwick, Coventry, CV4 7AL, UK.
- Glyoxalase Research Group, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, CV2 2DX, UK.
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Rabbani N, Ashour A, Thornalley PJ. Mass spectrometric determination of early and advanced glycation in biology. Glycoconj J 2016; 33:553-68. [PMID: 27438287 PMCID: PMC4975772 DOI: 10.1007/s10719-016-9709-8] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 05/27/2016] [Accepted: 06/22/2016] [Indexed: 01/30/2023]
Abstract
Protein glycation in biological systems occurs predominantly on lysine, arginine and N-terminal residues of proteins. Major quantitative glycation adducts are found at mean extents of modification of 1-5 mol percent of proteins. These are glucose-derived fructosamine on lysine and N-terminal residues of proteins, methylglyoxal-derived hydroimidazolone on arginine residues and N(ε)-carboxymethyl-lysine residues mainly formed by the oxidative degradation of fructosamine. Total glycation adducts of different types are quantified by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring mode. Metabolism of glycated proteins is followed by LC-MS/MS of glycation free adducts as minor components of the amino acid metabolome. Glycated proteins and sites of modification within them - amino acid residues modified by the glycating agent moiety - are identified and quantified by label-free and stable isotope labelling with amino acids in cell culture (SILAC) high resolution mass spectrometry. Sites of glycation by glucose and methylglyoxal in selected proteins are listed. Key issues in applying proteomics techniques to analysis of glycated proteins are: (i) avoiding compromise of analysis by formation, loss and relocation of glycation adducts in pre-analytic processing; (ii) specificity of immunoaffinity enrichment procedures, (iii) maximizing protein sequence coverage in mass spectrometric analysis for detection of glycation sites, and (iv) development of bioinformatics tools for prediction of protein glycation sites. Protein glycation studies have important applications in biology, ageing and translational medicine - particularly on studies of obesity, diabetes, cardiovascular disease, renal failure, neurological disorders and cancer. Mass spectrometric analysis of glycated proteins has yet to find widespread use clinically. Future use in health screening, disease diagnosis and therapeutic monitoring, and drug and functional food development is expected. A protocol for high resolution mass spectrometry proteomics of glycated proteins is given.
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Affiliation(s)
- Naila Rabbani
- Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry, CV4 7AL, UK.
| | - Amal Ashour
- Clinical Sciences Research Laboratories, Warwick Medical School, University Hospital, University of Warwick, Coventry, CV2 2DX, UK
| | - Paul J Thornalley
- Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry, CV4 7AL, UK
- Clinical Sciences Research Laboratories, Warwick Medical School, University Hospital, University of Warwick, Coventry, CV2 2DX, UK
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Role of Glucose Derived Reactive Metabolites in Diabetic Nephropathy. Indian J Clin Biochem 2015. [DOI: 10.1007/s12291-015-0486-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Hansen F, Battú CE, Dutra MF, Galland F, Lirio F, Broetto N, Nardin P, Gonçalves CA. Methylglyoxal and carboxyethyllysine reduce glutamate uptake and S100B secretion in the hippocampus independently of RAGE activation. Amino Acids 2015; 48:375-85. [PMID: 26347375 DOI: 10.1007/s00726-015-2091-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 08/28/2015] [Indexed: 01/29/2023]
Abstract
Diabetes is a metabolic disease characterized by high fasting-glucose levels. Diabetic complications have been associated with hyperglycemia and high levels of reactive compounds, such as methylglyoxal (MG) and advanced glycation endproducts (AGEs) formation derived from glucose. Diabetic patients have a higher risk of developing neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. Herein, we examined the effect of high glucose, MG and carboxyethyllysine (CEL), a MG-derived AGE of lysine, on oxidative, metabolic and astrocyte-specific parameters in acute hippocampal slices, and investigated some of the mechanisms that could mediate these effects. Glucose, MG and CEL did not alter reactive oxygen species (ROS) formation, glucose uptake or glutamine synthetase activity. However, glutamate uptake and S100B secretion were decreased after MG and CEL exposure. RAGE activation and glycation reactions, examined by aminoguanidine and L-lysine co-incubation, did not mediate these changes. Acute MG and CEL exposure, but not glucose, were able to induce similar effects on hippocampal slices, suggesting that conditions of high glucose concentrations are primarily toxic by elevating the rates of these glycation compounds, such as MG, and by generation of protein cross-links. Alterations in the secretion of S100B and the glutamatergic activity mediated by MG and AGEs can contribute to the brain dysfunction observed in diabetic patients.
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Affiliation(s)
- Fernanda Hansen
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Cíntia Eickhoff Battú
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Márcio Ferreira Dutra
- Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Trindade, Florianópolis, SC, 88040-970, Brazil
| | - Fabiana Galland
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Franciane Lirio
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Núbia Broetto
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, 90046-900, Brazil
| | - Patrícia Nardin
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Carlos-Alberto Gonçalves
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
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Chen SJ, Aikawa C, Yoshida R, Matsui T. Methylglyoxal-derived hydroimidazolone residue of plasma protein can behave as a predictor of prediabetes in Spontaneously Diabetic Torii rats. Physiol Rep 2015; 3:3/8/e12477. [PMID: 26265747 PMCID: PMC4562563 DOI: 10.14814/phy2.12477] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Prediabetes, typically defined as impaired glucose tolerance and/or impaired fasting blood glucose, is a high-risk state of developing diabetes. The association of diabetes-related metabolites with prediabetes has not been investigated intensively. This study aimed to get insights into the metabolic behaviors of some typical diabetes-related metabolites in plasma of male Spontaneously Diabetic Torii (SDT) rats during pathogenic progress of diabetes and to assess in vivo if the variation in these metabolites related to the progression of prediabetic stage. To address this question, SDT rats and Sprague Dawley (SD) rats as control were maintained from the age of 7 to 25 weeks. Five typical advanced glycation end products (AGEs) residue of plasma protein and their free adducts were determined by liquid chromatography with tandem mass detection over the duration of the investigation. The SDT rats exhibited impaired glucose tolerance since the age of 12 weeks and developed diabetes with significantly elevated fasting glucose levels after 22 weeks. At the prediabetic stage (12–21 weeks), no significant differences were observed on AGE-free adducts levels of SDT rats compared with SD rats. However, methylglyoxal-derived hydroimidazolone (MG-H1) residue contents of plasma protein were significantly elevated in SDT rats at the age of 16 weeks, whereas other AGE residues of plasma protein did not show marked difference. The present study has revealed significant increase in MG-H1 residue content of plasma protein at the prediabetic stage of a spontaneously diabetic rat model, irrespective of unaltered fasting blood glucose and constant plasma levels of other AGEs.
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Affiliation(s)
- Si Jing Chen
- Division of Bioscience and Bioenvironmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, Japan
| | - Chiwa Aikawa
- Division of Bioscience and Bioenvironmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, Japan
| | - Risa Yoshida
- Division of Bioscience and Bioenvironmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, Japan
| | - Toshiro Matsui
- Division of Bioscience and Bioenvironmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, Japan
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Abstract
Glyoxalase- and methylglyoxal-related research has required the development of quantitative and reliable techniques for the measurement of methylglyoxal-derived glycation adducts of protein and DNA. There are also other glycation adducts, oxidation adducts and nitration adducts of proteins and oxidation adducts of DNA. Proteolysis of protein releases glycation, oxidation and nitration free adducts (glycated, oxidized and nitrated amino acids) in plasma and nuclease digestion of DNA releases glycated and oxidized nucleosides into plasma and other body fluids for excretion in urine. The gold standard method for quantifying these adducts is stable isotopic dilution analysis LC-MS/MS. Protein and DNA adduct residues are determined by assay of enzymatic hydrolysates of protein and DNA extracts prepared using cocktails of proteases and nucleases respectively. Free adducts are determined by analysis of ultrafiltrates of plasma, urine and other physiological fluids. Protein damage markers (13 glycation adducts, five oxidation adducts and 3-nitrotyrosine) and DNA damage markers (three glycation adducts and one oxidation adduct) are quantified using 25 μg of protein, 10 μg of DNA or 5 μl of physiological fluid. Protein and nucleotide AGE (advanced glycation end-product) assay protocols resistant to interferences is described.
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Abstract
Methylglyoxal is a potent protein-glycating agent. It is an arginine-directed glycating agent and often modifies functionally important sites in proteins. Glycation forms mainly MG-H1 [Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine] residues. MG-H1 content of proteins is quantified by stable isotopic dilution analysis-MS/MS and also by immunoblotting with specific monoclonal antibodies. Methylglyoxal-modified proteins undergo cellular proteolysis and release MG-H1 free adduct for excretion. MG-H1 residues have been found in proteins of animals, plants, bacteria, fungi and protoctista. MG-H1 is often the major advanced glycation end-product in proteins of tissues and body fluids, increasing in diabetes and associated vascular complications, renal failure, cirrhosis, Alzheimer's disease, arthritis, Parkinson's disease and aging. Proteins susceptible to methylglyoxal modification with related functional impairment are called the DCP (dicarbonyl proteome). The DCP includes albumin, haemoglobin, transcription factors, mitochondrial proteins, extracellular matrix proteins, lens crystallins and others. DCP component proteins are linked to mitochondrial dysfunction in diabetes and aging, oxidative stress, dyslipidaemia, cell detachment and anoikis and apoptosis. Methylglyoxal also modifies DNA where deoxyguanosine residues are modified to imidazopurinone MGdG {3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one} isomers. MGdG was the major quantitative adduct detected in vivo. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell-permeant glyoxalase I inhibitor. Glyoxalase I metabolizes >99% methylglyoxal and thereby protects the proteome and genome. Gene deletion of GLO1 is embryonically lethal and GLO1 silencing increases methylglyoxal concentration, MG-H1 and MGdG, premature aging and disease. Studies of methylglyoxal glycation have importance for human health, longevity and treatment of disease.
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