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Liang X, Chen H, Zhang R, Xu Z, Zhang G, Xu C, Li Y, Zhang L, Xu FJ. Herbal micelles-loaded ROS-responsive hydrogel with immunomodulation and microenvironment reconstruction for diabetic wound healing. Biomaterials 2025; 317:123076. [PMID: 39805188 DOI: 10.1016/j.biomaterials.2024.123076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/22/2024] [Accepted: 12/30/2024] [Indexed: 01/16/2025]
Abstract
Persistent inflammation is a major cause of diabetic wounds that are difficult to heal. This is manifested in diabetic wounds with excessive reactive oxygen clusters (ROS), advanced glycation end products (AGE) and other inflammatory factors, and difficulty in polarizing macrophages toward inhibiting inflammation. Berberine is a natural plant molecule that inhibits inflammation; however, its low solubility limits its biological function through cytosis. In this study, we designed F127 micelles to encapsulate berberine with the aim of improving its solubility and bioavailability. Meanwhile, in order to achieve effective drug delivery at the wound site, we designed an injectable ferrocene-cyclodextrin self-assembled oxidation-reactive supramolecular hydrogel drug delivery system. Cellular experiments have shown that the hydrogel can reduce intracellular ROS and AGE production, attenuate cellular damage, promote macrophage polarization toward inhibition of inflammation, and reduce the secretion of inflammatory factors. In an animal model of diabetic mice, this hydrogel dressing reduces the level of inflammation in diabetic wounds, optimizes collagen deposition in diabetic wounds, and ultimately achieves high-quality diabetic wound healing. The work offers a straightforward and effective solution to the challenge of administering hydrophobic anti-inflammatory agents in the context of diabetic wound therapy.
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Affiliation(s)
- Xiaoyang Liang
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Honggui Chen
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Rui Zhang
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Zhixuan Xu
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Guo Zhang
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Chen Xu
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Yang Li
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China.
| | - Lei Zhang
- Department of Vascular Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Fu-Jian Xu
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China.
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Thorne CA, Grey AC, Lim JC, Donaldson PJ. The Synergistic Effects of Polyol Pathway-Induced Oxidative and Osmotic Stress in the Aetiology of Diabetic Cataracts. Int J Mol Sci 2024; 25:9042. [PMID: 39201727 PMCID: PMC11354722 DOI: 10.3390/ijms25169042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/13/2024] [Accepted: 08/16/2024] [Indexed: 09/03/2024] Open
Abstract
Cataracts are the world's leading cause of blindness, and diabetes is the second leading risk factor for cataracts after old age. Despite this, no preventative treatment exists for cataracts. The altered metabolism of excess glucose during hyperglycaemia is known to be the underlying cause of diabetic cataractogenesis, resulting in localised disruptions to fibre cell morphology and cell swelling in the outer cortex of the lens. In rat models of diabetic cataracts, this damage has been shown to result from osmotic stress and oxidative stress due to the accumulation of intracellular sorbitol, the depletion of NADPH which is used to regenerate glutathione, and the generation of fructose metabolites via the polyol pathway. However, differences in lens physiology and the metabolism of glucose in the lenses of different species have prevented the translation of successful treatments in animal models into effective treatments in humans. Here, we review the stresses that arise from hyperglycaemic glucose metabolism and link these to the regionally distinct metabolic and physiological adaptations in the lens that are vulnerable to these stressors, highlighting the evidence that chronic oxidative stress together with osmotic stress underlies the aetiology of human diabetic cortical cataracts. With this information, we also highlight fundamental gaps in the knowledge that could help to inform new avenues of research if effective anti-diabetic cataract therapies are to be developed in the future.
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Affiliation(s)
- Courtney A. Thorne
- Department of Physiology, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand; (C.A.T.); (A.C.G.); (P.J.D.)
- New Zealand National Eye Centre, University of Auckland, Auckland 1023, New Zealand
| | - Angus C. Grey
- Department of Physiology, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand; (C.A.T.); (A.C.G.); (P.J.D.)
- New Zealand National Eye Centre, University of Auckland, Auckland 1023, New Zealand
| | - Julie C. Lim
- Department of Physiology, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand; (C.A.T.); (A.C.G.); (P.J.D.)
- New Zealand National Eye Centre, University of Auckland, Auckland 1023, New Zealand
| | - Paul J. Donaldson
- Department of Physiology, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand; (C.A.T.); (A.C.G.); (P.J.D.)
- New Zealand National Eye Centre, University of Auckland, Auckland 1023, New Zealand
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Shen CY, Lu CH, Cheng CF, Li KJ, Kuo YM, Wu CH, Liu CH, Hsieh SC, Tsai CY, Yu CL. Advanced Glycation End-Products Acting as Immunomodulators for Chronic Inflammation, Inflammaging and Carcinogenesis in Patients with Diabetes and Immune-Related Diseases. Biomedicines 2024; 12:1699. [PMID: 39200164 PMCID: PMC11352041 DOI: 10.3390/biomedicines12081699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/22/2024] [Accepted: 07/27/2024] [Indexed: 09/02/2024] Open
Abstract
Increased production of advanced glycation end products (AGEs) among reducing sugars (glucose, fructose, galactose, or ribose) and amino acids/proteins via non-enzymatic Maillard reaction can be found in lifestyle-related disease (LSRD), metabolic syndrome (MetS), and obesity and immune-related diseases. Increased serum levels of AGEs may induce aging, diabetic complications, cardiovascular diseases (CVD), neurodegenerative diseases (NDD), cancer, and inflamm-aging (inflammation with immunosenescence). The Maillard reaction can also occur among reducing sugars and lipoproteins or DNAs to alter their structure and induce immunogenicity/genotoxicity for carcinogenesis. AGEs, as danger-associated molecular pattern molecules (DAMPs), operate via binding to receptor for AGE (RAGE) or other scavenger receptors on cell surface to activate PI3K-Akt-, P38-MAPK-, ERK1/2-JNK-, and MyD88-induced NF-κB signaling pathways to mediate various pathological effects. Recently, the concept of "inflamm-aging" became more defined, and we have unveiled some interesting findings in relation to it. The purpose of the present review is to dissect the potential molecular basis of inflamm-aging in patients with diabetes and immune-mediated diseases caused by different AGEs.
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Affiliation(s)
- Chieh-Yu Shen
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
| | - Cheng-Hsun Lu
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
- Institute of Clinical Medicine, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan
| | - Chiao-Feng Cheng
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
- Institute of Clinical Medicine, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan
| | - Ko-Jen Li
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
| | - Yu-Min Kuo
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
| | - Cheng-Han Wu
- Department of Internal Medicine, National Taiwan University Hospital-Hsinchu Branch, # 2, Section 1, Shengyi Road, Hsinchu County 302058, Taiwan;
| | - Chin-Hsiu Liu
- Department of Internal Medicine, National Taiwan University Hospital-Yunlin Branch, # 579, Section 2, Yunlin Road, Yunlin County 640203, Taiwan;
| | - Song-Chou Hsieh
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
| | - Chang-Youh Tsai
- Department of Internal Medicine, Fu-Jen Catholic University Hospital, College of Medicine, Fu-Jen Catholic University, # 69 Guizi Road, New Taipei City 24352, Taiwan
| | - Chia-Li Yu
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
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McIntyre CW. Update on Hemodialysis-Induced Multiorgan Ischemia: Brains and Beyond. J Am Soc Nephrol 2024; 35:653-664. [PMID: 38273436 PMCID: PMC11149050 DOI: 10.1681/asn.0000000000000299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 12/17/2023] [Indexed: 01/27/2024] Open
Abstract
Hemodialysis is a life-saving treatment for patients with kidney failure. However, patients requiring hemodialysis have a 10-20 times higher risk of cardiovascular morbidity and mortality than that of the general population. Patients encounter complications such as episodic intradialytic hypotension, abnormal perfusion to critical organs (heart, brain, liver, and kidney), and damage to vulnerable vascular beds. Recurrent conventional hemodialysis exposes patients to multiple episodes of circulatory stress, exacerbating and being aggravated by microvascular endothelial dysfunction. This promulgates progressive injury that leads to irreversible multiorgan injury and the well-documented higher incidence of cardiovascular disease and premature death. This review aims to examine the underlying pathophysiology of hemodialysis-related vascular injury and consider a range of therapeutic approaches to improving outcomes set within this evolved rubric..
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Affiliation(s)
- Christopher W McIntyre
- Lilibeth Caberto Kidney Clinical Research Unit, Lawson Health Research Institute, London, Ontario, Canada, and Departments of Medicine, Medical Biophysics and Pediatrics, Western University, London, Ontario, Canada
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Uceda AB, Mariño L, Casasnovas R, Adrover M. An overview on glycation: molecular mechanisms, impact on proteins, pathogenesis, and inhibition. Biophys Rev 2024; 16:189-218. [PMID: 38737201 PMCID: PMC11078917 DOI: 10.1007/s12551-024-01188-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2024] [Indexed: 05/14/2024] Open
Abstract
The formation of a heterogeneous set of advanced glycation end products (AGEs) is the final outcome of a non-enzymatic process that occurs in vivo on long-life biomolecules. This process, known as glycation, starts with the reaction between reducing sugars, or their autoxidation products, with the amino groups of proteins, DNA, or lipids, thus gaining relevance under hyperglycemic conditions. Once AGEs are formed, they might affect the biological function of the biomacromolecule and, therefore, induce the development of pathophysiological events. In fact, the accumulation of AGEs has been pointed as a triggering factor of obesity, diabetes-related diseases, coronary artery disease, neurological disorders, or chronic renal failure, among others. Given the deleterious consequences of glycation, evolution has designed endogenous mechanisms to undo glycation or to prevent it. In addition, many exogenous molecules have also emerged as powerful glycation inhibitors. This review aims to provide an overview on what glycation is. It starts by explaining the similarities and differences between glycation and glycosylation. Then, it describes in detail the molecular mechanism underlying glycation reactions, and the bio-molecular targets with higher propensity to be glycated. Next, it discusses the precise effects of glycation on protein structure, function, and aggregation, and how computational chemistry has provided insights on these aspects. Finally, it reports the most prevalent diseases induced by glycation, and the endogenous mechanisms and the current therapeutic interventions against it.
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Affiliation(s)
- Ana Belén Uceda
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| | - Laura Mariño
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| | - Rodrigo Casasnovas
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| | - Miquel Adrover
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
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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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Dewidar B, Mastrototaro L, Englisch C, Ress C, Granata C, Rohbeck E, Pesta D, Heilmann G, Wolkersdorfer M, Esposito I, Reina Do Fundo M, Zivehe F, Yavas A, Roden M. Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseases. EBioMedicine 2023; 94:104714. [PMID: 37454552 PMCID: PMC10384226 DOI: 10.1016/j.ebiom.2023.104714] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 06/30/2023] [Accepted: 06/30/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Disturbed hepatic energy metabolism contributes to non-alcoholic fatty liver (NAFLD), but the development of changes over time and obesity- or diabetes-related mechanisms remained unclear. METHODS Two-day old male C57BL/6j mice received streptozotocin (STZ) or placebo (PLC) and then high-fat (HFD) or regular chow diet (RCD) from week 4 (W4) to either W8 or W16, yielding control [CTRL = PLC + RCD], diabetes [DIAB = STZ + RCD], obesity [OBES = PLC + HFD] and diabetes-related non-alcoholic steatohepatitis [NASH = STZ + HFD] models. Mitochondrial respiration was measured by high-resolution respirometry and insulin-sensitive glucose metabolism by hyperinsulinemic-euglycemic clamps with stable isotope dilution. FINDINGS NASH showed higher steatosis and NAFLD activity already at W8 and liver fibrosis at W16 (all p < 0.01 vs CTRL). Ballooning was increased in DIAB and NASH at W16 (p < 0.01 vs CTRL). At W16, insulin sensitivity was 47%, 58% and 75% lower in DIAB, NASH and OBES (p < 0.001 vs CTRL). Hepatic uncoupled fatty acid oxidation (FAO)-associated respiration was reduced in OBES at W8, but doubled in DIAB and NASH at W16 (p < 0.01 vs CTRL) and correlated with biomarkers of unfolded protein response (UPR), oxidative stress and hepatic expression of certain enzymes (acetyl-CoA carboxylase 2, Acc2; carnitine palmitoyltransferase I, Cpt1a). Tricarboxylic acid cycle (TCA)-driven respiration was lower in OBES at W8 and doubled in DIAB at W16 (p < 0.0001 vs CTRL), which positively correlated with expression of genes related to lipolysis. INTERPRETATION Hepatic mitochondria adapt to various metabolic challenges with increasing FAO-driven respiration, which is linked to dysfunctional UPR, systemic oxidative stress, insulin resistance and altered lipid metabolism. In a diabetes model, higher TCA-linked respiration reflected mitochondrial adaptation to greater hepatic lipid turnover. FUNDING Funding bodies that contributed to this study were listed in the acknowledgements section.
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Affiliation(s)
- Bedair Dewidar
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Lucia Mastrototaro
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Cornelia Englisch
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Claudia Ress
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Christian Doppler Laboratory for Insulin Resistance, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Cesare Granata
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Elisabeth Rohbeck
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Dominik Pesta
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Geronimo Heilmann
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Martin Wolkersdorfer
- Landesapotheke Salzburg, Department of Production, Hospital Pharmacy, Salzburg, Austria
| | - Irene Esposito
- Institute of Pathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Michelle Reina Do Fundo
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Fariba Zivehe
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Aslihan Yavas
- Institute of Pathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
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8
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Zgutka K, Tkacz M, Tomasiak P, Tarnowski M. A Role for Advanced Glycation End Products in Molecular Ageing. Int J Mol Sci 2023; 24:9881. [PMID: 37373042 PMCID: PMC10298716 DOI: 10.3390/ijms24129881] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Ageing is a composite process that involves numerous changes at the cellular, tissue, organ and whole-body levels. These changes result in decreased functioning of the organism and the development of certain conditions, which ultimately lead to an increased risk of death. Advanced glycation end products (AGEs) are a family of compounds with a diverse chemical nature. They are the products of non-enzymatic reactions between reducing sugars and proteins, lipids or nucleic acids and are synthesised in high amounts in both physiological and pathological conditions. Accumulation of these molecules increases the level of damage to tissue/organs structures (immune elements, connective tissue, brain, pancreatic beta cells, nephrons, and muscles), which consequently triggers the development of age-related diseases, such as diabetes mellitus, neurodegeneration, and cardiovascular and kidney disorders. Irrespective of the role of AGEs in the initiation or progression of chronic disorders, a reduction in their levels would certainly provide health benefits. In this review, we provide an overview of the role of AGEs in these areas. Moreover, we provide examples of lifestyle interventions, such as caloric restriction or physical activities, that may modulate AGE formation and accumulation and help to promote healthy ageing.
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Affiliation(s)
- Katarzyna Zgutka
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, Żołnierska 54, 70-210 Szczecin, Poland
| | - Marta Tkacz
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, Żołnierska 54, 70-210 Szczecin, Poland
| | - Patrycja Tomasiak
- Institute of Physical Culture Sciences, University of Szczecin, 70-453 Szczecin, Poland
| | - Maciej Tarnowski
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, Żołnierska 54, 70-210 Szczecin, Poland
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Reynaert NL, Vanfleteren LEGW, Perkins TN. The AGE-RAGE Axis and the Pathophysiology of Multimorbidity in COPD. J Clin Med 2023; 12:jcm12103366. [PMID: 37240472 DOI: 10.3390/jcm12103366] [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: 02/02/2023] [Revised: 04/24/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review.
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Affiliation(s)
- Niki L Reynaert
- Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
| | - Lowie E G W Vanfleteren
- COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
| | - Timothy N Perkins
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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10
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Curukoglu A, Gungor GCA, Akan G, Kukner A, Ogutcu G, Kalayci M, Temizel M, Ozgencil FE. The effect of cold atmospheric plasma (NO) alone and in combination with NPH insulin on the full-thickness excisional wound healing in a diabetic rat model. VET MED-CZECH 2023; 68:152-163. [PMID: 37982089 PMCID: PMC10581533 DOI: 10.17221/109/2022-vetmed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/22/2023] [Indexed: 11/21/2023] Open
Abstract
This study was planned to investigate an alternative treatment modality in diabetic wound healing. In this experimental study, the efficacy of both cold atmospheric plasma/nitric oxide (NO) and NPH insulin ointment, recently known to have beneficial effects on wound healing, was investigated in diabetic wound healing. Twenty-four (24) diabetic rats were divided into four groups DC, DI, DNO and DINO (diabetic control, diabetic insulin, diabetic nitric oxide, diabetic insulin + nitric oxide groups). No treatment was applied to the DC group, NPH insulin was applied to the DI group, CAP/NO was applied to the DNO group, and CAP/NO + NPH insulin was applied to the DINO group once daily for 14 days. The wound area reduction and the wound contraction rate were calculated on the basis of the tissue sections taken, and histopathological and genetic analyses were carried out. Compared to the control group, exogenous NO gas was found to be a potent antibacterial agent in the diabetic wound healing, causing a reduction in the wound area (P = 0.034), an increased contraction rate (P = 0.021), epithelialisation (P = 0.02), collagen organisation (P = 0.006) and a reduction in the number of inflammatory cells (P = 0.002). A significant increase in the expression of IL-8 mRNA was observed (P = 0.026). It was concluded that NPH insulin alone contributes to wound healing, but it is not necessary to use it together with exogenous NO gas.
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Affiliation(s)
- Ali Curukoglu
- Surgery Department, Faculty of Veterinary Medicine, Near East University, Yakin Dogu St, Nicosia, Mersin, Turkiye
| | - Gul Ciray Akbas Gungor
- Surgery Department, Faculty of Veterinary Medicine, Near East University, Yakin Dogu St, Nicosia, Mersin, Turkiye
| | - Gokce Akan
- DESAM Institute, Near East University, Yakin Dogu St, Nicosia, Mersin, Turkiye
| | - Aysel Kukner
- Histology Department, Faculty of Medicine, Near East University, Yakin Dogu St, Nicosia, Mersin, Turkiye
| | - Gozde Ogutcu
- Histology Department, Faculty of Medicine, Near East University, Yakin Dogu St, Nicosia, Mersin, Turkiye
| | - Melis Kalayci
- DESAM Institute, Near East University, Yakin Dogu St, Nicosia, Mersin, Turkiye
| | - Meliha Temizel
- Experimental Animal Research Center, Faculty of Veterinary Medicine, Near East University, Yakin Dogu St, Nicosia, Mersin, Turkiye
| | - Fatma Eser Ozgencil
- Surgery Department, Faculty of Veterinary Medicine, Near East University, Yakin Dogu St, Nicosia, Mersin, Turkiye
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11
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Zhang S, Ge G, Qin Y, Li W, Dong J, Mei J, Ma R, Zhang X, Bai J, Zhu C, Zhang W, Geng D. Recent advances in responsive hydrogels for diabetic wound healing. Mater Today Bio 2022; 18:100508. [PMID: 36504542 PMCID: PMC9729074 DOI: 10.1016/j.mtbio.2022.100508] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/26/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022]
Abstract
Poor wound healing after diabetes mellitus remains a challenging problem, and its pathophysiological mechanisms have not yet been fully elucidated. Persistent bleeding, disturbed regulation of inflammation, blocked cell proliferation, susceptible infection and impaired tissue remodeling are the main features of diabetic wound healing. Conventional wound dressings, including gauze, films and bandages, have a limited function. They generally act as physical barriers and absorbers of exudates, which fail to meet the requirements of the whol diabetic wound healing process. Wounds in diabetic patients typically heal slowly and are susceptible to infection due to hyperglycemia within the wound bed. Once bacterial cells develop into biofilms, diabetic wounds will exhibit robust drug resistance. Recently, the application of stimuli-responsive hydrogels, also known as "smart hydrogels", for diabetic wound healing has attracted particular attention. The basic feature of this system is its capacities to change mechanical properties, swelling ability, hydrophilicity, permeability of biologically active molecules, etc., in response to various stimuli, including temperature, potential of hydrogen (pH), protease and other biological factors. Smart hydrogels can improve therapeutic efficacy and limit total toxicity according to the characteristics of diabetic wounds. In this review, we summarized the mechanism and application of stimuli-responsive hydrogels for diabetic wound healing. It is hoped that this work will provide some inspiration and suggestions for research in this field.
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Affiliation(s)
- Siming Zhang
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China
| | - Gaoran Ge
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
| | - Yi Qin
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
| | - Wenhao Li
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
| | - Jiale Dong
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China
| | - Jiawei Mei
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China
| | - Ruixiang Ma
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China
| | - Xianzuo Zhang
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China
| | - Jiaxiang Bai
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
| | - Chen Zhu
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China,Corresponding author.
| | - Weiwei Zhang
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China,Corresponding author.
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China,Corresponding author.
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12
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Panasenko OM, Ivanov VA, Mikhalchik EV, Gorudko IV, Grigorieva DV, Basyreva LY, Shmeleva EV, Gusev SA, Kostevich VA, Gorbunov NP, Sokolov AV. Methylglyoxal-Modified Human Serum Albumin Binds to Leukocyte Myeloperoxidase and Inhibits its Enzymatic Activity. Antioxidants (Basel) 2022; 11:2263. [PMID: 36421449 PMCID: PMC9686918 DOI: 10.3390/antiox11112263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/01/2022] [Accepted: 11/10/2022] [Indexed: 11/15/2023] Open
Abstract
Hyperglycemia in diabetes mellitus induces modification of proteins by glucose and its derivative methylglyoxal (MG). Neutrophils perform their bactericidal activity mainly via reactive halogen (RHS) and oxygen (ROS) species generation catalyzed by myeloperoxidase (MPO) stored in neutrophil azurophilic granules (AGs) and membrane NADPH oxidase, respectively. Herein, we study the binding of human serum albumin (HSA) modified with MG (HSA-MG) to MPO and its effects on MPO activity and release by neutrophils. Peroxidase activity of MPO was registered by oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, and chlorinating activity by decolorization of Celestine blue B dye. Binding of HSA-MG to MPO was studied by affinity chromatography, disc-electrophoresis, ligand Western blotting and enzyme-linked solid phase immunoassay using monoclonal antibodies (mAbs) to MPO. ROS and RHS generation were detected by lucigenin (Luc) and luminol (Lum) chemiluminescence (CL), respectively. Neutrophil degranulation was assessed by flow cytometry using fluorescent labeled antibodies to the marker proteins CD63 from AGs and CD11b from peroxidase-negative granules (PNGs). NETosis was assayed by quantifying DNA network-like structures (NET-like structures) in blood smears stained by Romanowsky. HSA-MG bound to MPO, giving a stable complex (Kd = 1.5 nM) and competing with mAbs, and non-competitively inhibited peroxidase and chlorinating MPO activity and induced degranulation of PNGs but not of AGs. HSA-MG enhanced Luc-CL per se or following PMA, unlike Lum-CL, and did not affect spontaneous or PMA-stimulated NETosis. Thus, HSA modified under hyperglycemia-like conditions stimulated NADPH oxidase of neutrophils but dampened their functions dependent on activity of MPO, with no effect on its release via degranulation or NETosis. This phenomenon could underlie the downregulation of bactericidal activity of MPO and neutrophils, and hence of innate immunity, giving rise to wound healing impairment and susceptibility to infection in patients with hyperglycemia.
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Affiliation(s)
- Oleg M. Panasenko
- Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
- Department of Medical Biophysics of the Institute for Translative Medicine, Pirogov Russian National Research Medical University, Moscow 117997, Russia
| | - Viktor A. Ivanov
- Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Elena V. Mikhalchik
- Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Irina V. Gorudko
- Department of Biophysics, Belarusian State University, 220030 Minsk, Belarus
| | - Daria V. Grigorieva
- Department of Biophysics, Belarusian State University, 220030 Minsk, Belarus
| | - Liliya Yu. Basyreva
- Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Ekaterina V. Shmeleva
- Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Sergey A. Gusev
- Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Valeria A. Kostevich
- Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
- Department of Molecular Genetics, Institute of Experimental Medicine, St. Petersburg 197376, Russia
| | - Nikolay P. Gorbunov
- Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
- Department of Molecular Genetics, Institute of Experimental Medicine, St. Petersburg 197376, Russia
| | - Alexey V. Sokolov
- Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
- Department of Molecular Genetics, Institute of Experimental Medicine, St. Petersburg 197376, Russia
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13
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Santambrogio L, Franco A. The yin/yang balance of the MHC-self -immunopeptidome. Front Immunol 2022; 13:1035363. [PMID: 36405763 PMCID: PMC9666884 DOI: 10.3389/fimmu.2022.1035363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/07/2022] [Indexed: 07/22/2023] Open
Abstract
The MHC-self immunopeptidome of professional antigen presenting cells is a cognate ligand for the TCRs expressed on both conventional and thymic-derived natural regulatory T cells. In regulatory T cells, the TCR signaling associated with MHC-peptide recognition induces antigen specific as well as bystander immunosuppression. On the other hand, TCR activation of conventional T cells is associated with protective immunity. As such the peripheral T cell repertoire is populated by a number of T cells with different phenotypes and different TCRs, which can recognize the same MHC-self-peptide complex, resulting in opposite immunological outcomes. This article summarizes what is known about regulatory and conventional T cell recognition of the MHC-self-immunopeptidome at steady state and in inflammatory conditions associated with increased T and B cell self-reactivity, discussing how changes in the MHC-ligandome including epitope copy number and post-translational modifications can tilt the balance toward the expansion of pro-inflammatory or regulatory T cells.
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Affiliation(s)
- Laura Santambrogio
- Department of Radiation Oncology, Physiology and Biophysics, Englander Institute of Precision Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Alessandra Franco
- University of California San Diego School of Medicine, Department of Pediatrics, La Jolla, CA, United States
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14
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Adebayo AA, Oboh G, Ademosun AO. Almond and date fruits enhance antioxidant status and have erectogenic effect: Evidence from in vitro and in vivo studies. J Food Biochem 2022; 46:e14255. [PMID: 35644948 DOI: 10.1111/jfbc.14255] [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] [Received: 01/06/2022] [Revised: 03/30/2022] [Accepted: 04/27/2022] [Indexed: 12/29/2022]
Abstract
This study was designed to investigate the efficacies of almond and date fruits on redox imbalance and enzymes relevant to the pathogenesis of erectile dysfunction. The total polyphenol contents, ferric reducing antioxidant power, and vitamin C content were determined spectrophotometrically. Phenolic and amino acid compositions were quantified using HPLC; meanwhile, the antioxidant activities were determined using DPPH, ABTS, FRAP, and metal chelation. Also, the effect of almond and date extract on advanced glycated end-products (AGEs) formation, arginase, and phosphodiesterase-5 activities was evaluated in vitro. Thereafter, the influence of almond and date supplemented diets on copulatory behaviors in normal rats was assessed, followed by arginase and phosphodiesterase-5 activities determination in vivo. The results revealed that date and almond extracts exerted antioxidant properties, prevented AGEs formation in vitro, and inhibited arginase and phosphodiesterase-5 activities in vitro and in vivo. Besides, almond and date supplemented diets significantly enhance sexual behaviors in normal rats when compared with the control. Among the active compounds identified were gallic acid, ellagic acid, quercetin, and rutin. All the 20 basic amino acids were identified. Given the aforementioned, date and almond could represent a reliable source of functional foods highly rich in compounds with antioxidant activity, and arginase and PDE-5 inhibitory properties. PRACTICAL APPLICATIONS: Fruits are essential part of the human diet that furnish the body with important nutrients. Despite the crucial roles of fruits in human diets, some fruits like almond and date are underutilized among Nigerians. However, we characterized the important compounds present in these fruits and how their presence contributes to the biological activities of the fruits. Finally, we relate the chemical composition and the observed biological activities to the overall health and wellness of the consumers.
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Affiliation(s)
- Adeniyi A Adebayo
- Functional Foods and Nutraceutical Research Unit, Biochemistry Department, Federal University of Technology, Akure, Nigeria.,Chemical Sciences Department (Biochemistry Option), Joseph Ayo Babalola University, Ikeji-Arakeji, Nigeria
| | - Ganiyu Oboh
- Functional Foods and Nutraceutical Research Unit, Biochemistry Department, Federal University of Technology, Akure, Nigeria
| | - Ayokunle O Ademosun
- Functional Foods and Nutraceutical Research Unit, Biochemistry Department, Federal University of Technology, Akure, Nigeria
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15
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Zhang X, Feng J, Feng W, Xu B, Zhang K, Ma G, Li Y, Yang M, Xu FJ. Glycosaminoglycan-Based Hydrogel Delivery System Regulates the Wound Microenvironment to Rescue Chronic Wound Healing. ACS APPLIED MATERIALS & INTERFACES 2022; 14:31737-31750. [PMID: 35802505 DOI: 10.1021/acsami.2c08593] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Chronic wounds cannot proceed through the normal, orderly, and timely sequence of repair. The adverse cycle between excess reactive oxide species (ROS) and a persistent inflammatory response is an important mechanism of impaired wound healing. Herein, by combining the intrinsic bioactivities of natural polysaccharides and natural drugs, a glycosaminoglycan-based hydrogel delivery system is proposed to regulate the wound microenvironment. Dynamic supramolecular cross-linking enables the hydrogel to easily encapsulate the drug and fully fill the wound area. As the backbone of the hydrogel, heparin captures inflammatory chemokines at the wound site, while hyaluronic acid mimics the function of ECM. The hydrophobic drug curcumin has been ingeniously encapsulated in the hydrogel through micellization, thereby exerting good ROS scavenging ability and anti-inflammatory activity. Evaluations in diabetic mice showed that this antioxidant and anti-inflammatory hydrogel was effective in reducing the influx of immune cells at the wound site and in down-regulating the inflammatory response. Accelerated wound healing was also observed, as evidenced by faster re-epithelialization and better ECM remodeling. The proposed hydrogel can regulate the microenvironment of wounds from multiple aspects and thereby achieve regression of wound repair, which may provide a new therapeutic strategy for chronic wounds.
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Affiliation(s)
- Xiang Zhang
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Jin Feng
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Weina Feng
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Buxuan Xu
- Department of Orthopedics, The First Hospital of China Medical University, No. 155 Nanjingbei Street, Shenyang 110001, Liaoning, China
| | - Kai Zhang
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Guiping Ma
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Yang Li
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Maowei Yang
- Department of Orthopedics, The First Hospital of China Medical University, No. 155 Nanjingbei Street, Shenyang 110001, Liaoning, China
| | - Fu-Jian Xu
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
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16
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The Correlation between the Level of Skin Advanced Glycation End Products in Type 2 Diabetes Mellitus and the Stages of Diabetic Retinopathy and the Types of Traditional Chinese Medicine Syndrome. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5193944. [PMID: 35845597 PMCID: PMC9286975 DOI: 10.1155/2022/5193944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 02/06/2022] [Accepted: 05/09/2022] [Indexed: 12/20/2022]
Abstract
Objective We aimed to analyze the correlation between the level of skin advanced glycation end products (AGEs) in type 2 diabetes mellitus (T2DM) patients and the diabetic retinopathy (DR) staging in different traditional Chinese medicine (TCM) syndromes. Methods 416 T2DM patients were divided into normal group, nonproliferative diabetic retinopathy (NPDR) group (mild, moderate, and severe), and proliferative diabetic retinopathy (PDR) group according to the DR grade. Patients' height, weight, fasting blood glucose (FBG), hemoglobin A1C (HbA1c), blood lipid, renal function, and skin AGEs were measured. According to TCM syndrome differentiation criteria, 230 patients with T2DM and DR were divided into I. qi and yin deficiency, collateral stasis group; II. liver and kidney deficiency, eye collaterals loss group; and III. yin and yang deficiency, blood stasis, and phlegm coagulation group. Results The skin AGEs levels of different DR staging groups were statistically significant (P < 0.05), and the skin AGEs levels in the mild and moderate NPDR groups were significantly higher (P < 0.05) than those of the normal group. It was significantly higher (P < 0.05) in the severe NPDR group than in the normal group, mild and moderate NPDR groups. The skin AGEs levels of the PDR group were significantly higher (P < 0.05) than the normal group, mild and moderate NPDR groups. It was positively correlated with DR stage, HbA1c, total cholesterol (TC), low-density lipoprotein (LDL), and urine metal analysis (UMA) (r = 0.467, 0.411, 0.413, 0.503, 0.424, P < 0.05). The skin AGEs levels of the qi and yin deficiency and collaterals stasis syndrome group were significantly higher (P < 0.05) than in the liver and kidney deficiency and eye collaterals loss groups. It was also significantly higher (P < 0.05) in yin and yang deficiency, blood stasis, and phlegm coagulation syndrome groups than in qi and yin deficiency and collaterals stasis syndrome groups. Conclusion There is a positive correlation between skin AGEs and DR staging in T2DM patients. Skin AGEs level is predictive for the risk of DR complications in T2DM patients and is vital in assessing DR degree per TCM syndrome type.
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17
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Rau R, Glomb MA. Novel Pyridinium Cross-Link Structures Derived from Glycolaldehyde and Glyoxal. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:4434-4444. [PMID: 35348319 DOI: 10.1021/acs.jafc.2c00906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Short-chained α-hydroxycarbonyl compounds such as glycolaldehyde (GA) and its oxidized counterpart glyoxal (GX) are known as potent glycating agents. Here, a novel fluorescent lysine-lysine cross-link 1-(5-amino-5-carboxypentyl)-3-(5-amino-5-carboxy-pentylamino)pyridinium salt (meta-DLP) was synthesized and its structure unequivocally proven by 1H NMR, 13C-NMR attached proton test, and 2D NMR. Further characterization of chemical properties and mechanistic background was obtained in comparison to the known monovalent protein modification 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate (OP-lysine). Identification and quantitation in various sugar incubations with N2-t-Boc-lysine revealed a novel alternative formation pathway for both advanced glycation end products (AGEs) by the interplay of both carbonyl compounds, GA and GX, which was confirmed by isotope labeling experiments. The concentration of pyridinium AGEs was about 1000-fold lower compared to the well-established N6-carboxymethyl lysine. However, pyridinium AGEs were shown to lead to the photosensitized generation of singlet oxygen in irradiation experiments, which was verified by the detection of 3,3'-(naphthalene-1,4-diyl)-dipropionate endoperoxide. Furthermore, meta-DLP was identified in hydrolyzed potato chip proteins by collision-induced dissociation mass spectrometry after HPLC enrichment.
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Affiliation(s)
- Robert Rau
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale 06120, Germany
| | - Marcus A Glomb
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle/Saale 06120, Germany
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18
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Johnson J, Jaggers RM, Gopalkrishna S, Dahdah A, Murphy AJ, Hanssen NMJ, Nagareddy PR. Oxidative Stress in Neutrophils: Implications for Diabetic Cardiovascular Complications. Antioxid Redox Signal 2022; 36:652-666. [PMID: 34148367 PMCID: PMC9057880 DOI: 10.1089/ars.2021.0116] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Neutrophil behavior and function are altered by hyperglycemia associated with diabetes. Aberrant activation by hyperglycemia causes neutrophils to respond with increased production of reactive oxidative species (ROS). Excess ROS, a signature of primed neutrophils, can intracellularly induce neutrophils to undergo NETosis, flooding surrounding tissues with ROS and damage-associated molecular patterns such as S100 calcium binding proteins (S100A8/A9). The cargo associated with NETosis also attracts more immune cells to the site and signals for increased immune cell production. This inflammatory response to diabetes can accelerate other associated conditions such as atherosclerosis and thrombosis, increasing the risk of cardiovascular disease. Recent Advances: As the prevalence of diabetes continues to grow, more attention has been focused on developing effective treatment options. Currently, glucose-lowering medications and insulin injections are the most widely utilized treatments. As the disease progresses, medications are usually stacked to maintain glucose at desired target levels, but this approach often fails and does not effectively reduce cardiovascular risk, even with the latest drugs. Critical Issues: Despite advances in treatment options, diabetes remains a progressive disease as glucose lowering alone has failed to abolish the associated cardiovascular complications. Future Directions: Significant interest is being generated in developing treatments that do not solely focus on glucose control but rather mitigate glucotoxicity. Several therapies have been proposed that target cellular dysfunction downstream of hyperglycemia, such as using antioxidants to scavenge ROS, inhibiting ROS production from NOX, and suppressing neutrophil release of S100A8/A9 proteins. Antioxid. Redox Signal. 36, 652-666.
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Affiliation(s)
- Jillian Johnson
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Robert M Jaggers
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Sreejit Gopalkrishna
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Albert Dahdah
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Andrew J Murphy
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Nordin M J Hanssen
- Amsterdam Diabetes Centrum, Internal and Vascular Medicine, Amsterdam UMC, Amsterdam, Netherlands
| | - Prabhakara R Nagareddy
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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19
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Takanche JS, Kim JE, Jang S, Yi HK. Insulin growth factor binding protein-3 enhances dental implant osseointegration against methylglyoxal-induced bone deterioration in a rat model. J Periodontal Implant Sci 2022; 52:155-169. [PMID: 35505576 PMCID: PMC9064780 DOI: 10.5051/jpis.2101200060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 11/08/2022] Open
Abstract
PURPOSE The aim of this study was to determine the effect of insulin growth factor binding protein-3 (IGFBP-3) on the inhibition of glucose oxidative stress and promotion of bone formation near the implant site in a rat model of methylglyoxal (MGO)-induced bone loss. METHODS An in vitro study was performed in MC3T3 E1 cells treated with chitosan gold nanoparticles (Ch-GNPs) conjugated with IGFBP-3 cDNA followed by MGO. An in vivo study was conducted in a rat model induced by MGO administration after the insertion of a dental implant coated with IGFBP-3. RESULTS MGO treatment downregulated molecules involved in osteogenic differentiation and bone formation in MC3T3 E1 cells and influenced the bone mineral density and bone volume of the femur and alveolar bone. In contrast, IGFBP-3 inhibited oxidative stress and inflammation and enhanced osteogenesis in MGO-treated MC3T3 E1 cells. In addition, IGFBP-3 promoted bone formation by reducing inflammatory proteins in MGO-administered rats. The application of Ch-GNPs conjugated with IGFBP-3 as a coating of titanium implants enhanced osteogenesis and the osseointegration of dental implants. CONCLUSIONS This study demonstrated that IGFBP-3 could be applied as a therapeutic component in dental implants to promote the osseointegration of dental implants in patients with diabetes, which affects MGO levels.
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Affiliation(s)
- Jyoti Shrestha Takanche
- Department of Oral Biochemistry, Institute of Oral Bioscience, School of Dentistry, Jeonbuk National University, Jeonju, Korea.,Department of Biochemistry, School of Medical Sciences, Kathmandu University, Nepal
| | - Ji-Eun Kim
- Department of Oral Biochemistry, Institute of Oral Bioscience, School of Dentistry, Jeonbuk National University, Jeonju, Korea
| | - Sungil Jang
- Department of Oral Biochemistry, Institute of Oral Bioscience, School of Dentistry, Jeonbuk National University, Jeonju, Korea
| | - Ho-Keun Yi
- Department of Oral Biochemistry, Institute of Oral Bioscience, School of Dentistry, Jeonbuk National University, Jeonju, Korea.
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20
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Omofuma OO, Peterson LL, Turner DP, Merchant AT, Zhang J, Thomson CA, Neuhouser ML, Snetselaar LG, Caan BJ, Shadyab AH, Saquib N, Banack HR, Uribarri J, Steck SE. Dietary Advanced Glycation End-Products and Mortality after Breast Cancer in the Women's Health Initiative. Cancer Epidemiol Biomarkers Prev 2021; 30:2217-2226. [PMID: 34583965 PMCID: PMC8643311 DOI: 10.1158/1055-9965.epi-21-0610] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/24/2021] [Accepted: 09/22/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Advanced glycation end-products (AGE) are formed through nonenzymatic glycation of free amino groups in proteins or lipid. They are associated with inflammation and oxidative stress, and their accumulation in the body is implicated in chronic disease morbidity and mortality. We examined the association between postdiagnosis dietary Nε-carboxymethyl-lysine (CML)-AGE intake and mortality among women diagnosed with breast cancer. METHODS Postmenopausal women aged 50 to 79 years were enrolled in the Women's Health Initiative (WHI) between 1993 and 1998 and followed up until death or censoring through March 2018. We included 2,023 women diagnosed with first primary invasive breast cancer during follow-up who completed a food frequency questionnaire (FFQ) after diagnosis. Cox proportional hazards (PH) regression models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) of association between tertiles of postdiagnosis CML-AGE intake and mortality risk from all causes, breast cancer, and cardiovascular disease. RESULTS After a median 15.1 years of follow-up, 630 deaths from all causes were reported (193 were breast cancer-related, and 129 were cardiovascular disease-related). Postdiagnosis CML-AGE intake was associated with all-cause (HRT3vsT1, 1.37; 95% CI, 1.09-1.74), breast cancer (HRT3vsT1, 1.49; 95% CI, 0.98-2.24), and cardiovascular disease (HRT3vsT1, 1.91; 95% CI, 1.09-3.32) mortality. CONCLUSIONS Higher intake of AGEs was associated with higher risk of major causes of mortality among postmenopausal women diagnosed with breast cancer. IMPACT Our findings suggest that dietary AGEs may contribute to the risk of mortality after breast cancer diagnosis. Further prospective studies examining dietary AGEs in breast cancer outcomes and intervention studies targeting dietary AGE reduction are needed to confirm our findings.
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Affiliation(s)
- Omonefe O Omofuma
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Lindsay L Peterson
- Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - David P Turner
- Medical University of South Carolina, Charleston, South Carolina
| | - Anwar T Merchant
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Jiajia Zhang
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Cynthia A Thomson
- Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona
| | | | | | - Bette J Caan
- Kaiser Permanente, University of California Berkeley, Oakland, California
| | - Aladdin H Shadyab
- Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, California
| | - Nazmus Saquib
- College of Medicine, Sulaiman AlRajhi University, Saudi Arabia
| | - Hailey R Banack
- School of Public Health and Health Professions, University at Buffalo-SUNY, Buffalo, New York
| | - Jaime Uribarri
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York
| | - Susan E Steck
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina.
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21
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Chen Y, Guo TL. Dietary advanced glycation end-products elicit toxicological effects by disrupting gut microbiome and immune homeostasis. J Immunotoxicol 2021; 18:93-104. [PMID: 34436982 PMCID: PMC9885815 DOI: 10.1080/1547691x.2021.1959677] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
The aging immune system is characterized by a low-grade chronic systemic inflammatory state ("inflammaging") marked by elevated serum levels of inflammatory molecules such as interleukin (IL)-6 and C-reactive protein (CRP). These inflammatory markers were also reported to be strong predictors for the development/severity of Type 2 diabetes, obesity, and COVID-19. The levels of these markers have been positively associated with those of advanced glycation end-products (AGEs) generated via non-enzymatic glycation and oxidation of proteins and lipids during normal aging and metabolism. Based on the above observations, it is clinically important to elucidate how dietary AGEs modulate inflammation and might thus increase the risk for aging-exacerbated diseases. The present narrative review discusses the potential pro-inflammatory properties of dietary AGEs with a focus on the inflammatory mediators CRP, IL-6 and ferritin, and their relations to aging in general and Type 2 diabetes in particular. In addition, underlying mechanisms - including those related to gut microbiota and the receptors for AGEs, and the roles AGEs might play in affecting physiologies of the healthy elderly, obese individuals, and diabetics are discussed in regard to any greater susceptibility to COVID-19.
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Affiliation(s)
- Yingjia Chen
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - Tai L. Guo
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
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22
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The effect of methylethylpiridinol addition to the therapy on the level of pigment epithelium-derived factor and oxidative status in patients with diabetic nephropathy: randomized controlled open-label clinical study. J Diabetes Metab Disord 2021; 20:709-717. [PMID: 34222086 DOI: 10.1007/s40200-021-00802-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 04/20/2021] [Indexed: 10/21/2022]
Abstract
Purpose The diabetic nephropathy is associated with oxidative stress and increases in pigment epithelium-derived factor (PEDF) level in the patient's blood. For the first time, authors investigated the effect of methylethylpiridinol addition to the therapy on oxidative status and pigment epithelium-derived factor concentrations, and examined the relationship between these indicators and clinical markers of pathology development. Methods Study design: open label randomized controlled trial study. Authors assessed the effect of methylethylpiridinol addition to the therapy vs basic treatment on antioxidant and NADPH-generating enzymes activity, glutathione's concentration and free radical-induced oxidation's intensity using a spectrophotometric method and iron-induced biochemiluminescence. The pigment epithelium-derived factor concentration in the serum was measured by enzyme-linked immunosorbent assay. Results Patients receiving combination therapy with methylethylpiridinol showed a more substantial increase in activity of glutathione peroxidase (Δ = 0.04 ± 0.11, p = 0.002), glutathione transferase (Δ = 0.12 ± 0.08, p < 0.001) and the concentration of reduced glutathione (Δ = 0.30 ± 0.17, p = 0.039). In addition, there was a significant decrease in PEDF level (Δ = -6.4 ± 5.4, p = 0.004). Correlation analysis showed a negative link between Δ postprandial glucose and Δ NADP-isocitrate dehydrogenase (-0.39, p = 0.033), Δ reduced glutathione and Δ postprandial glucose (-0.372, p = 0.043), Δ glutathione transferase and Δ PEDF (-0.37, p = 0.044). Conclusions The methylethylpiridinol addition to the therapy had a more potent stimulating effect on the patients' oxidative status in comparison with standard treatment, and reliably decreased pigment epithelium-derived factor level in patients' serum. The observed differences seem to be associated with the antioxidant activity of methylethylpiridinol which contributing to the mitigation of oxidative stress reducing at diabetes mellitus.
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23
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Allam VSRR, Faiz A, Lam M, Rathnayake SNH, Ditz B, Pouwels SD, Brandsma C, Timens W, Hiemstra PS, Tew GW, Neighbors M, Grimbaldeston M, van den Berge M, Donnelly S, Phipps S, Bourke JE, Sukkar MB. RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD. Allergy 2021; 76:1123-1135. [PMID: 32799375 DOI: 10.1111/all.14563] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 07/08/2020] [Accepted: 07/14/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND The receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients. METHODS We measured airway inflammation and AHR in wild-type, RAGE-/- , TLR4-/- and TLR4-/- RAGE-/- mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients. RESULTS RAGE-/- mice were protected against CS-induced neutrophilia and AHR. In contrast, TLR4-/- mice were not protected against CS-induced neutrophilia and had more severe CS-induced AHR. TLR4-/- RAGE-/- mice were not protected against CS-induced neutrophilia but were partially protected against CS-induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR. CONCLUSIONS Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.
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Affiliation(s)
| | - Alen Faiz
- School of Life Sciences Faculty of Science The University of Technology Sydney Ultimo NSW Australia
- Department of Pulmonary Diseases University of Groningen University Medical Center Groningen Groningen The Netherlands
- Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - Maggie Lam
- Biomedicine Discovery Institute and Department of Pharmacology School of Biomedical Sciences Monash University Melbourne Vic. Australia
| | - Senani N. H. Rathnayake
- School of Life Sciences Faculty of Science The University of Technology Sydney Ultimo NSW Australia
| | - Benedikt Ditz
- Department of Pulmonary Diseases University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - Simon D. Pouwels
- Department of Pulmonary Diseases University of Groningen University Medical Center Groningen Groningen The Netherlands
- Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - Corry‐Anke Brandsma
- Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands
- Groningen Research Institute for Asthma and COPD University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - Wim Timens
- Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Groningen The Netherlands
- Groningen Research Institute for Asthma and COPD University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - Pieter S. Hiemstra
- Department of Pulmonology Leiden University Medical Center Leiden The Netherlands
| | - Gaik W. Tew
- OMNI‐Biomarker Development, Genentech Inc South San Francisco CA USA
| | | | | | - Maarten van den Berge
- Department of Pulmonary Diseases University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - Sheila Donnelly
- School of Life Sciences Faculty of Science The University of Technology Sydney Ultimo NSW Australia
| | - Simon Phipps
- QIMR Berghofer Medical Research Institute Herston Qld Australia
| | - Jane E. Bourke
- Biomedicine Discovery Institute and Department of Pharmacology School of Biomedical Sciences Monash University Melbourne Vic. Australia
| | - Maria B. Sukkar
- Graduate School of Health Faculty of Health The University of Technology Sydney Ultimo NSW Australia
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Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery. Immunity 2021; 54:721-736.e10. [PMID: 33725478 DOI: 10.1016/j.immuni.2021.02.019] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 12/30/2020] [Accepted: 02/24/2021] [Indexed: 01/11/2023]
Abstract
Hyperglycemia and hyperlipidemia are often observed in individuals with type II diabetes (T2D) and related mouse models. One dysmetabolic biochemical consequence is the non-enzymatic reaction between sugars, lipids, and proteins, favoring protein glycation, glycoxidation, and lipoxidation. Here, we identified oxidative alterations in key components of the major histocompatibility complex (MHC) class II molecule antigen processing and presentation machinery in vivo under conditions of hyperglycemia-induced metabolic stress. These modifications were linked to epitope-specific changes in endosomal processing efficiency, MHC class II-peptide binding, and DM editing activity. Moreover, we observed some quantitative and qualitative changes in the MHC class II immunopeptidome of Ob/Ob mice on a high-fat diet compared with controls, including changes in the presentation of an apolipoprotein B100 peptide associated previously with T2D and metabolic syndrome-related clinical complications. These findings highlight a link between glycation reactions and altered MHC class II antigen presentation that may contribute to T2D complications.
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25
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Beeraka NM, Bovilla VR, Doreswamy SH, Puttalingaiah S, Srinivasan A, Madhunapantula SV. The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers. Cancers (Basel) 2021; 13:cancers13020281. [PMID: 33466626 PMCID: PMC7828646 DOI: 10.3390/cancers13020281] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Aim of this review is to provide an overview on (a) Fructosamine-3-Kinase (FN3K) and its role in regulating Nuclear Factor Erythorid-2-Related Factor-2 (Nrf2); (b) the role of glycation and deglycation mechanisms in modulating the functional properties of proteins, in particular, the Nrf2; (c) the dual role of Nrf2 in the prevention and treatment of cancers. Since controlling the glycation of Nrf2 is one of the key mechanisms determining the fate of a cell; whether to get transformed into a cancerous one or to stay as a normal one, it is important to regulate Nrf2 and deglycating FN3K using pharmacological agents. Inhibitors of FN3K are being explored currently to modulate Nrf2 activity thereby control the cancers. Abstract Glycated stress is mediated by the advanced glycation end products (AGE) and the binding of AGEs to the receptors for advanced glycation end products (RAGEs) in cancer cells. RAGEs are involved in mediating tumorigenesis of multiple cancers through the modulation of several downstream signaling cascades. Glycated stress modulates various signaling pathways that include p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa–B (NF-κB), tumor necrosis factor (TNF)-α, etc., which further foster the uncontrolled proliferation, growth, metastasis, angiogenesis, drug resistance, and evasion of apoptosis in several cancers. In this review, a balanced overview on the role of glycation and deglycation in modulating several signaling cascades that are involved in the progression of cancers was discussed. Further, we have highlighted the functional role of deglycating enzyme fructosamine-3-kinase (FN3K) on Nrf2-driven cancers. The activity of FN3K is attributed to its ability to deglycate Nrf2, a master regulator of oxidative stress in cells. FN3K is a unique protein that mediates deglycation by phosphorylating basic amino acids lysine and arginine in various proteins such as Nrf2. Deglycated Nrf2 is stable and binds to small musculoaponeurotic fibrosarcoma (sMAF) proteins, thereby activating cellular antioxidant mechanisms to protect cells from oxidative stress. This cellular protection offered by Nrf2 activation, in one way, prevents the transformation of a normal cell into a cancer cell; however, in the other way, it helps a cancer cell not only to survive under hypoxic conditions but also, to stay protected from various chemo- and radio-therapeutic treatments. Therefore, the activation of Nrf2 is similar to a double-edged sword and, if not controlled properly, can lead to the development of many solid tumors. Hence, there is a need to develop novel small molecule modulators/phytochemicals that can regulate FN3K activity, thereby maintaining Nrf2 in a controlled activation state.
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Affiliation(s)
- Narasimha M. Beeraka
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
| | - Venugopal R. Bovilla
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
- Public Health Research Institute of India (PHRII), Mysuru, Karnataka 570020, India
| | - Shalini H. Doreswamy
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
| | - Sujatha Puttalingaiah
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
| | - Asha Srinivasan
- Division of Nanoscience and Technology, Faculty of Life Sciences, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India;
| | - SubbaRao V. Madhunapantula
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
- Special Interest Group in Cancer Biology and Cancer Stem Cells, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India
- Correspondence: ; Tel.: +91-810-527-8621
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Garciafigueroa Y, Phillips BE, Engman C, Trucco M, Giannoukakis N. Neutrophil-Associated Inflammatory Changes in the Pre-Diabetic Pancreas of Early-Age NOD Mice. Front Endocrinol (Lausanne) 2021; 12:565981. [PMID: 33776903 PMCID: PMC7988208 DOI: 10.3389/fendo.2021.565981] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 02/01/2021] [Indexed: 12/23/2022] Open
Abstract
A growing body of evidence indicates that neutrophils are the first major leukocyte population accumulating inside the pancreas even before the onset of a lymphocytic-driven impairment of functional beta cells in type 1 diabetes mellitus (T1D). In humans, pancreata from T1D deceased donors exhibit significant neutrophil accumulation. We present a time course of previously unknown inflammatory changes that accompany neutrophil and neutrophil elastase accumulation in the pancreas of the non-obese diabetic (NOD) mouse strain as early as 2 weeks of age. We confirm earlier findings in NOD mice that neutrophils accumulate as early as 2 weeks of age. We also observe a concurrent increase in the expression of neutrophil elastase in this time period. We also detect components of neutrophil extracellular traps (NET) mainly in the exocrine tissue of the pancreas during this time as well as markers of vascular pathology as early as 2 weeks of age. Age- and sex-matched C57BL/6 mice do not exhibit these features inside the pancreas. When we treated NOD mice with inhibitors of myeloperoxidase and neutrophil elastase, two key effectors of activated neutrophil activity, alone or in combination, we were unable to prevent the progression to hyperglycemia in any manner different from untreated control mice. Our data confirm and add to the body of evidence demonstrating neutrophil accumulation inside the pancreas of mice genetically susceptible to T1D and also offer novel insights into additional pathologic mechanisms involving the pancreatic vasculature that have, until now, not been discovered inside the pancreata of these mice. However, inhibition of key neutrophil enzymes expressed in activated neutrophils could not prevent diabetes. These findings add to the body of data supporting a role for neutrophils in the establishment of early pathology inside the pancreas, independently of, and earlier from the time at onset of lymphocytic infiltration. However, they also suggest that inhibition of neutrophils alone, acting via myeloperoxidase and neutrophil elastase only, in the absence of other other effector cells, is insufficient to alter the natural course of autoimmune diabetes, at least in the NOD model of the disease.
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Affiliation(s)
- Yesica Garciafigueroa
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
| | - Brett E. Phillips
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
| | - Carl Engman
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
| | - Massimo Trucco
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Nick Giannoukakis
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
- *Correspondence: Nick Giannoukakis,
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Shen CY, Lu CH, Wu CH, Li KJ, Kuo YM, Hsieh SC, Yu CL. The Development of Maillard Reaction, and Advanced Glycation End Product (AGE)-Receptor for AGE (RAGE) Signaling Inhibitors as Novel Therapeutic Strategies for Patients with AGE-Related Diseases. Molecules 2020; 25:molecules25235591. [PMID: 33261212 PMCID: PMC7729569 DOI: 10.3390/molecules25235591] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/21/2020] [Accepted: 11/25/2020] [Indexed: 12/12/2022] Open
Abstract
Advanced glycation end products (AGEs) are generated by nonenzymatic modifications of macromolecules (proteins, lipids, and nucleic acids) by saccharides (glucose, fructose, and pentose) via Maillard reaction. The formed AGE molecules can be catabolized and cleared by glyoxalase I and II in renal proximal tubular cells. AGE-related diseases include physiological aging, neurodegenerative/neuroinflammatory diseases, diabetes mellitus (DM) and its complications, autoimmune/rheumatic inflammatory diseases, bone-degenerative diseases, and chronic renal diseases. AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause vascular endothelial/smooth muscular/connective tissue-cell and renal mesangial/endothelial/podocytic-cell damage in AGE-related diseases. In the present review, we first focus on the cellular and molecular bases of AGE–RAGE axis signaling pathways in AGE-related diseases. Then, we discuss in detail the modes of action of newly discovered novel biomolecules and phytochemical compounds, such as Maillard reaction and AGE–RAGE signaling inhibitors. These molecules are expected to become the new therapeutic strategies for patients with AGE-related diseases in addition to the traditional hypoglycemic and anti-hypertensive agents. We particularly emphasize the importance of “metabolic memory”, the “French paradox”, and the pharmacokinetics and therapeutic dosing of the effective natural compounds associated with pharmacogenetics in the treatment of AGE-related diseases. Lastly, we propose prospective investigations for solving the enigmas in AGE-mediated pathological effects.
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Affiliation(s)
- Chieh-Yu Shen
- Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-H.W.); (Y.-M.K.)
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan;
| | - Cheng-Hsun Lu
- Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-H.W.); (Y.-M.K.)
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan;
| | - Cheng-Han Wu
- Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-H.W.); (Y.-M.K.)
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan;
| | - Ko-Jen Li
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan;
| | - Yu-Min Kuo
- Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-H.W.); (Y.-M.K.)
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan;
| | - Song-Chou Hsieh
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan;
- Correspondence: (S.-C.H.); (C.-L.Y.)
| | - Chia-Li Yu
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan;
- Department of Internal Medicine, Kaohsiung Medical University College of Medicine, Kaohsiung 80756, Taiwan
- Correspondence: (S.-C.H.); (C.-L.Y.)
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van der Lugt T, Opperhuizen A, Bast A, Vrolijk MF. Dietary Advanced Glycation Endproducts and the Gastrointestinal Tract. Nutrients 2020; 12:nu12092814. [PMID: 32937858 PMCID: PMC7551018 DOI: 10.3390/nu12092814] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/10/2020] [Accepted: 09/11/2020] [Indexed: 12/19/2022] Open
Abstract
The prevalence of inflammatory bowel diseases (IBD) is increasing in the world. The introduction of the Western diet has been suggested as a potential explanation of increased prevalence. The Western diet includes highly processed food products, and often include thermal treatment. During thermal treatment, the Maillard reaction can occur, leading to the formation of dietary advanced glycation endproducts (dAGEs). In this review, different biological effects of dAGEs are discussed, including their digestion, absorption, formation, and degradation in the gastrointestinal tract, with an emphasis on their pro-inflammatory effects. In addition, potential mechanisms in the inflammatory effects of dAGEs are discussed. This review also specifically elaborates on the involvement of the effects of dAGEs in IBD and focuses on evidence regarding the involvement of dAGEs in the symptoms of IBD. Finally, knowledge gaps that still need to be filled are identified.
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Affiliation(s)
- Timme van der Lugt
- Department of Pharmacology and Toxicology, Maastricht University, 6229 ER Maastricht, The Netherlands;
- Office for Risk Assessment and Research, Netherlands Food and Consumer Product Safety Authority (NVWA), 3540 AA Utrecht, The Netherlands
- Correspondence:
| | - Antoon Opperhuizen
- Department of Pharmacology and Toxicology, Maastricht University, 6229 ER Maastricht, The Netherlands;
- Office for Risk Assessment and Research, Netherlands Food and Consumer Product Safety Authority (NVWA), 3540 AA Utrecht, The Netherlands
| | - Aalt Bast
- Department of Pharmacology and Toxicology, Maastricht University, 6229 ER Maastricht, The Netherlands;
- Campus Venlo, Maastricht University, 5911 BV Venlo, The Netherlands; (A.B.); (M.F.V.)
| | - Misha F. Vrolijk
- Campus Venlo, Maastricht University, 5911 BV Venlo, The Netherlands; (A.B.); (M.F.V.)
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Omofuma OO, Turner DP, Peterson LL, Merchant AT, Zhang J, Steck SE. Dietary Advanced Glycation End-products (AGE) and Risk of Breast Cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Cancer Prev Res (Phila) 2020; 13:601-610. [PMID: 32169887 PMCID: PMC7335328 DOI: 10.1158/1940-6207.capr-19-0457] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 02/03/2020] [Accepted: 03/09/2020] [Indexed: 12/11/2022]
Abstract
Advanced glycation end-products (AGEs) are implicated in the pathogenesis of several chronic diseases including cancer. AGEs are produced endogenously but can also be consumed from foods. AGE formation in food is accelerated during cooking at high temperatures. Certain high fat or highly processed foods have high AGE values. The objective of the study was to assign and quantify Nϵ-carboxymethyl-lysine (CML)-AGE content in food and investigate the association between dietary AGE intake and breast cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The study included women enrolled in the intervention arm who were cancer-free at baseline and completed a baseline questionnaire and food frequency questionnaire (DQX). CML-AGE values were assigned and quantified to foods in the DQX using a published AGE database. Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer among all women, and stratified by race/ethnicity, invasiveness of disease, and hormone receptor status. After a median 11.5 years of follow-up, 1,592 women were diagnosed with breast cancer. Higher CML-AGE intake was associated with increased risk of breast cancer among all women (HRQ5VSQ1, 1.30; 95% CI, 1.04-1.62; P trend = 0.04) and in non-Hispanic white women (HRT3VST1, 1.21; 95% CI, 1.02-1.44). Increased CML-AGE intake was associated with increased risk of in situ (HRT3VST1, 1.49; 95% CI, 1.11-2.01) and hormone receptor-positive (HRT3VST1, 1.24; 95% CI, 1.01-1.53) breast cancers. In conclusion, high intake of dietary AGE may contribute to increased breast cancer.
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Affiliation(s)
- Omonefe O Omofuma
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - David P Turner
- Medical University of South Carolina, Charleston, South Carolina
| | - Lindsay L Peterson
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Anwar T Merchant
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Jiajia Zhang
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Susan E Steck
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina.
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Dietary Advanced Glycation Endproducts Decrease Glucocorticoid Sensitivity In Vitro. Nutrients 2020; 12:nu12020441. [PMID: 32050634 PMCID: PMC7071239 DOI: 10.3390/nu12020441] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 01/31/2020] [Accepted: 02/06/2020] [Indexed: 12/20/2022] Open
Abstract
Glucocorticoids are very effective anti-inflammatory drugs and widely used for inflammatory bowel disease (IBD) patients. However, approximately 20% of IBD patients do not respond to glucocorticoids and the reason for this is largely unknown. Dietary advanced glycation endproducts (AGEs) are formed via the Maillard reaction during the thermal processing of food products and can induce a pro-inflammatory reaction in human cells. To investigate whether this pro-inflammatory response could be mitigated by glucocorticoids, human macrophage-like cells were exposed to both LPS and AGEs to induce interleukin-8 (IL8) secretion. This pro-inflammatory response was then modulated by adding pharmacological compounds interfering in different steps of the anti-inflammatory mechanism of glucocorticoids: rapamycin, quercetin, and theophylline. Additionally, intracellular reactive oxygen species (ROS) were measured and the glucocorticoid receptor phosphorylation state was assessed. The results show that AGEs induced glucocorticoid resistance, which could be mitigated by quercetin and rapamycin. No change in the phosphorylation state of the glucocorticoid receptor was observed. Additionally, intracellular ROS formation was induced by AGEs, which was mitigated by quercetin. This suggests that AGE-induced ROS is an underlying mechanism to AGE-induced glucocorticoid resistance. This study shows for the first time the phenomenon of dietary AGE-induced glucocorticoid resistance due to the formation of ROS. Our findings indicate that food products with a high inflammatory potential can induce glucocorticoid resistance; these results may be of great importance to IBD patients suffering from glucocorticoid resistance.
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Malone-Povolny MJ, Maloney SE, Schoenfisch MH. Nitric Oxide Therapy for Diabetic Wound Healing. Adv Healthc Mater 2019; 8:e1801210. [PMID: 30645055 PMCID: PMC6774257 DOI: 10.1002/adhm.201801210] [Citation(s) in RCA: 279] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/12/2018] [Indexed: 12/13/2022]
Abstract
Nitric oxide (NO) represents a potential wound therapeutic agent due to its ability to regulate inflammation and eradicate bacterial infections. Two broad strategies exist to utilize NO for wound healing; liberating NO from endogenous reservoirs, and supplementing NO from exogenous sources. This progress report examines the efficacy of a variety of NO-based methods to improve wound outcomes, with particular attention given to diabetes-associated chronic wounds.
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Affiliation(s)
- Maggie J Malone-Povolny
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Sara E Maloney
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Mark H Schoenfisch
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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AGE-RAGE stress: a changing landscape in pathology and treatment of Alzheimer's disease. Mol Cell Biochem 2019; 459:95-112. [PMID: 31079281 DOI: 10.1007/s11010-019-03553-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 05/04/2019] [Indexed: 12/27/2022]
Abstract
Numerous hypotheses including amyloid cascade, cholinergic, and oxidative have been proposed for pathogenesis of Alzheimer's disease (AD). The data suggest that advanced glycation end products (AGEs) and its receptor RAGE (receptor for AGE) are involved in the pathogenesis of AD. AGE-RAGE stress, defined as a balance between stressors (AGE, RAGE) and anti-stressors (sRAGE, AGE degraders) in favor of stressors, has been implicated in pathogenesis of diseases. AGE and its interaction with RAGE-mediated increase in the reactive oxygen species (ROS) damage brain because of its increased vulnerability to ROS. AGE and ROS increase the synthesis of amyloid β (Aβ) leading to deposition of Aβ and phosphorylation of tau, culminating in formation of plaques and neurofibrillary tangles. ROS increase the synthesis of Aβ, high-mobility group box 1(HMGB1), and S100 that interacts with RAGE to produce additional ROS resulting in enhancement of AD pathology. Elevation of ROS precedes the Aβ plaques formation. Because of involvement of AGE and RAGE in AD pathology, the treatment should be targeted at lowering AGE levels through reduction in consumption and formation of AGE, and lowering expression of RAGE, blocking of RAGE ligand binding, increasing levels of soluble RAGE (sRAGE), and use of antioxidants. The above treatment aspect of AD is lacking. In conclusion, AGE-RAGE stress initiates, and Aβ, HMGB1, and S100 enhance the progression of AD. Reduction of levels of AGE and RAGE, elevation of sRAGE, and antioxidants would be beneficial therapeutic modalities in the prevention, regression, and slowing of progression of AD.
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Bansal S, Kare PK, Tripathi AK, Madhu SV. Advanced Glycation End Products: A Potential Contributor of Oxidative Stress for Cardio-Vascular Problems in Diabetes. OXIDATIVE STRESS IN HEART DISEASES 2019:437-459. [DOI: 10.1007/978-981-13-8273-4_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Cai JG, Luo LM, Tang H, Zhou L. Cytotoxicity of Malondialdehyde and Cytoprotective Effects of Taurine via Oxidative Stress and PGC-1α Signal Pathway in C2C12 Cells. Mol Biol 2018. [DOI: 10.1134/s0026893318040040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Alejandra Sánchez-Muñoz M, Valdez-Solana MA, Campos-Almazán MI, Flores-Herrera Ó, Esparza-Perusquía M, Olvera-Sánchez S, García-Arenas G, Avitia-Domínguez C, Téllez-Valencia A, Sierra-Campos E. Streptozotocin-Induced Adaptive Modification of Mitochondrial Supercomplexes in Liver of Wistar Rats and the Protective Effect of Moringa oleifera Lam. Biochem Res Int 2018; 2018:5681081. [PMID: 29686903 PMCID: PMC5852898 DOI: 10.1155/2018/5681081] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 12/28/2017] [Indexed: 12/04/2022] Open
Abstract
The increasing prevalence of diabetes continues to be a major health issue worldwide. Alteration of mitochondrial electron transport chain is a recognized hallmark of the diabetic-associated decline in liver bioenergetics; however, the molecular events involved are only poorly understood. Moringa oleifera is used for the treatment of diabetes. However, its role on mitochondrial functionality is not yet established. This study was aimed to evaluate the effect of M. oleifera extract on supercomplex formation, ATPase activity, ROS production, GSH levels, lipid peroxidation, and protein carbonylation. The levels of lipid peroxidation and protein carbonylation were increased in diabetic group. However, the levels were decreased in Moringa-treated diabetic rats. Analysis of in-gel activity showed an increase in all complex activities in the diabetic group, but spectrophotometric determinations of complex II and IV activities were unaffected in this treatment. However, we found an oxygen consumption abolition through complex I-III-IV pathway in the diabetic group treated with Moringa. While respiration with succinate feeding into complex II-III-IV was increased in the diabetic group. These findings suggest that hyperglycemia modifies oxygen consumption, supercomplexes formation, and increases ROS levels in mitochondria from the liver of STZ-diabetic rats, whereas M. oleifera may have a protective role against some alterations.
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Affiliation(s)
| | | | - Mara Ibeth Campos-Almazán
- Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango Campus, Durango, DGO, Mexico
| | - Óscar Flores-Herrera
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Mercedes Esparza-Perusquía
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Sofia Olvera-Sánchez
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Guadalupe García-Arenas
- Facultad de Ciencias de la Salud, Universidad Juárez del Estado de Durango Campus, Gómez Palacio, DGO, Mexico
| | - Claudia Avitia-Domínguez
- Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango Campus, Durango, DGO, Mexico
| | - Alfredo Téllez-Valencia
- Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango Campus, Durango, DGO, Mexico
| | - Erick Sierra-Campos
- Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango Campus, Gómez Palacio, DGO, Mexico
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Bacevic M, Brkovic B, Albert A, Rompen E, Radermecker RP, Lambert F. Does Oxidative Stress Play a Role in Altered Characteristics of Diabetic Bone? A Systematic Review. Calcif Tissue Int 2017; 101:553-563. [PMID: 29063963 DOI: 10.1007/s00223-017-0327-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 09/12/2017] [Indexed: 01/22/2023]
Abstract
Diabetes mellitus (DM) has been associated with increased bone fracture rates, impaired bone regeneration, delayed bone healing, and depressed osteogenesis. However, the plausible pathogenic mechanisms remain incompletely understood. The aim of the present systematic review was to investigate whether oxidative stress (OS) plays a role in altered characteristics of diabetic bone under in vivo conditions. An electronic search of the MEDLINE (via PubMed) and Embase databases was performed. In vivo animal studies involving DM and providing information regarding assessment of OS markers combined with analyses of bone histology/histomorphometry parameters were selected. A descriptive analysis of selected articles was performed. Ten studies were included in the present review. Both bone formation and bone resorption parameters were significantly decreased in the diabetic groups of animals compared to the healthy groups. This finding was consistent regardless of different animal/bone models employed or different evaluation periods. A statistically significant increase in systemic and/or local OS status was also emphasised in the diabetic groups in comparison to the healthy ones. Markers of OS were associated with histological and/or histomorphometric parameters, including decreased trabecular bone and osteoid volumes, suppressed bone formation, defective bone mineralisation, and reduced osteoclastic activity, in diabetic animals. Additionally, insulin and antioxidative treatment proved to be efficient in reversing the deleterious effects of high glucose and associated OS. The present findings support the hypotheses that OS in the diabetic condition contributes at least partially to defective bone features, and that antioxidative supplementation can be a valuable adjunctive strategy in treating diabetic bone disease, accelerating bone healing, and improving osteointegration.
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Affiliation(s)
- Miljana Bacevic
- Dental Biomaterials Research Unit (d-BRU), Faculty of Medicine, University of Liege, Liège, Belgium
- Clinic of Oral Surgery, School of Dental Medicine, University of Belgrade, Belgrade, Serbia
| | - Bozidar Brkovic
- Clinic of Oral Surgery, School of Dental Medicine, University of Belgrade, Belgrade, Serbia
| | - Adelin Albert
- Department of Biostatistics, University Hospital of Liege, Liège, Belgium
| | - Eric Rompen
- Department of Periodontology and Oral Surgery, Faculty of Medicine, University of Liege, Liège, Belgium
| | - Regis P Radermecker
- Department of Diabetes, Nutrition and Metabolic Disorders, University Hospital of Liege, Liège, Belgium
| | - France Lambert
- Dental Biomaterials Research Unit (d-BRU), Faculty of Medicine, University of Liege, Liège, Belgium.
- Department of Periodontology and Oral Surgery, Faculty of Medicine, University of Liege, Liège, Belgium.
- Service de Médecine Dentaire, Domaine du Sart Tilman Bat B-35, 4000, Liège, Belgium.
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Abstract
Hepato-cellular carcinoma (HCC) is one of the frequent cause of cancer-related death worldwide and dominant form of primary liver cancer. However, the reason behind a steady increase in the incidence of this form of cancer remains elusive. Glycation has been reported to play a significant role in the induction of several chronic diseases including cancer. Several risk factors that could induce HCC have been reported in the literature. Deciphering the complex patho-physiology associated with HCC is expected to provide new targets for the early detection, prevention, progression and recurrence. Even-though, some of the causative aspects of HCC is known, the advanced glycation end products (AGEs) related mechanism still needs further research. In the current manuscript, we have tried to uncover the possible role of glycation in the induction of HCC. In the light of the available scientific literature, we advocate in-depth comprehensive studies which will shed light towards mechanistic association of glycation with HCC.
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Affiliation(s)
- Nasimudeen R Jabir
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Saheem Ahmad
- Department of Bio-Sciences, Integral University, Lucknow, 226021, India
| | - Shams Tabrez
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
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Aral CA, Nalbantoğlu Ö, Nur BG, Altunsoy M, Aral K. Metabolic control and periodontal treatment decreases elevated oxidative stress in the early phases of type 1 diabetes onset. Arch Oral Biol 2017. [PMID: 28628802 DOI: 10.1016/j.archoralbio.2017.06.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Recently, increasing concern has been focused on the contribution of oxidative stress in the pathology of periodontal disease and diabetes mellitus. Firstly, the present study aimed to analyze gingival crevicular fluid (GCF), salivary, and serum oxidative status in children with type 1 diabetes mellitus (T1DM) at diagnosis and systemically healthy children with and without gingivitis. Additionally, the diabetic patients were reevaluated after diabetes and periodontal treatment. DESIGN The study groups were composed of 32 T1DM patients at diagnosis, and age- and gender-matched thirty-six systemically healthy children with (G) and without (H) gingivitis. The diabetic patients who took insulin therapy (1.5 units/kg/day totally) and periodontal treatment (oral hygiene education with professional scaling) were reevaluated after 3 months. The levels of total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were recorded. RESULTS GCF, salivary, and serum OSI were elevated in group T1DM compared to the other groups at baseline (p<0.05), and decreased in group T1DM at reevaluation compared to baseline (p<0.05). GCF OSI was positively correlated with periodontal clinical parameters (p<0.05). Glycated hemoglobin was positively correlated with GCF TOS (r=0.302, p=0.007), GCF OSI (r=0.346, p=0.002), salivary TOS (r=0.326, p=0.046), and serum TOS (r=0.239, p=0.044). CONCLUSION The instability in the oxidative status that accompanies diabetes may be considered a significant pathogenic factor of diabetes-related periodontal inflammation.
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Affiliation(s)
- Cüneyt A Aral
- Division of Periodontology, Malatya Oral and Dental Health Hospital, The Turkish Ministry of Health, Malatya, Turkey.
| | - Özlem Nalbantoğlu
- Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Hospital, İzmir, Turkey
| | - Bilge G Nur
- Division of Pediatric Dentistry, Private Practice, İzmir, Turkey
| | - Mustafa Altunsoy
- Division of Pediatric Dentistry, Private Practice, İzmir, Turkey
| | - Kübra Aral
- Division of Periodontology, Malatya Oral and Dental Health Hospital, The Turkish Ministry of Health, Malatya, Turkey
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Suh KS, Chon S, Choi EM. Actein protects against methylglyoxal-induced oxidative damage in osteoblastic MC3T3-E1 cells. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2017; 97:207-214. [PMID: 26991449 DOI: 10.1002/jsfa.7713] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 02/24/2016] [Accepted: 03/07/2016] [Indexed: 06/05/2023]
Abstract
BACKGROUND Methylglyoxal (MG) is an endogenous product of glucose metabolism known to be toxic to cells and to be present in elevated concentrations under certain pathophysiological conditions. In the present study the effect of actein isolated from black cohosh on MG-induced cytotoxicity was investigated in MC3T3-E1 osteoblastic cells. RESULTS Treatment of MC3T3-E1 osteoblastic cells with actein prevented MG-induced cell death and the production of intracellular reactive oxygen species (ROS), mitochondrial superoxide, inflammatory cytokines and soluble receptor for advanced glycation end-products (sRAGE). In addition, actein increased the activity of glyoxalase I and levels of reduced glutathione (GSH) and the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). These findings suggest that actein protects against MG-induced cell damage by reducing oxidative stress and increasing MG detoxification. Treatment with actein prior to MG exposure reduced MG-induced mitochondrial dysfunction by preventing mitochondrial membrane potential dissipation and adenosine triphosphate (ATP) loss. Additionally, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and nitric oxide (NO) levels were significantly increased by actein, suggesting that actein may induce mitochondrial biogenesis. CONCLUSION This study demonstrates that actein reduces MG-induced damage in osteoblastic MC3T3-E1 cells by enhancing antioxidant defenses, the glyoxalase system and mitochondrial biogenesis. © 2016 Society of Chemical Industry.
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Affiliation(s)
- Kwang Sik Suh
- Research Institute of Endocrinology, Kyung Hee University Hospital, 1, Hoegi-dong, Dongdaemun-gu, Seoul, 130-702, Republic of Korea
| | - Suk Chon
- Department of Endocrinology and Metabolism, School of Medicine, Kyung Hee University, 1, Hoegi-dong, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
| | - Eun Mi Choi
- Department of Endocrinology and Metabolism, School of Medicine, Kyung Hee University, 1, Hoegi-dong, Dongdaemun-gu, Seoul, 130-701, Republic of Korea
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Immunomodulatory effects of adipose tissue-derived stem cells on elastin scaffold remodeling in diabetes. Tissue Eng Regen Med 2016; 13:701-712. [PMID: 30603451 DOI: 10.1007/s13770-016-0018-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/02/2016] [Accepted: 03/04/2016] [Indexed: 01/11/2023] Open
Abstract
Diabetes is a major risk factor for the progression of vascular disease, contributing to elevated levels of glycoxidation, chronic inflammation and calcification. Tissue engineering emerges as a potential solution for the treatment of vascular diseases however there is a considerable gap in the understanding of how scaffolds and stem cells will perform in patients with diabetes. We hypothesized that adipose tissue-derived stem cells (ASCs) by virtue of their immunosuppressive potential would moderate the diabetes-intensified inflammatory reactions and induce positive construct remodeling. To test this hypothesis, we prepared arterial elastin scaffolds seeded with autologous ASCs and implanted them subdermally in diabetic rats and compared inflammatory markers, macrophage polarization, matrix remodeling, calcification and bone protein expression to control scaffolds implanted with and without cells in nondiabetic rats. ASC-seeded scaffolds exhibited lower levels of CD8+ T-cells and CD68+ pan-macrophages and higher numbers of M2 macrophages, smooth muscle cell-like and fibroblast-like cells. Calcification and osteogenic markers were reduced in ASCseeded scaffolds implanted in non-diabetic rats but remained unchanged in diabetes, unless the scaffolds were first pre-treated with penta-galloyl glucose (PGG), a known anti-oxidative elastin-binding polyphenol. In conclusion, autologous ASC seeding in elastin scaffolds is effective in combating diabetes-related complications. To prevent calcification, the oxidative milieu needs to be reduced by elastin-binding antioxidants such as PGG.
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Korabecna M, Tesar V. NETosis provides the link between activation of neutrophils on hemodialysis membrane and comorbidities in dialyzed patients. Inflamm Res 2016; 66:369-378. [PMID: 27885378 PMCID: PMC5380691 DOI: 10.1007/s00011-016-1010-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 11/11/2016] [Accepted: 11/15/2016] [Indexed: 01/11/2023] Open
Abstract
INTRODUCTION Neutrophil extracellular traps (NETs) are formed by activated neutrophils during the process of NETosis in which the nuclear material is released into extracellular space, including DNA molecules, citrullinated histones, and neutrophil granule enzymes, such as elastase. This material forms networks that are able not only to physically entrap bacteria but also to provide elevated concentration of bactericidal components. Over the last years, it has become clear that NETs can also be formed under numerous sterile inflammatory conditions, i.e., thrombosis, cancer, SLE, atherosclerosis, and diabetes. METHOD We reviewed studies published until July 2016 to find possible associations between elevated cell-free DNA levels in dialyzed patients and the process of NETosis and its consequences. RESULTS The process of NETosis, its elevated activation, or impaired clearance provides the link between clinical conditions and elevated levels of cell-free DNA found in plasma after the hemodialytic procedure which itself is able to activate neutrophils via platelets and ROS formation. NETs stimulate thrombosis and endothelial damage, and their formation may contribute to the development of spectrum of comorbidities described in dialyzed patients. CONCLUSION The study of plasma cell-free DNA levels together with markers of NETosis could contribute to the evaluation of the influence of hemodialysis on the immune system of patients.
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Affiliation(s)
- Marie Korabecna
- Department of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Albertov 4, 128 00, Prague, Czech Republic.
| | - Vladimir Tesar
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 128 08, Prague, Czech Republic
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Abstract
While the socioeconomic and environmental factors associated with cancer disparity have been well documented, the contribution of biological factors is an emerging field of research. Established disparity factors such as low income, poor diet, drinking alcohol, smoking, and a sedentary lifestyle may have molecular effects on the inherent biological makeup of the tumor itself, possibly altering cell signaling events and gene expression profiles to profoundly alter tumor development and progression. Our understanding of the molecular and biological consequences of poor lifestyle is lacking, but such information may significantly change how we approach goals to reduce cancer incidence and mortality rates within minority populations. In this review, we will summarize the biological, socioeconomic, and environmental associations between a group of reactive metabolites known as advanced glycation end-products (AGEs) and cancer health disparity. Due to their links with lifestyle and the activation of disease-associated pathways, AGEs may represent both a biological consequence and a bio-behavioral indicator of poor lifestyle which may be targeted within specific populations to reduce disparities in cancer incidence and mortality.
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Affiliation(s)
- D P Turner
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.
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Fadini GP, Menegazzo L, Scattolini V, Gintoli M, Albiero M, Avogaro A. A perspective on NETosis in diabetes and cardiometabolic disorders. Nutr Metab Cardiovasc Dis 2016; 26:1-8. [PMID: 26719220 DOI: 10.1016/j.numecd.2015.11.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 11/12/2015] [Accepted: 11/16/2015] [Indexed: 01/18/2023]
Abstract
AIMS To review the significance of a new type of neutrophil cell death (NETosis) in diabetes and cardiometabolic diseases. DATA SYNTHESIS Diabetes and the metabolic syndrome are characterized by activation of the innate immune system. In this framework, neutrophils are front line defences against infections, but can also turn deleterious if abnormally stimulated. NETosis refers to a type of cell death whereby neutrophils release nuclear material and granule enzymes that together form the NETs (neutrophil extracellular traps). As NETs entrap bacteria, NETosis is instrumental to the clearance of microorganisms, but an exaggerated NETosis response can also lead to tissue damage in several pathological conditions. In diabetes, the finely tuned balance of NETosis required to protect the human body from microorganisms yet avoiding self-damage seems to be lost. In fact, in vitro induction of NETosis and circulating concentrations of NET-associated proteins appear to be enhanced in diabetic patients. Furthermore, NETs contribute to endothelial damage, thrombosis, and ischemia/reperfusion injury, making it a novel player in the pathobiology of cardiovascular disease. Though the cellular events taking place during NETosis have been described and directly visualized, its molecular machinery is still incompletely understood. Protein kinase C (PKC) and NADPH oxidase (NOX) are two important targets to counter NETosis in the setting of diabetes. CONCLUSIONS NETosis appears to be part of an abnormal response to damage in diabetes that, in turn, can promote or aggravate end-organ complications. We suggest that this will be a hot topic of investigation in diabetology in the near future.
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Affiliation(s)
- G P Fadini
- Department of Medicine, University of Padova, 35128 Padova, Italy; Venetian Institute of Molecular Medicine, 35129 Padova, Italy.
| | - L Menegazzo
- Department of Medicine, University of Padova, 35128 Padova, Italy; Venetian Institute of Molecular Medicine, 35129 Padova, Italy
| | - V Scattolini
- Department of Medicine, University of Padova, 35128 Padova, Italy; Venetian Institute of Molecular Medicine, 35129 Padova, Italy
| | - M Gintoli
- Department of Physics and Astronomy "G. Galilei", University of Padova, 35131 Padova, Italy
| | - M Albiero
- Department of Medicine, University of Padova, 35128 Padova, Italy; Venetian Institute of Molecular Medicine, 35129 Padova, Italy
| | - A Avogaro
- Department of Medicine, University of Padova, 35128 Padova, Italy; Venetian Institute of Molecular Medicine, 35129 Padova, Italy
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44
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Xiang L, Mittwede PN, Clemmer JS. Glucose Homeostasis and Cardiovascular Alterations in Diabetes. Compr Physiol 2015; 5:1815-39. [PMID: 26426468 DOI: 10.1002/cphy.c150001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Glorieux G, Mullen W, Duranton F, Filip S, Gayrard N, Husi H, Schepers E, Neirynck N, Schanstra JP, Jankowski J, Mischak H, Argilés À, Vanholder R, Vlahou A, Klein J. New insights in molecular mechanisms involved in chronic kidney disease using high-resolution plasma proteome analysis. Nephrol Dial Transplant 2015; 30:1842-52. [PMID: 26160894 DOI: 10.1093/ndt/gfv254] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 05/21/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The reduced glomerular filtration rate in the advanced stages of chronic kidney disease (CKD) leads to plasma accumulation of uraemic retention solutes including proteins. It has been hypothesized that these changes may, at least in part, be responsible for CKD-associated morbidity and mortality. However, most studies focused on the role of individual proteins, while a holistic, large-scale, integrative approach may generate significant additional insight. METHODS In a discovery study, we analysed the plasma proteome of patients with stage 2-3 CKD (n = 14) and stage 5 CKD with haemodialysis (HD) (n = 15), using high-resolution LC-MS/MS analysis. Selected results were validated in a cohort of 40 patients with different CKD stages with or without HD, using ELISA. RESULTS Of a total of 2054 detected proteins, 127 displayed lower, while 206 displayed higher abundance in the plasma of patients on HD. Molecular pathway analysis confirmed the modification of known processes involved in CKD complications, including decreased haemostasis and increased inflammation, complement activation and vascular damage. In addition, we identified the plasma increase during CKD progression of lysozyme C and leucine-rich alpha-2 glycoprotein, two proteins related to vascular damage and heart failure. High level of leucine-rich alpha-2 glycoprotein was associated with higher mortality in stage 5 CKD patients on HD. CONCLUSIONS This study provides for the first time a comprehensive assessment of CKD plasma proteome, contributing to new knowledge and potential markers of CKD. These results will serve as a basis for future studies investigating the relevance of these molecules in CKD associated morbidity and mortality.
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Affiliation(s)
- Griet Glorieux
- Nephrology Section, Ghent University Hospital, Gent, Belgium
| | - William Mullen
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | | | - Szymon Filip
- Biomedical Research Foundation, Academy of Athens, Athens, Greece Charité - Universitätsmedizin Berlin, Berlin, Germany
| | | | - Holger Husi
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Eva Schepers
- Nephrology Section, Ghent University Hospital, Gent, Belgium
| | | | - Joost P Schanstra
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Joachim Jankowski
- University Hospital RWTH, Institute for Molecular Cardiovascular Research, Aachen, Germany
| | - Harald Mischak
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK Mosaiques Diagnostics, Hannover, Germany
| | | | | | - Antonia Vlahou
- Biomedical Research Foundation, Academy of Athens, Athens, Greece School of Biomedical & Healthcare Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | - Julie Klein
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France
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Wang XL, Yu T, Yan QC, Wang W, Meng N, Li XJ, Luo YH. AGEs Promote Oxidative Stress and Induce Apoptosis in Retinal Pigmented Epithelium Cells RAGE-dependently. J Mol Neurosci 2015; 56:449-60. [PMID: 25682235 DOI: 10.1007/s12031-015-0496-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 01/13/2015] [Indexed: 12/11/2022]
Abstract
Advanced glycation end products (AGEs) are extremely accumulated in diabetes mellitus, particularly in retinal vascular and epithelium cells, and are confirmed to contribute to diabetic retinopathy (DR). In the present study, we determined the promotion by AGEs to the oxidative stress and mitochondrial dysfunction in retinal pigmented epithelium ARPE-19 cells and investigated the influence by the knockdown or the overexpression of receptor for AGEs (RAGE) on the AGE-promoted oxidative stress and mitochondrial dysfunction. Furthermore, we determined the induction by AGEs to the cell apoptosis and to the activation of B-cell lymphoma 2 (Bcl-2) families in the AGE-BSA-induced apoptosis, and examined the RAGE-dependence in such induction. Results demonstrated that AGE-BSA upregulated the hydrogen peroxide production and induced mitochondrial dysfunction in ARPE-19 cells, dose-dependently. And the further investigation indicated that the AGE-RAGE interaction was required for the induction of oxidative stress and mitochondrial dysfunction. Moreover, the AGE-BSA treatment promoted a significantly high level of apoptotic cells, and the Bcl-2 family was implicated in the AGE-BSA-induced apoptosis, there was a significant high level of Cyt c release, Bcl-2-associated X protein (Bax) induction, Bcl-2 reduction, and caspase 9 activation in the AGE-BSA-treated cells. In conclusion, the present study recognized the apoptosis induction by AGE-BSAs in the retinal epithelium ARPE-19 cells, RAGE-dependently. The mitochondrial dysfunction was induced, and the Bcl-2 family was deregulated during the AGE-BSA-induced ARPE-19 cell apoptosis.
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Affiliation(s)
- Xin-Ling Wang
- Department of Ophthalmology, The Fourth Affiliated Hospital, China Medical University, No. 11 Xinhua Road, Heping District, Shenyang, 110005, China,
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Abstract
Cardiovascular disease is the most common cause of the greatly elevated rates of mortality characteristic of patients undergoing maintenance hemodialysis. This article is an attempt to describe the complex and evolving features of cardiac disease routinely encountered in HD patients. Furthermore, by trying to appreciate the pathophysiological drivers, and the crucial interaction with the HD treatment itself, this article seeks to define cardiac disease in this setting (HD-associated cardiomyopathy) as a unique and complex entity. By understanding the phenotype and basis of HD-associated cardiomyopathy, we can develop an evolved understanding of the dominant processes involved in its development and offer up dialysis-based interventions specifically designed to mitigate the cumulative ischemic insults consequent to conventional HD treatment. This article explores the justification of this approach and recent evidence of its efficacy.
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48
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Gamage AM, Lee KO, Gan YH. Effect of oral N-acetyl cysteine supplementation in type 2 diabetic patients on intracellular glutathione content and innate immune responses to Burkholderia pseudomallei. Microbes Infect 2014; 16:661-71. [PMID: 25088507 DOI: 10.1016/j.micinf.2014.07.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 07/10/2014] [Accepted: 07/21/2014] [Indexed: 01/23/2023]
Abstract
Type 2 diabetic patients have increased susceptibility to melioidosis, an infectious disease caused by Burkholderia pseudomallei. We had previously shown that peripheral blood mononuclear cells (PBMCs) from diabetic patients with poor glycemic control had a defective IL-12 and IFNγ response to B. pseudomallei infection, resulting in poor intracellular bacterial control. The impaired IL-12 response was due to glutathione (GSH) deficiency characterized by a low reduced to oxidized glutathione ratio (GSH ratio) and could be restored by the addition of reduced GSH to the infected cells. Our goal is to determine whether N-acetyl cysteine (NAC, a GSH pro-drug) supplementation in diabetic patients could improve their immune control of B. pseudomallei. Type 2 diabetic patients with poor glycemic control were given oral supplementation of NAC for six weeks at 1200 mg daily. Their PBMCs and subsets of immune cells showed a significant increase in free GSH concentration. However, the GSH ratio, IL-12 and IFNγ production, and intracellular bacterial killing upon ex-vivo infection did not improve. Thus, oral NAC supplementation in diabetic patients is sufficient to increase intracellular GSH content in blood cells. However, modulating the free GSH content is not sufficient to improve infection outcome as it is the GSH ratio that regulates the IL-12 response in monocytes.
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Affiliation(s)
- Akshamal M Gamage
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD7, 8 Medical Drive, Singapore 117597, Singapore
| | - Kok Onn Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road NUHS Tower Block Level 10 Singapore 119228, Singapore
| | - Yunn-Hwen Gan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD7, 8 Medical Drive, Singapore 117597, Singapore; Immunology Program, National University of Singapore, Singapore.
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Suh KS, Rhee SY, Kim YS, Choi EM. Inhibitory effect of apocynin on methylglyoxal-mediated glycation in osteoblastic MC3T3-E1 cells. J Appl Toxicol 2014; 35:350-7. [PMID: 25042521 DOI: 10.1002/jat.3016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 03/17/2014] [Accepted: 03/17/2014] [Indexed: 12/31/2022]
Abstract
Methylglyoxal (MG), a highly reactive metabolite of hyperglycemia, can enhance protein glycation, oxidative stress or inflammation. The present study investigated the effects of apocynin on the mechanisms associated with MG toxicity in osteoblastic MC3T3-E1 cells. Pretreatment of MC3T3-E1 cells with apocynin prevented the MG-induced protein glycation and formation of intracellular reactive oxygen species and mitochondrial superoxide in MC3T3-E1 cells. In addition, apocynin increased glutathione levels and restored the activity of glyoxalase I inhibited by MG. These findings suggest that apocynin provide a protective action against MG-induced cell damage by reducing oxidative stress and by increasing the MG detoxification system. Apocynin treatment decreased the levels of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6 induced by MG. Additionally, the nitric oxide level reduced by MG was significantly increased by apocynin. These findings indicate that apocynin might exert its therapeutic effects via upregulation of glyoxalase system and antioxidant activity. Taken together, apocynin may prove to be an effective treatment for diabetic osteopathy.
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Affiliation(s)
- Kwang Sik Suh
- Research Institute of Endocrinology, Kyung Hee University Hospital, 1, Hoegi-dong, Dongdaemun-gu, Seoul, 130-702, Republic of Korea
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Chawla D, Bansal S, Banerjee BD, Madhu SV, Kalra OP, Tripathi AK. Role of advanced glycation end product (AGE)-induced receptor (RAGE) expression in diabetic vascular complications. Microvasc Res 2014; 95:1-6. [PMID: 24984291 DOI: 10.1016/j.mvr.2014.06.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 06/20/2014] [Accepted: 06/21/2014] [Indexed: 12/19/2022]
Abstract
AIMS Vascular complications are the major causes of morbidity and mortality in diabetic subjects. Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) induces signal transduction that culminates in vascular complications. Therefore, in the present study we investigated the dependence of RAGE expression on circulating AGEs and evaluated the outcome of AGE-RAGE interaction by the oxidative stress and nature of vascular complications in type 2 diabetes mellitus (T2DM) patients. METHODS RAGE expression was determined by quantitative real-time PCR and western blotting, serum AGEs were estimated by ELISA and spectrofluorometry and oxidative stress markers namely protein carbonyl (PCO), advanced oxidation protein products (AOPP) and lipid peroxidation (MDA) were assayed spectrophotometerically in 75 T2DM patients (DM without vascular complication n=25; DM with microvascular complications n=25; DM with macrovascular complications n=25) and 25 healthy controls. RESULTS Serum AGE level was significantly higher in diabetic patients having vascular complications as compared to T2DM without complications (p<0.01). RAGE m-RNA expression level in PBMCs assayed by quantitative real time PCR was four times higher in diabetic subjects without vascular complications while DM patients having microvascular and macrovascular complications showed 12 fold and 8 fold higher RAGE m-RNA expression respectively compared to healthy controls. Circulating AGE level showed significant positive correlation with RAGE m-RNA expression and oxidative stress markers. CONCLUSION AGE-mediated exacerbation of RAGE expression may contribute to oxidative stress generation that plays a key role in pathogenesis of vascular complications in diabetes.
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Affiliation(s)
- Diwesh Chawla
- Biochemistry and Immunology Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Savita Bansal
- Biochemistry and Immunology Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Basu Dev Banerjee
- Biochemistry and Immunology Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Sri Venkata Madhu
- Department of Medicine, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Om Prakash Kalra
- Department of Medicine, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Ashok Kumar Tripathi
- Biochemistry and Immunology Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
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