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Li W, Chen Q, Peng C, Yang D, Liu S, Lv Y, Jiang L, Xu S, Huang L. Roles of the Receptor for Advanced Glycation End Products and Its Ligands in the Pathogenesis of Alzheimer's Disease. Int J Mol Sci 2025; 26:403. [PMID: 39796257 PMCID: PMC11721675 DOI: 10.3390/ijms26010403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/02/2025] [Accepted: 01/04/2025] [Indexed: 01/13/2025] Open
Abstract
The Receptor for Advanced Glycation End Products (RAGE), part of the immunoglobulin superfamily, plays a significant role in various essential functions under both normal and pathological conditions, especially in the progression of Alzheimer's disease (AD). RAGE engages with several damage-associated molecular patterns (DAMPs), including advanced glycation end products (AGEs), beta-amyloid peptide (Aβ), high mobility group box 1 (HMGB1), and S100 calcium-binding proteins. This interaction impairs the brain's ability to clear Aβ, resulting in increased Aβ accumulation, neuronal injury, and mitochondrial dysfunction. This further promotes inflammatory responses and oxidative stress, ultimately leading to a range of age-related diseases. Given RAGE's significant role in AD, inhibitors that target RAGE and its ligands hold promise as new strategies for treating AD, offering new possibilities for alleviating and treating this serious neurodegenerative disease. This article reviews the various pathogenic mechanisms of AD and summarizes the literature on the interaction between RAGE and its ligands in various AD-related pathological processes, with a particular focus on the evidence and mechanisms by which RAGE interactions with AGEs, HMGB1, Aβ, and S100 proteins induce cognitive impairment in AD. Furthermore, the article discusses the principles of action of RAGE inhibitors and inhibitors targeting RAGE-ligand interactions, along with relevant clinical trials.
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Affiliation(s)
- Wen Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (W.L.); (Q.C.); (C.P.); (D.Y.); (S.L.); (Y.L.); (L.J.)
| | - Qiuping Chen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (W.L.); (Q.C.); (C.P.); (D.Y.); (S.L.); (Y.L.); (L.J.)
| | - Chengjie Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (W.L.); (Q.C.); (C.P.); (D.Y.); (S.L.); (Y.L.); (L.J.)
| | - Dan Yang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (W.L.); (Q.C.); (C.P.); (D.Y.); (S.L.); (Y.L.); (L.J.)
| | - Si Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (W.L.); (Q.C.); (C.P.); (D.Y.); (S.L.); (Y.L.); (L.J.)
| | - Yanwen Lv
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (W.L.); (Q.C.); (C.P.); (D.Y.); (S.L.); (Y.L.); (L.J.)
| | - Langqi Jiang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (W.L.); (Q.C.); (C.P.); (D.Y.); (S.L.); (Y.L.); (L.J.)
| | - Shijun Xu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (W.L.); (Q.C.); (C.P.); (D.Y.); (S.L.); (Y.L.); (L.J.)
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China
- Institute of Material Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Lihua Huang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (W.L.); (Q.C.); (C.P.); (D.Y.); (S.L.); (Y.L.); (L.J.)
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China
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Shemesh S, Itzikovitch R, Atzmon R, Kadar A. Risk Factors for the Development of Olecranon Bursitis-A Large-Scale Population-Based Study. J Clin Med 2024; 13:7801. [PMID: 39768728 PMCID: PMC11728362 DOI: 10.3390/jcm13247801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 12/02/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025] Open
Abstract
Background: Olecranon bursitis (OB) involves fluid accumulation in the bursa, with common causes being trauma and preexisting conditions. Its incidence is difficult to quantify, and risk factors such as diabetes, obesity, and male gender are frequently noted. Hyperlipidemia has been linked to musculoskeletal disorders, but its role as a risk factor for OB remains unexplored. This study aimed to investigate the association between OB and hyperlipidemia, diabetes, obesity, cardiovascular disease, and statin use. Methods: A retrospective cohort study analyzed a large-scale database (2005-2020), ultimately including 10,301 patients with olecranon bursitis and 44,608 controls after applying exclusion criteria. Participants were aged 18-90 years, with BMI between 10 and 55. Key variables such as smoking, diabetes, hyperlipidemia, statin use, cardiovascular diseases (CVDs), and cerebrovascular accidents (CVAs) were analyzed. Logistic regression models were applied with stabilized inverse probability of treatment weighting (IPTW) to estimate odds ratios (ORs) for risk factors, and p-values were adjusted using the Benjamini-Hochberg method. Results: OB was significantly associated with male gender (OR: 1.406; p < 0.0001), hyperlipidemia (OR: 1.239; p < 0.0001), statin use (OR: 1.117; p = 0.0035), and smoking (OR: 1.068; p = 0.0094). Age and BMI were significant continuous variables influencing OB risk, particularly in older patients and those with elevated BMI. CVDs and diabetes were not significantly linked to OB. Hyperlipidemia increased OB risk, especially in males and individuals with higher BMI. Conclusions: Male gender, hyperlipidemia, and smoking are key risk factors for OB, with hyperlipidemia posing a notable risk in older individuals and those with higher BMI. Statin use did not significantly alter OB risk in hyperlipidemic patients. Further studies are needed to clarify the mechanisms behind these associations.
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Affiliation(s)
- Shai Shemesh
- Department of Orthopaedic Surgery, Samson Assuta Ashdod University Hospital, 7 Ha’Refua Street, Ashdod 77476, Israel;
- Faculty of Health Sciences, Ben Gurion University, Beer-Sheva 8410501, Israel
| | | | - Ran Atzmon
- Department of Orthopaedic Surgery, Samson Assuta Ashdod University Hospital, 7 Ha’Refua Street, Ashdod 77476, Israel;
- Faculty of Health Sciences, Ben Gurion University, Beer-Sheva 8410501, Israel
| | - Assaf Kadar
- Roth|McFarlane Hand & Upper Limb Centre, St. Joseph’s Hospital and Western University, London, ON N6A 4V2, Canada;
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Hayat C, Yaseen M, Ahmad S, Khalid K, Alamri MA, Khalid A, Shah SQ, Ejiohuo O, Wadood A, Maigoro AY, Kwon HW. Elucidating the interactions of advanced glycation end products with RAGE, employing molecular docking and MD simulation approaches: Implications of potent therapeutic for diabetes and its related complications. J Mol Liq 2024; 416:126467. [DOI: 10.1016/j.molliq.2024.126467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Nameni G, Jazayeri S, Fatahi S, Jamshidi S, Zaroudi M. Soluble receptor of advanced glycation end product as a biomarker in neurocognitive and neuropsychiatric disorders: A meta-analysis of controlled studies. Eur J Clin Invest 2024; 54:e14232. [PMID: 38700073 DOI: 10.1111/eci.14232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/27/2024] [Accepted: 04/06/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND & OBJECTIVES Currently, there is a significant focus on the decrease of soluble receptor of advanced glycation end products (sRAGE) in neurocognitive and neuropsychiatric disorders. sRAGE plays a decoy role against the inflammatory response of advanced glycation end products (AGE), which has led to increased interest in its role in these disorders. This meta-analysis aimed to investigate the significant differences in sRAGE levels between neurocognitive and neuropsychiatric disorders compared to control groups. METHOD A systematic review was conducted using the PUBMED, Scopus and Embase databases up to October 2023. Two reviewers assessed agreement for selecting papers based on titles and abstracts, with kappa used to measure agreement and finally publications were scanned according to controlled studies. Effect sizes were calculated as weighted mean differences (WMD) and pooled using a random effects model. Heterogeneity was assessed using I2, followed by subgroup analysis and meta-regression tests. Quality assessment was performed using the Newcastle-Ottawa Quality Assessment Scale. RESULTS In total, 16 studies were included in the present meta-analysis. Subjects with neurocognitive (n = 1444) and neuropsychiatric (n = 444) disorders had lower sRAGE levels in case-control (WMD: -0.21, 95% CI: -0.33, -0.10; p <.001) and cross-sectional (WMD: -0.29, 95% CI = -0.44, -0.13, p <.001) studies with high heterogeneity and no publication bias. In subgroup analysis, subjects with cognitive impairment (WMD: -0.87, 95% CI: -1.61, -0.13, p =.000), and age >50 years (WMD: -0.39, 95% CI: -0.74, -0.05, p =.000), had lower sRAGE levels in case-control studies. Also, dementia patients (WMD: -0.41, 95% CI: -0.72, -0.10, p =.014) with age >50 years (WMD: -0.33, 95% CI: -0.54, -0.13, p = 0.000) and in Asian countries (WMD: -0.28, 95% CI: -0.42, -0.13, p =.141) had lower sRAGE levels in cross-sectional studies. CONCLUSION This meta-analysis revealed a significant reduction in sRAGE in neurocognitive and neuropsychiatric disorders particularly in Asians and moderate age.
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Affiliation(s)
- Ghazaleh Nameni
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Shima Jazayeri
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Somaye Fatahi
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sanaz Jamshidi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Marsa Zaroudi
- Student Research Committee, Department of Nutrition, Faculty of Public Health Branch, Iran University of Medical Sciences, Tehran, Iran
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Durak Ş, Yılmazer Y, Çelik F, Yeşiloğlu E, Karaköse D, Dinçol S, Uçak S, Yaman M, Zeybek Ü. Investigation of Advanced Glycation End Products in Liver, Adipose, and Renal Tissue of Mice on a High-Fat Diet. Cell Biochem Biophys 2024; 82:1101-1108. [PMID: 38630412 DOI: 10.1007/s12013-024-01260-6] [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] [Accepted: 03/22/2024] [Indexed: 08/25/2024]
Abstract
Obesity is a complex condition associated with disruptions in carbohydrate, protein, and fat metabolism, linked to increased insulin resistance and glucose intolerance. High levels of Advanced Glycation End-products (AGEs) are associated with a range of chronic diseases, including kidney diseases, diabetic complications, cardiovascular diseases, and neurodegenerative diseases. Our study aims to investigate the accumulation of AGEs in the liver, renal and adipose tissues of mice fed a high-fat diet, contributing to a deeper understanding of obesity and its related metabolic disorders. Our study consists of three different groups fed with diets containing 60% and 10% fat. The Experiment 1 group was maintained on their diet for 12 weeks, while the obese 2 and control groups continued their diets for 24 weeks. AGEs in the liver and kidney tissues obtained were measured using the High-performance liquid chromatography grade (HPLC) method. Higher accumulation of AGEs has been observed in kidney tissue compared to adipose and liver tissues (p < 0.05). Moreover, the GO levels were notably higher in liver tissue than in adipose tissue of the D1 and D2 groups (p < 0.0001). Our results suggest that particularly in kidney tissue, increased filtration burden, functional impairment, and receptor interaction due to obesity may be effective. The lower levels of AGEs detected, especially in the obese groups compared to the control, can be attributed to the inability to metabolize AGEs due to tissue damage caused by obesity.
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Affiliation(s)
- Şermin Durak
- Faculty of Medicine, Department of Medical Microbiology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Yasemin Yılmazer
- Deparment of Molecular Biology and Genetics, Istanbul Sabahattin Zaim University, Istanbul, Turkey
| | - Faruk Çelik
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Ebrar Yeşiloğlu
- Deparment of Molecular Biology and Genetics, Istanbul Sabahattin Zaim University, Istanbul, Turkey
| | - Dilara Karaköse
- Deparment of Molecular Biology and Genetics, Istanbul Sabahattin Zaim University, Istanbul, Turkey
| | - Sena Dinçol
- Deparment of Molecular Biology and Genetics, Istanbul Sabahattin Zaim University, Istanbul, Turkey
| | - Sümeyye Uçak
- Deparment of Molecular Biology and Genetics, Istanbul Sabahattin Zaim University, Istanbul, Turkey
| | - Mustafa Yaman
- Deparment of Molecular Biology and Genetics, Istanbul Sabahattin Zaim University, Istanbul, Turkey
| | - Ümit Zeybek
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
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Fan KQ, Huang T, Yu JS, Li YY, Jin J. The clinical features and potential mechanisms of cognitive disorders in peripheral autoimmune and inflammatory diseases. FUNDAMENTAL RESEARCH 2024; 4:226-236. [PMID: 38933510 PMCID: PMC11197673 DOI: 10.1016/j.fmre.2022.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 10/15/2022] [Accepted: 12/05/2022] [Indexed: 12/26/2022] Open
Abstract
According to a study from World Health Organization's Global Burden of Disease, mental and neurological disorders have accounted for 13% of global diseases in recent years and are on the rise. Neuropsychiatric conditions or neuroinflammatory disorders are linked by the presence of an exaggerated immune response both peripherally and in the central nervous system (CNS). Cognitive dysfunction (CD) encompasses a complex group of diseases and has frequently been described in the field of autoimmune diseases, especially in multiple non-CNS-related autoimmune diseases. Recent studies have provided various hypotheses regarding the occurrence of cognitive impairment in autoimmune diseases, including that abnormally activated immune cells can disrupt the integrity of the blood-brain barrier (BBB) to trigger a central neuroinflammatory response. When the BBB is intact, autoantibodies and pro-inflammatory molecules in peripheral circulation can enter the brain to activate microglia, inducing CNS inflammation and CD. However, the mechanisms explaining the association between the immune system and neural function and their contribution to diseases are uncertain. In this review, we used clinical statistics to illustrate the correlation between CD and autoimmune diseases that do not directly affect the CNS, summarized the clinical features and mechanisms by which autoimmune diseases trigger cognitive impairment, and explored existing knowledge regarding the link between CD and autoimmune diseases from the perspective of the field of neuroimmunology.
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Affiliation(s)
- Ke-qi Fan
- MOE Laboratory of Biosystem Homeostasis and Protection, and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Gastroenterology, Sir Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
| | - Tao Huang
- MOE Laboratory of Biosystem Homeostasis and Protection, and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Gastroenterology, Sir Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
| | - Jian-shuai Yu
- MOE Laboratory of Biosystem Homeostasis and Protection, and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Yi-yuan Li
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China
| | - Jin Jin
- MOE Laboratory of Biosystem Homeostasis and Protection, and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Gastroenterology, Sir Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
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Kulovic-Sissawo A, Tocantins C, Diniz MS, Weiss E, Steiner A, Tokic S, Madreiter-Sokolowski CT, Pereira SP, Hiden U. Mitochondrial Dysfunction in Endothelial Progenitor Cells: Unraveling Insights from Vascular Endothelial Cells. BIOLOGY 2024; 13:70. [PMID: 38392289 PMCID: PMC10886154 DOI: 10.3390/biology13020070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 02/24/2024]
Abstract
Endothelial dysfunction is associated with several lifestyle-related diseases, including cardiovascular and neurodegenerative diseases, and it contributes significantly to the global health burden. Recent research indicates a link between cardiovascular risk factors (CVRFs), excessive production of reactive oxygen species (ROS), mitochondrial impairment, and endothelial dysfunction. Circulating endothelial progenitor cells (EPCs) are recruited into the vessel wall to maintain appropriate endothelial function, repair, and angiogenesis. After attachment, EPCs differentiate into mature endothelial cells (ECs). Like ECs, EPCs are also susceptible to CVRFs, including metabolic dysfunction and chronic inflammation. Therefore, mitochondrial dysfunction of EPCs may have long-term effects on the function of the mature ECs into which EPCs differentiate, particularly in the presence of endothelial damage. However, a link between CVRFs and impaired mitochondrial function in EPCs has hardly been investigated. In this review, we aim to consolidate existing knowledge on the development of mitochondrial and endothelial dysfunction in the vascular endothelium, place it in the context of recent studies investigating the consequences of CVRFs on EPCs, and discuss the role of mitochondrial dysfunction. Thus, we aim to gain a comprehensive understanding of mechanisms involved in EPC deterioration in relation to CVRFs and address potential therapeutic interventions targeting mitochondrial health to promote endothelial function.
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Affiliation(s)
- Azra Kulovic-Sissawo
- Perinatal Research Laboratory, Department of Obstetrics and Gynaecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
- Research Unit Early Life Determinants (ELiD), Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
| | - Carolina Tocantins
- Perinatal Research Laboratory, Department of Obstetrics and Gynaecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
- Research Unit Early Life Determinants (ELiD), Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
- CNC-UC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-504 Coimbra, Portugal
- Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Mariana S Diniz
- Perinatal Research Laboratory, Department of Obstetrics and Gynaecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
- Research Unit Early Life Determinants (ELiD), Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
- CNC-UC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-504 Coimbra, Portugal
- Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Elisa Weiss
- Perinatal Research Laboratory, Department of Obstetrics and Gynaecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
- Research Unit Early Life Determinants (ELiD), Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
| | - Andreas Steiner
- Perinatal Research Laboratory, Department of Obstetrics and Gynaecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
- Research Unit Early Life Determinants (ELiD), Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
| | - Silvija Tokic
- Research Unit of Analytical Mass Spectrometry, Cell Biology and Biochemistry of Inborn Errors of Metabolism, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 34, 8036 Graz, Austria
| | - Corina T Madreiter-Sokolowski
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
| | - Susana P Pereira
- CNC-UC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-504 Coimbra, Portugal
- Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sports, University of Porto, 4200-450 Porto, Portugal
| | - Ursula Hiden
- Perinatal Research Laboratory, Department of Obstetrics and Gynaecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
- Research Unit Early Life Determinants (ELiD), Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
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Lai SWT, Bhattacharya S, Lopez Gonzalez EDJ, Shuck SC. Methylglyoxal-Derived Nucleoside Adducts Drive Vascular Dysfunction in a RAGE-Dependent Manner. Antioxidants (Basel) 2024; 13:85. [PMID: 38247509 PMCID: PMC10812505 DOI: 10.3390/antiox13010085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 12/29/2023] [Accepted: 01/04/2024] [Indexed: 01/23/2024] Open
Abstract
Diabetic kidney disease (DKD) is a leading cause of death in patients with diabetes. An early precursor to DKD is endothelial cell dysfunction (ECD), which often precedes and exacerbates vascular disease progression. We previously discovered that covalent adducts formed on DNA, RNA, and proteins by the reactive metabolic by-product methylglyoxal (MG) predict DKD risk in patients with type 1 diabetes up to 16 years pre-diagnosis. However, the mechanisms by which MG adducts contribute to vascular disease onset and progression remain unclear. Here, we report that the most predominant MG-induced nucleoside adducts, N2-(1-carboxyethyl)-deoxyguanosine (CEdG) and N2-(1-carboxyethyl)-guanosine (CEG), drive endothelial dysfunction. Following CEdG or CEG exposure, primary human umbilical vein endothelial cells (HUVECs) undergo endothelial dysfunction, resulting in enhanced monocyte adhesion, increased reactive oxygen species production, endothelial permeability, impaired endothelial homeostasis, and exhibit a dysfunctional transcriptomic signature. These effects were discovered to be mediated through the receptor for advanced glycation end products (RAGE), as an inhibitor for intracellular RAGE signaling diminished these dysfunctional phenotypes. Therefore, we found that not only are MG adducts biomarkers for DKD, but that they may also have a role as potential drivers of vascular disease onset and progression and a new therapeutic modality.
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Affiliation(s)
- Seigmund Wai Tsuen Lai
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (S.W.T.L.); (E.D.J.L.G.)
| | - Supriyo Bhattacharya
- Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Edwin De Jesus Lopez Gonzalez
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (S.W.T.L.); (E.D.J.L.G.)
| | - Sarah C. Shuck
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (S.W.T.L.); (E.D.J.L.G.)
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9
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Liu J, Pan S, Wang X, Liu Z, Zhang Y. Role of advanced glycation end products in diabetic vascular injury: molecular mechanisms and therapeutic perspectives. Eur J Med Res 2023; 28:553. [PMID: 38042909 PMCID: PMC10693038 DOI: 10.1186/s40001-023-01431-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/04/2023] [Indexed: 12/04/2023] Open
Abstract
BACKGROUND In diabetic metabolic disorders, advanced glycation end products (AGEs) contribute significantly to the development of cardiovascular diseases (CVD). AIMS This comprehensive review aims to elucidate the molecular mechanisms underlying AGE-mediated vascular injury. CONCLUSIONS We discuss the formation and accumulation of AGEs, their interactions with cellular receptors, and the subsequent activation of signaling pathways leading to oxidative stress, inflammation, endothelial dysfunction, smooth muscle cell proliferation, extracellular matrix remodeling, and impaired angiogenesis. Moreover, we explore potential therapeutic strategies targeting AGEs and related pathways for CVD prevention and treatment in diabetic metabolic disorders. Finally, we address current challenges and future directions in the field, emphasizing the importance of understanding the molecular links between AGEs and vascular injury to improve patient outcomes.
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Affiliation(s)
- Jing Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China
| | - Shuo Pan
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China
| | - Xiqiang Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China
| | - Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China.
- Affiliated Shaanxi Provincial People's Hospital, Medical Research Institute, Northwestern Polytechnical University, Xi'an, China.
| | - Yong Zhang
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China.
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Ding S, Wang C, Wang W, Yu H, Chen B, Liu L, Zhang M, Lang Y. Autocrine S100B in astrocytes promotes VEGF-dependent inflammation and oxidative stress and causes impaired neuroprotection. Cell Biol Toxicol 2023; 39:1-25. [PMID: 34792689 DOI: 10.1007/s10565-021-09674-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 10/11/2021] [Indexed: 12/20/2022]
Abstract
Minimal hepatic encephalopathy (MHE) is strongly associated with neuroinflammation. Nevertheless, the underlying mechanism of the induction of inflammatory response in MHE astrocytes remains not fully understood. In the present study, we investigated the effect and mechanism of S100B, a predominant isoform expressed and released from mature astrocytes, on MHE-like neuropathology in the MHE rat model. We discovered that S100B expressions and autocrine were significantly increased in MHE rat brains and MHE rat brain-derived astrocytes. Furthermore, S100B stimulates VEGF expression via the interaction between TLR2 and RAGE in an autocrine manner. S100B-facilitated VEGF autocrine expression further led to a VEGFR2 and COX-2 interaction, which in turn induced the activation of NFƙB, eventually resulting in inflammation and oxidative stress in MHE astrocytes. MHE astrocytes supported impairment of neuronal survival and growth in a co-culture system. To sum up, a comprehensive understanding of the role of S100B-overexpressed MHE astrocyte in MHE pathogenesis may provide insights into the etiology of MHE.
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Affiliation(s)
- Saidan Ding
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
| | - Chengde Wang
- Neurosurgery department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Weikan Wang
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
| | - He Yu
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Baihui Chen
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Leping Liu
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Minxue Zhang
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yan Lang
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
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11
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Kadar A, Itzikovitch R, Warschawski Y, Morgan S, Shemesh S. Diabetes Mellitus Is a Possible Risk Factor for the Development of Trochanteric Bursitis-A Large-Scale Population-Based Study. J Clin Med 2023; 12:6174. [PMID: 37834819 PMCID: PMC10573166 DOI: 10.3390/jcm12196174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/22/2023] [Accepted: 09/23/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Trochanteric Bursitis (TB) is a common reason to seek primary care, previously shown to be associated with female gender and obesity. Diabetes mellitus (DM) has several musculoskeletal manifestations, but was never found to be associated with TB. PURPOSE To explore the association between DM and TB, based on a large database. The secondary aim was to explore the influence of gender and insulin usage on the occurrence of TB. STUDY DESIGN cross-sectional study. METHODS A population-based cohort consisting of 60,610 patients (55,428 without DM and 5182 with DM), of whom 5418 were diagnosed with TB. A logistic regression model was applied to estimate propensity scores. RESULTS The odds of individuals with DM being diagnosed with TB were 55.8% higher compared to the odds of patients without DM (OR: 1.558, 95% CI: [1.429, 1.70], p < 0.0001). We found that insulin users had a lower risk of TB than patients not using insulin (log-rank p < 0.0001). Females are 3.3 times more likely to have TB than males (RR: 3.337, 95% CI: [3.115, 3.584], p < 0.0001). CONCLUSIONS DM is a risk factor for developing TB. Insulin had a protective effect against TB, suggesting that better glycemic control might prevent this painful infliction.
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Affiliation(s)
- Assaf Kadar
- Roth|McFarlane Hand and Upper Limb Centre, St. Joseph’s Health Care London, Western University, London, ON N6A 4V2, Canada;
| | | | - Yaniv Warschawski
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv 4424309, Israel; (Y.W.); (S.M.)
- Division of Orthopaedic Surgery, Tel Aviv Medical Center, Tel-Aviv 6423906, Israel
| | - Samuel Morgan
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv 4424309, Israel; (Y.W.); (S.M.)
| | - Shai Shemesh
- Department of Orthopaedic Surgery, Samson Assuta Ashdod University Hospital, 7 Ha’Refua Street, Ashdod 7747629, Israel
- Faculty of Health Sciences, Ben Gurion University, Beer-Sheva 8410501, Israel
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12
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Tsirebolos G, Tsoporis JN, Drosatos IA, Izhar S, Gkavogiannakis N, Sakadakis E, Triantafyllis AS, Parker TG, Rallidis LS, Rizos I. Emerging markers of inflammation and oxidative stress as potential predictors of coronary artery disease. Int J Cardiol 2023; 376:127-133. [PMID: 36758863 DOI: 10.1016/j.ijcard.2023.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/20/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023]
Abstract
BACKGROUND AND AIMS The multi-ligand receptor for advanced glycation end products (RAGE) and its ligands AGEs and S100/calgranulin proteins are important mediators of inflammation and oxidative stress whereas the soluble form of RAGE (sRAGE) by acting as a decoy and the antioxidant PARK7/DJ-1 exert antiatherogenic effects. We examined whether sRAGE and its ligands AGEs, S100A8/A9, S100B, S100A12 and DJ-1 are associated with the presence of angiographic coronary artery disease (CAD) in asymptomatic patients with and without diabetes. METHODS AND RESULTS Plasma levels of RAGE ligands, sRAGE and DJ-1 were determined in 50 patients with angiographically proven CAD and in 50 age-matched healthy controls. In the whole cohort, lower levels of sRAGE and higher levels of interleukin-6 (IL-6), the RAGE ligands S100B, S100A12 and the AGEs/sRAGE ratio were associated with CAD. In patients without diabetes (n = 72), lower levels of sRAGE and DJ-1 and higher levels of IL-6 and AGEs/sRAGE ratio were associated with CAD. In multivariable analysis, AGEs/sRAGE ratio was an independent predictor of CAD both in the whole cohort (p = 0.034, OR = 1.247, [95%CI: 1.024, 1.0519]) and in the subgroup of patients without diabetes (p = 0.021, OR = 1.363, 95%CI [1.048, 1.771]) on top of established cardiovascular risk factors. CONCLUSION Alterations in plasma RAGE axis inflammatory mediators are associated with atherosclerosis, and higher levels of AGEs/sRAGE ratio are independently associated with CAD in asymptomatic patients and may act as a novel biomarker for predicting CAD. DJ-1 emerges as promising marker of oxidative stress in CAD patients without diabetes, a finding that deserves further study.
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Affiliation(s)
- George Tsirebolos
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece; Department of Cardiology, 401 General Military Hospital of Athens, Athens, Greece
| | - James N Tsoporis
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Ontario, Canada.
| | - Ioannis-Alexandros Drosatos
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece; Department of Cardiology, 414 Military Hospital, P.Penteli, Athens, Greece
| | - Shehla Izhar
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Ontario, Canada
| | - Nikolaos Gkavogiannakis
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece; Department of Cardiology, 401 General Military Hospital of Athens, Athens, Greece
| | | | | | - Thomas G Parker
- Department of Cardiology, 414 Military Hospital, P.Penteli, Athens, Greece
| | | | - Ioannis Rizos
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece
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13
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The Potential Influence of Advanced Glycation End Products and (s)RAGE in Rheumatic Diseases. Int J Mol Sci 2023; 24:ijms24032894. [PMID: 36769213 PMCID: PMC9918052 DOI: 10.3390/ijms24032894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/21/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Advanced glycation end products (AGEs) are a class of compounds formed by nonenzymatic interactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs can alter the protein structure and activate one of their receptors, specifically the receptor for advanced glycation end products (RAGE). These phenomena impair the functions of cells, extracellular matrix, and tissues. RAGE is expressed by a variety of cells and has been linked to chronic inflammatory autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. The soluble (s)RAGE cleavage product is a positively charged 48-kDa cleavage product that retains the ligand binding site but loses the transmembrane and signaling domains. By acting as a decoy, this soluble receptor inhibits the pro-inflammatory processes mediated by RAGE and its ligands. In the present review, we will give an overview of the role of AGEs, sRAGE, and RAGE polymorphisms in several rheumatic diseases. AGE overproduction may play a role in the pathogenesis and is linked to accelerated atherosclerosis. Low serum sRAGE concentrations are linked to an increased cardiovascular risk profile and a poor prognosis. Some RAGE polymorphisms may be associated with increased disease susceptibility. Finally, sRAGE levels can be used to track disease progression.
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14
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Birben E, Şahiner ÜM, Kalaycı CÖ. Determination of the effects of advanced glycation end products receptor polymorphisms and its activation on structural cell responses and inflammation in asthma. Turk J Med Sci 2023; 53:160-170. [PMID: 36945930 PMCID: PMC10387853 DOI: 10.55730/1300-0144.5569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 11/30/2022] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Advanced glycation end products receptor (RAGE) is a pattern recognition receptor which attracted attention in chronic airway diseases recently. This study aimed to determine the association of RAGE with asthma and the cellular responses resulting from RAGE signaling pathway activation. METHODS Asthmatic (n = 362) and healthy (n = 134) children were genotyped by PCR-RFLP. Plasma sRAGE levels were determined by ELISA. Lung structural cells were stimulated with AGEs (advanced glycation end products) and control BSA. Expressions of cytokines and protein levels were determined by real-time PCR and ELISA. RESULTS : Gly82Ser and -374 T/A polymorphisms in RAGE gene were associated with lower plasma sRAGE levels (p < 0.001 and p < 0.025, respectively). AGE stimulation increased the expression of RAGE (p = 0.002), ICAM-1 (p = 0.010) and VCAM-1 (p = 0.002) in endothelial cells; TIMP-1 (p = 0.003) and MCP-1 (p = 0.005) in fibroblasts. AGE stimulation increased protein levels of IL-6 (p < 0.001) in endothelial cells; VEGF (p = 0.025) and IL-8 (p < 0.001) in fibroblasts; IL-1b (p < 0.001) and VEGF (p = 0.007) in epithelial cells. DISCUSSION Activation of RAGE pathway may contribute to asthma pathogenesis by increasing the expression of several asthmarelated genes. These findings suggest that suppression of RAGE signaling may be an alternative candidate for treating asthma.
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Affiliation(s)
- Esra Birben
- Department of Biology, Faculty of Science, Hacettepe University, Ankara, Turkey
| | - Ümit Murat Şahiner
- Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Can Ömer Kalaycı
- Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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15
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Giri A, O'Hanlon D, Jain NB. Risk factors for rotator cuff disease: A systematic review and meta-analysis of diabetes, hypertension, and hyperlipidemia. Ann Phys Rehabil Med 2023; 66:101631. [PMID: 35257948 PMCID: PMC9974529 DOI: 10.1016/j.rehab.2022.101631] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 10/02/2021] [Accepted: 10/08/2021] [Indexed: 10/17/2022]
Abstract
BACKGROUND Rotator cuff disease is a common cause of shoulder pain. Comorbidities such as diabetes, hypertension, and hyperlipidemia may be associated with rotator cuff disease, likely because of mechanisms related to vascular insufficiency. OBJECTIVES We performed a systematic review of the association of diabetes, hypertension, and hyperlipidemia with the diagnosis of rotator cuff disease. METHODS Following systematic queries of PubMed, Embase, Cochrane, CINAHL, and Science Direct, articles meeting eligibility criteria and reporting on the association of one or more risk factors (diabetes, hypertension, and hyperlipidemia) and rotator cuff disease were considered. Meta-analysis was performed to quantitatively summarize the associations between each risk factor and rotator cuff disease. We assessed study quality with the Newcastle-Ottawa Scale (NOS) and performed a qualitative assessment of risk of bias. RESULTS After a full-text review of 212 articles, 12 articles assessing diabetes, 5 assessing hypertension and 8 assessing hyperlipidemia were eligible. The odds of having rotator cuff disease was increased with diabetes (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.43-1.55), hypertension (OR 1.40, 95% CI 1.19-1.65) and hyperlipidemia/dyslipidemia (OR 1.48, 95% CI 1.42-1.55). Diabetes was also specifically associated with rotator cuff tears (OR 1.28, 95% CI 1.07-1.52). Synthesizing assessment for risk of bias suggested that current epidemiologic evidence for an association was plausible for diabetes and hyperlipidemia but not hypertension. CONCLUSIONS Diabetes, hypertension, and hyperlipidemia were associated with rotator cuff disease in our meta-analysis. However, the possibility of bias exists for all 3 co-morbidities evaluated and is likely highest for hypertension. High-quality studies with the ability to incorporate time since first diagnosis of co-morbidity are scarce and much needed.
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Affiliation(s)
- Ayush Giri
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
| | | | - Nitin B Jain
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Physical Medicine and Rehabilitation, Orthopedics, and Population and Data Sciences, University of Texas Southwestern, Dallas, TX, United States of America
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16
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Vaidya R, Lake SP, Zellers JA. Effect of Diabetes on Tendon Structure and Function: Not Limited to Collagen Crosslinking. J Diabetes Sci Technol 2023; 17:89-98. [PMID: 35652696 PMCID: PMC9846394 DOI: 10.1177/19322968221100842] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Diabetes mellitus (DM) is associated with musculoskeletal complications-including tendon dysfunction and injury. Patients with DM show altered foot and ankle mechanics that have been attributed to tendon dysfunction as well as impaired recovery post-tendon injury. Despite the problem of DM-related tendon complications, treatment guidelines specific to this population of individuals are lacking. DM impairs tendon structure, function, and healing capacity in tendons throughout the body, but the Achilles tendon is of particular concern and most studied in the diabetic foot. At macroscopic levels, asymptomatic, diabetic Achilles tendons may show morphological abnormalities such as thickening, collagen disorganization, and/or calcific changes at the tendon enthesis. At smaller length scales, DM affects collagen sliding and discrete plasticity due to glycation of collagen. However, how these alterations translate to mechanical deficits observed at larger length scales is an area of continued investigation. In addition to dysfunction of the extracellular matrix, tendon cells such as tenocytes and tendon stem/progenitor cells show significant abnormalities in proliferation, apoptosis, and remodeling capacity in the presence of hyperglycemia and advanced glycation end-products, thus contributing to the disruption of tendon homeostasis and healing. Improving our understanding of the effects of DM on tendons-from molecular pathways to patients-will progress toward targeted therapies in this group at high risk of foot and ankle morbidity.
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Affiliation(s)
- Rachana Vaidya
- Washington University School of
Medicine, St. Louis, MO, USA
| | | | - Jennifer A. Zellers
- Washington University School of
Medicine, St. Louis, MO, USA
- Jennifer A. Zellers, PT, DPT, PhD,
Washington University School of Medicine, 4444 Forest Park Ave., Suite
1101, St. Louis, MO 63108, USA.
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17
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Prasad K. Involvement of AGE and Its Receptors in the Pathogenesis of Hypertension in Elderly People and Its Treatment. Int J Angiol 2022; 31:213-221. [PMID: 36588874 PMCID: PMC9803554 DOI: 10.1055/s-0042-1756175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Both systolic and diastolic blood pressures increase with age up to 50 to 60 years of age. After 60 years of age systolic pressure rises to 84 years of age but diastolic pressure remains stable or even decreases. In the oldest age group (85-99 years), the systolic blood pressure (SBP) is high and diastolic pressure (DBP) is the lowest. Seventy percent of people older than 65 years are hypertensive. This paper deals with the role of advanced glycation end products (AGE) and its cell receptor (RAGE) and soluble receptor (sRAGE) in the development of hypertension in the elderly population. Plasma/serum levels of AGE are higher in older people as compared with younger people. Serum levels of AGE are positively correlated with age, arterial stiffness, and hypertension. Low serum levels of sRAGE are associated with arterial stiffness and hypertension. Levels of sRAGE are negatively correlated with age and blood pressure. Levels of sRAGE are lower in patients with arterial stiffness and hypertension than patients with high levels of sRAGE. AGE could induce hypertension through numerous mechanisms including, cross-linking with collagen, reduction of nitric oxide, increased expression of endothelin-1, and transforming growth factor-β (TGF-β). Interaction of AGE with RAGE could produce hypertension through the generation of reactive oxygen species, increased sympathetic activity, activation of nuclear factor-kB, and increased expression of cytokines, cell adhesion molecules, and TGF- β. In conclusion, the AGE-RAGE axis could be involved in hypertension in elderly people. Treatment for hypertension in elderly people should be targeted at reduction of AGE levels in the body, prevention of AGE formation, degradation of AGE in vivo, downregulation of RAGE expression, blockade of AGE-RAGE interaction, upregulation of sRAGE expression, and use of antioxidants.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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18
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Accumulation of Advanced Glycation End-Products in the Body and Dietary Habits. Nutrients 2022; 14:nu14193982. [PMID: 36235635 PMCID: PMC9572209 DOI: 10.3390/nu14193982] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/07/2022] [Accepted: 09/22/2022] [Indexed: 11/17/2022] Open
Abstract
The formation of advanced glycation end-products (AGE) in tissues is a physiological process; however, excessive production and storage are pathological and lead to inflammation. A sedentary lifestyle, hypercaloric and high-fructose diet and increased intake of processed food elements contribute to excessive production of compounds, which are created in the non-enzymatic multi-stage glycation process. The AGE’s sources can be endogenous and exogenous, mainly due to processing food at high temperatures and low moisture, including grilling, roasting, and frying. Accumulation of AGE increases oxidative stress and initiates various disorders, leading to the progression of atherosclerosis, cardiovascular disease, diabetes and their complications. Inborn defensive mechanisms, recovery systems, and exogenous antioxidants (including polyphenols) protect from excessive AGE accumulation. Additionally, numerous products have anti-glycation properties, occurring mainly in fruits, vegetables, herbs, and spices. It confirms the role of diet in the prevention of civilization diseases.
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19
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Relationship between the Levels of Calprotectin and Soluble Receptor for Advanced Glycation End Products with Abdominal Aortic Aneurysm Diameter: A Preliminary Clinical Trial. J Clin Med 2022; 11:jcm11185448. [PMID: 36143093 PMCID: PMC9501553 DOI: 10.3390/jcm11185448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/06/2022] [Accepted: 09/13/2022] [Indexed: 11/19/2022] Open
Abstract
An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta greater than 50% of the diameter of a healthy aorta. Previous experimental studies confirm the effect of calprotectin (CAL) on the onset of arterial pathology. It has been suggested that low levels of soluble receptors for advanced glycation end products (RAGEs) increase levels of cytokines that lead to the inhibition of matrix metalloproteinases (MMPs), affecting AAA formation. This study aimed to analyze the correlation of levels of RAGE and CAL with AAA diameter. A group of 32 patients aged 50−75 with diagnosed AAA was enrolled in the study. This group of patients was further divided into three subgroups based on AAA diameter: (1) <4.5 cm, (2) 4.5−5.5 cm, (3) >5.5 cm. Peripheral blood was drawn from all participants on admission to measure the serum CAL and RAGE levels. An enumeration survey was performed three months after AAA surgical treatment. CAL and RAGE plasma levels were measured with the enzyme-linked immunosorbent assay (ELISA). The median CAL levels were 2273.0 ng/mL before and 1217.0 ng/mL after treatment. There was a statistically significant decrease in CAL levels following the surgical treatment (p = 0.003). The correlation analysis between CAL levels and RAGE levels before and after surgical treatment showed no statistically significant correlations. In addition, there were no statistically significant correlations between CAL and RAGE levels with AAA size. In conclusion, CAL levels appear to be a significant marker in patients with AAA. There is an almost twofold decrease in CAL levels after AAA excision.
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20
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Aftermath of AGE-RAGE Cascade in the pathophysiology of cardiovascular ailments. Life Sci 2022; 307:120860. [PMID: 35940220 DOI: 10.1016/j.lfs.2022.120860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 07/20/2022] [Accepted: 08/01/2022] [Indexed: 11/21/2022]
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21
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Caldiroli L, Molinari P, Dozio E, Rigolini R, Giubbilini P, Romanelli MMC, Castellano G, Vettoretti S. In Patients with Chronic Kidney Disease Advanced Glycation End-Products Receptors Isoforms (sRAGE and esRAGE) Are Associated with Malnutrition. Antioxidants (Basel) 2022; 11:antiox11071253. [PMID: 35883745 PMCID: PMC9312066 DOI: 10.3390/antiox11071253] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 02/04/2023] Open
Abstract
Background: in patients with chronic kidney disease (CKD), the inflammatory and pro-oxidant milieu may contribute to malnutrition development. In this study, we investigated the relationship between inflammation, advanced glycation end-products (AGEs), and their receptors (RAGEs) with malnutrition in CKD patients. Methods: we evaluated 117 patients. AGEs were quantified by fluorescence intensity using a fluorescence spectrophotometer, soluble RAGEs isoforms, and inflammatory interleukins by ELISA. Malnutrition was assessed by a malnutrition inflammation score. Results: mean age was 80 ± +11 years, eGFR was 25 ± +11 mL/min/1.73 m2 and BMI was 28 ± 5 Kg/m2. Malnourished individuals were older, had lower estimated protein intake (nPCR 0.65 ± 0.2 vs. 0.8 ± 0.2 vs. 0.8 ± 0.3, p = 0.01), higher C reactive protein (CRP 0.6 ± 1 vs. 0.6 ± 0.7 vs. 0.17 ± 0.13, p = 0.02) and tumor necrosis factor α (TNF α 14.7 ± 8.7 vs. 15.6 ± 8 vs. 11.8 ± 5.8, p = 0.029). Malnourished patients had higher sRAGE (2813 ± 1477 vs. 2158 ± 1236 vs. 2314 ± 1115, p = 0.035) and esRAGE (648 [408–1049] vs. 476 [355–680] vs. 545 [380–730] p = 0.033). In the multivariate analysis, only sRAGE maintained its association with malnutrition (p = 0.02) independently of aging and inflammation. Conclusions: in CKD patients, RAGEs isoforms, but not AGEs, are associated with malnutrition, irrespective of systemic inflammation, aging, and renal function.
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Affiliation(s)
- Lara Caldiroli
- Unit of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (L.C.); (P.M.); (G.C.)
| | - Paolo Molinari
- Unit of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (L.C.); (P.M.); (G.C.)
| | - Elena Dozio
- Laboratory of Clinical Pathology, Department of Biomedical Science for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.D.); (M.M.C.R.)
| | - Roberta Rigolini
- Service of Laboratory Medicine1-Clinical Pathology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy; (R.R.); (P.G.)
| | - Paola Giubbilini
- Service of Laboratory Medicine1-Clinical Pathology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy; (R.R.); (P.G.)
| | - Massimiliano M. Corsi Romanelli
- Laboratory of Clinical Pathology, Department of Biomedical Science for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.D.); (M.M.C.R.)
- Service of Laboratory Medicine1-Clinical Pathology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy; (R.R.); (P.G.)
| | - Giuseppe Castellano
- Unit of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (L.C.); (P.M.); (G.C.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Simone Vettoretti
- Unit of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (L.C.); (P.M.); (G.C.)
- Correspondence: ; Tel.: +39-02-55-03-45-52; Fax: +39-02-55-03-45-50
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22
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Hayashi K, Sato K, Ochi S, Kawano S, Munesue S, Harashima A, Oshima Y, Kimura K, Kyoi T, Yamamoto Y. Inhibitory Effects of Saururus chinensis Extract on Receptor for Advanced Glycation End-Products-Dependent Inflammation and Diabetes-Induced Dysregulation of Vasodilation. Int J Mol Sci 2022; 23:ijms23105757. [PMID: 35628567 PMCID: PMC9147798 DOI: 10.3390/ijms23105757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 02/04/2023] Open
Abstract
Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) are implicated in inflammatory reactions and vascular complications in diabetes. Signaling pathways downstream of RAGE are involved in NF-κB activation. In this study, we examined whether ethanol extracts of Saururus chinensis (Lour.) Baill. (SE) could affect RAGE signaling and vascular relaxation in streptozotocin (STZ)-induced diabetic rats. Treatment with SE inhibited AGEs-modified bovine serum albumin (AGEs-BSA)-elicited activation of NF-κB and could compete with AGEs-BSA binding to RAGE in a dose-dependent manner. Tumor necrosis factor-α (TNF-α) secretion induced by lipopolysaccharide (LPS)-a RAGE ligand-was also reduced by SE treatment in wild-type Ager+/+ mice as well as in cultured peritoneal macrophages from Ager+/+ mice but not in Ager-/- mice. SE administration significantly ameliorated diabetes-related dysregulation of acetylcholine-mediated vascular relaxation in STZ-induced diabetic rats. These results suggest that SE would inhibit RAGE signaling and would be useful for the improvement of vascular endothelial dysfunction in diabetes.
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Affiliation(s)
- Kenjiro Hayashi
- Food Development Labs, Functional Food Division, Nippon Shinyaku Co., Ltd., Kyoto 601-8550, Japan; (K.H.); (K.S.); (S.O.); (S.K.); (T.K.)
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan; (S.M.); (A.H.); (Y.O.); (K.K.)
| | - Koichi Sato
- Food Development Labs, Functional Food Division, Nippon Shinyaku Co., Ltd., Kyoto 601-8550, Japan; (K.H.); (K.S.); (S.O.); (S.K.); (T.K.)
| | - Seishi Ochi
- Food Development Labs, Functional Food Division, Nippon Shinyaku Co., Ltd., Kyoto 601-8550, Japan; (K.H.); (K.S.); (S.O.); (S.K.); (T.K.)
| | - Shuhei Kawano
- Food Development Labs, Functional Food Division, Nippon Shinyaku Co., Ltd., Kyoto 601-8550, Japan; (K.H.); (K.S.); (S.O.); (S.K.); (T.K.)
| | - Seiichi Munesue
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan; (S.M.); (A.H.); (Y.O.); (K.K.)
| | - Ai Harashima
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan; (S.M.); (A.H.); (Y.O.); (K.K.)
| | - Yu Oshima
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan; (S.M.); (A.H.); (Y.O.); (K.K.)
| | - Kumi Kimura
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan; (S.M.); (A.H.); (Y.O.); (K.K.)
| | - Takashi Kyoi
- Food Development Labs, Functional Food Division, Nippon Shinyaku Co., Ltd., Kyoto 601-8550, Japan; (K.H.); (K.S.); (S.O.); (S.K.); (T.K.)
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan; (S.M.); (A.H.); (Y.O.); (K.K.)
- Correspondence:
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23
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Singh S, Siva BV, Ravichandiran V. Advanced Glycation End Products: key player of the pathogenesis of atherosclerosis. Glycoconj J 2022; 39:547-563. [PMID: 35579827 DOI: 10.1007/s10719-022-10063-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/07/2022] [Accepted: 05/02/2022] [Indexed: 01/08/2023]
Abstract
Atherosclerosis is the most common type of cardiovascular disease, and it causes intima thickening, plaque development, and ultimate blockage of the artery lumen. Advanced glycation end products (AGEs) are thought to have a role in the development and progression of atherosclerosis. there is developing an enthusiasm for AGEs as a potential remedial target. AGES mainly induce arterial damage and exacerbate the development of atherosclerotic plaques by triggering cell receptor-dependent signalling. The interplay of AGEs with RAGE, a transmembrane signalling receptor present across all cells important to atherosclerosis, changes cell activity, boosts expression of genes, and increases the outflow of inflammatory compounds, resulting in arterial wall injury and plaque formation. Here in this review, function of AGEs in the genesis, progression, and instability of atherosclerosis is discussed. In endothelial and smooth muscle cells, as well as platelets, the interaction of AGEs with their transmembrane cell receptor, RAGE, triggers intracellular signalling, resulting in endothelial damage, vascular smooth muscle cell function modification, and changed platelet activity.
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Affiliation(s)
- Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, 844102, Dist:Vaishali, Hajipur, Bihar, India.
| | - Boddu Veerabadra Siva
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, 844102, Dist:Vaishali, Hajipur, Bihar, India
| | - V Ravichandiran
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, 844102, Dist:Vaishali, Hajipur, Bihar, India
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24
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Fiorucci S, Urbani G. Role of mRAGEs and ACE2 in SARS-CoV-2-Related Inflammation. RECENT ADVANCES IN INFLAMMATION & ALLERGY DRUG DISCOVERY 2022; 16:2-4. [PMID: 36508263 DOI: 10.2174/277227081601221018140453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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25
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Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N 6-carboxymethyllysine. Nat Neurosci 2022; 25:295-305. [PMID: 35241804 DOI: 10.1038/s41593-022-01027-3] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 01/28/2022] [Indexed: 11/08/2022]
Abstract
Microglial function declines during aging. The interaction of microglia with the gut microbiota has been well characterized during development and adulthood but not in aging. Here, we compared microglial transcriptomes from young-adult and aged mice housed under germ-free and specific pathogen-free conditions and found that the microbiota influenced aging associated-changes in microglial gene expression. The absence of gut microbiota diminished oxidative stress and ameliorated mitochondrial dysfunction in microglia from the brains of aged mice. Unbiased metabolomic analyses of serum and brain tissue revealed the accumulation of N6-carboxymethyllysine (CML) in the microglia of the aging brain. CML mediated a burst of reactive oxygen species and impeded mitochondrial activity and ATP reservoirs in microglia. We validated the age-dependent rise in CML levels in the sera and brains of humans. Finally, a microbiota-dependent increase in intestinal permeability in aged mice mediated the elevated levels of CML. This study adds insight into how specific features of microglia from aged mice are regulated by the gut microbiota.
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26
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Prasad K, Khan AS, Bhanumathy KK. Does AGE-RAGE Stress Play a Role in the Development of Coronary Artery Disease in Obesity? Int J Angiol 2022; 31:1-9. [PMID: 35221846 PMCID: PMC8881108 DOI: 10.1055/s-0042-1742587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
This article deals with the role of AGE (advanced glycation end products)-RAGE (receptor for AGE) stress (AGE/sRAGE) in the development of coronary artery disease (CAD) in obesity. CAD is due to atherosclerosis in coronary artery. The serum/plasma levels of AGE and sRAGE are reduced, while AGE-RAGE stress and expression of RAGE are elevated in obese individuals. However, the levels of AGE are elevated in obese individuals with more than one metabolic syndrome. The increases in the AGE-RAGE stress would elevate the expression and production of atherogenic factors, including reactive oxygen species, nuclear factor-kappa B, cytokines, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecules, monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and growth factors. Low levels of sRAGE would also increase the atherogenic factors. The increases in the AGE-RAGE stress and decreases in the levels of sRAGE would induce development of atherosclerosis, leading to CAD. The therapeutic regimen for AGE-RAGE stress-induced CAD in obesity would include lowering of AGE intake, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of AGE-RAGE interaction, downregulation of sRAGE expression, and use of antioxidants. In conclusion, the data suggest that AGE-RAGE stress is involved in the development of CAD in obesity, and the therapeutic interventions to reduce AGE-RAGE would be helpful in preventing, regressing, and slowing the progression of CAD in obesity.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada,Address for correspondence Kailash Prasad, MBBS, MD, PhD, DSc Department of Physiology (APP), College of Medicine, University of Saskatoon107 Wiggins Road, Saskatoon, SK, S7N 5E5Canada
| | - Amal S. Khan
- Community, Health and Epidemiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Kalpana K. Bhanumathy
- Division of Oncology, Cancer Cluster Unit, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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27
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Linkens AMA, Houben AJ, Niessen PM, Wijckmans N, de Goei E, Van den Eynde MD, Scheijen JLJM, Waarenburg M, Mari A, Berendschot TT, Streese L, Hanssen H, van Dongen MC, van Gool C, Stehouwer CDA, Eussen SJ, Schalkwijk C. A 4-week high-AGE diet does not impair glucose metabolism and vascular function in obese individuals. JCI Insight 2022; 7:156950. [PMID: 35133989 PMCID: PMC8986074 DOI: 10.1172/jci.insight.156950] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 02/04/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Accumulation of advanced glycation endproducts (AGEs) may contribute to the pathophysiology of type 2 diabetes and its vascular complications. AGEs are widely present in food, but whether restricting AGE intake improves risk factors for type 2 diabetes and vascular dysfunction is controversial. METHODS Abdominally obese but otherwise healthy individuals were randomly assigned to a specifically designed 4-week diet low or high in AGEs in a double-blind, parallel design. Insulin sensitivity, secretion, and clearance were assessed by a combined hyperinsulinemic-euglycemic and hyperglycemic clamp. Micro- and macrovascular function, inflammation, and lipid profiles were assessed by state-of-the-art in vivo measurements and biomarkers. Specific urinary and plasma AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were assessed by mass spectrometry. RESULTS In 73 individuals (22 males, mean ± SD age and BMI 52 ± 14 years, 30.6 ± 4.0 kg/m2), intake of CML, CEL, and MG-H1 differed 2.7-, 5.3-, and 3.7-fold between the low- and high-AGE diets, leading to corresponding changes of these AGEs in urine and plasma. Despite this, there was no difference in insulin sensitivity, secretion, or clearance; micro- and macrovascular function; overall inflammation; or lipid profile between the low and high dietary AGE groups (for all treatment effects, P > 0.05). CONCLUSION This comprehensive RCT demonstrates very limited biological consequences of a 4-week diet low or high in AGEs in abdominally obese individuals. TRIAL REGISTRATION Clinicaltrials.gov, NCT03866343; trialregister.nl, NTR7594. FUNDING Diabetesfonds and ZonMw.
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Affiliation(s)
- Armand M A Linkens
- Cardiovascular Research Center, Maastricht (CARIM), Maastricht, Netherlands
| | - Alfons J Houben
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Petra M Niessen
- Department of Internal Medicine, Cardiovascular Research Institute Maastric, Maastricht University Medical Center, Maastricht, Netherlands
| | - Nicole Wijckmans
- Department of Epidemiology, Maastricht University, Maastricht, the Netherla, CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands, Maastricht, Netherlands
| | - Erica de Goei
- CARIM School for Cardiovascular Diseases, Maastricht University, the Nether, Department of Epidemiology, Maastricht University, Maastricht, the Netherlands, Maastricht, Netherlands
| | - Mathias Dg Van den Eynde
- Department of Internal Medicine, Maastricht University Medical Center, the , CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands, Maastricht, Netherlands
| | - Jean L J M Scheijen
- Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Marjo Waarenburg
- Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Andrea Mari
- Institute of Biomedical Engineering, National Research Council, Padova, Italy
| | - Tos Tjm Berendschot
- University Eye Clinic Maastricht, Maastricht University Medical Center, the Netherlands., Maastricht, Netherlands
| | - Lukas Streese
- Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Henner Hanssen
- Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Martien Cjm van Dongen
- Department of Epidemiology, Maastricht University, Maastricht, the Netherlands, Maastricht, Netherlands
| | - Christel van Gool
- Department of Epidemiology, Maastricht University, Maastricht, the Netherlands, Maastricht, Netherlands
| | - Coen DA Stehouwer
- Department of Internal Medicine, Cardiovascular Research Institute Maastric, Maastricht University Medical Center, Maastricht, Netherlands
| | - Simone Jpm Eussen
- Department of Epidemiology, Maastricht University, Maastricht, the Netherlands, Maastricht, Netherlands
| | - Casper Schalkwijk
- Department of Internal Medicine, Cardiovascular Research Institute Maastric, Maastricht University Medical Center, Maastricht, Netherlands
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28
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Dhaliwal R, Ewing SK, Vashishth D, Semba RD, Schwartz AV. Greater Carboxy-Methyl-Lysine Is Associated With Increased Fracture Risk in Type 2 Diabetes. J Bone Miner Res 2022; 37:265-272. [PMID: 34820902 PMCID: PMC8828668 DOI: 10.1002/jbmr.4466] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 09/20/2021] [Accepted: 10/02/2021] [Indexed: 02/06/2023]
Abstract
Accumulation of advanced glycation end-products (AGE) in bone alters collagen structure and function. Fluorescent AGEs are associated with fractures but less is known regarding non-fluorescent AGEs. We examined associations of carboxy-methyl-lysine (CML), with incident clinical and prevalent vertebral fractures by type 2 diabetes (T2D) status, in the Health, Aging, and Body Composition cohort of older adults. Incident clinical fractures and baseline vertebral fractures were assessed. Cox regression was used to analyze the associations between serum CML and clinical fracture incidence, and logistic regression for vertebral fracture prevalence. At baseline, mean ± standard deviation (SD) age was 73.7 ± 2.8 and 73.6 ± 2.9 years in T2D (n = 712) and non-diabetes (n = 2332), respectively. Baseline CML levels were higher in T2D than non-diabetes (893 ± 332 versus 771 ± 270 ng/mL, p < 0.0001). In multivariate models, greater CML was associated with higher risk of incident clinical fracture in T2D (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.24-1.79 per 1-SD increase in log CML) but not in non-diabetes (HR 1.03; 95% CI, 0.94-1.13; p for interaction = 0.001). This association was independent of bone mineral density (BMD), glycated hemoglobin (hemoglobin A1c), weight, weight loss, smoking, cystatin-C, and medication use. CML was not significantly associated with the odds of prevalent vertebral fractures in either group. In conclusion, higher CML levels are associated with increased risk of incident clinical fractures in T2D, independent of BMD. These results implicate CML in the pathogenesis of bone fragility in diabetes. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Ruban Dhaliwal
- Metabolic Bone Disease Center, State University of New York Upstate Medical University, New York, NY, USA
| | - Susan K. Ewing
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - Deepak Vashishth
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, New York, NY, USA
| | - Richard D. Semba
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ann V. Schwartz
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
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29
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Jessop F, Schwarz B, Scott D, Roberts LM, Bohrnsen E, Hoidal JR, Bosio CM. Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection in mice. JCI Insight 2022; 7:155896. [PMID: 35076028 PMCID: PMC8855831 DOI: 10.1172/jci.insight.155896] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/08/2021] [Indexed: 12/14/2022] Open
Abstract
Cellular and molecular mechanisms driving morbidity following SARS-CoV-2 infection have not been well defined. The receptor for advanced glycation end products (RAGE) is a central mediator of tissue injury and contributes to SARS-CoV-2 disease pathogenesis. In this study, we temporally delineated key cell and molecular events leading to lung injury in mice following SARS-CoV-2 infection and assessed efficacy of therapeutically targeting RAGE to improve survival. Early following infection, SARS-CoV-2 replicated to high titers within the lungs and evaded triggering inflammation and cell death. However, a significant necrotic cell death event in CD45– populations, corresponding with peak viral loads, was observed on day 2 after infection. Metabolic reprogramming and inflammation were initiated following this cell death event and corresponded with increased lung interstitial pneumonia, perivascular inflammation, and endothelial hyperplasia together with decreased oxygen saturation. Therapeutic treatment with the RAGE antagonist FPS-ZM1 improved survival in infected mice and limited inflammation and associated perivascular pathology. Together, these results provide critical characterization of disease pathogenesis in the mouse model and implicate a role for RAGE signaling as a therapeutic target to improve outcomes following SARS-CoV-2 infection.
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Affiliation(s)
- Forrest Jessop
- Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, and
| | - Benjamin Schwarz
- Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, and
| | - Dana Scott
- Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, Montana, USA
| | - Lydia M. Roberts
- Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, and
| | - Eric Bohrnsen
- Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, and
| | - John R. Hoidal
- Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Catharine M. Bosio
- Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, and
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30
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Baek CH, Kim H, Moon SY, Yang WS. Liraglutide, a glucagon-like peptide-1 receptor agonist, induces ADAM10-dependent ectodomain shedding of RAGE via AMPK activation in human aortic endothelial cells. Life Sci 2022; 292:120331. [PMID: 35041837 DOI: 10.1016/j.lfs.2022.120331] [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: 10/22/2021] [Revised: 01/06/2022] [Accepted: 01/10/2022] [Indexed: 10/19/2022]
Abstract
AIMS Glucagon-like peptide-1 alleviates the deleterious effects of advanced glycation end products (AGEs), but the underlying mechanisms are not fully understood. In this study, we investigated the protective mechanism using liraglutide, a glucagon-like peptide-1 receptor agonist, in cultured human aortic endothelial cells (HAECs). MAIN METHODS Following liraglutide treatment in HAECs, the receptor for AGEs (RAGE) was measured in both cell lysate and culture supernatant, the cytosolic free Ca2+ level was monitored using Fluo-4 AM, the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was analyzed, and immunofluorescence staining was used to visualize a disintegrin and metalloprotease 10 (ADAM10) on the cell surface. KEY FINDINGS Liraglutide (100 nM) induced ectodomain shedding of RAGE within 30 min and inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) induced by AGEs of bovine serum albumin (AGE-BSA). Further experiments revealed that liraglutide rapidly increased extracellular Ca2+ influx through L-type calcium channels and activated AMPK, resulting in translocation of ADAM10 to the cell surface, whereas siRNA-mediated ADAM10 depletion prevented liraglutide-induced ectodomain shedding of RAGE and eliminated liraglutide's inhibitory effect on AGE-BSA-induced ICAM-1 expression. Moreover, compound C-mediated AMPK inhibition and siRNA-mediated AMPK depletion both prevented ADAM10 translocation to the cell surface and ADAM10-mediated ectodomain shedding of RAGE. SIGNIFICANCE Liraglutide reduces the number of intact RAGE on the cell surface by inducing ADAM10-mediated ectodomain shedding, which decreases the inflammatory effects of AGEs. AMPK activated by extracellular Ca2+ influx is critically involved in the translocation of ADAM10 to the cell surface, where it cleaves RAGE.
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Affiliation(s)
- Chung Hee Baek
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyosang Kim
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Soo Young Moon
- Asan Institute for Life Sciences, Seoul, Republic of Korea
| | - Won Seok Yang
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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32
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Marini S, Georgakis MK, Anderson CD. Interactions Between Kidney Function and Cerebrovascular Disease: Vessel Pathology That Fires Together Wires Together. Front Neurol 2021; 12:785273. [PMID: 34899586 PMCID: PMC8652045 DOI: 10.3389/fneur.2021.785273] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 10/26/2021] [Indexed: 12/15/2022] Open
Abstract
The kidney and the brain, as high-flow end organs relying on autoregulatory mechanisms, have unique anatomic and physiological hemodynamic properties. Similarly, the two organs share a common pattern of microvascular dysfunction as a result of aging and exposure to vascular risk factors (e.g., hypertension, diabetes and smoking) and therefore progress in parallel into a systemic condition known as small vessel disease (SVD). Many epidemiological studies have shown that even mild renal dysfunction is robustly associated with acute and chronic forms of cerebrovascular disease. Beyond ischemic SVD, kidney impairment increases the risk of acute cerebrovascular events related to different underlying pathologies, notably large artery stroke and intracerebral hemorrhage. Other chronic cerebral manifestations of SVD are variably associated with kidney disease. Observational data have suggested the hypothesis that kidney function influences cerebrovascular disease independently and adjunctively to the effect of known vascular risk factors, which affect both renal and cerebral microvasculature. In addition to confirming this independent association, recent large-scale human genetic studies have contributed to disentangling potentially causal associations from shared genetic predisposition and resolving the uncertainty around the direction of causality between kidney and cerebrovascular disease. Accelerated atherosclerosis, impaired cerebral autoregulation, remodeling of the cerebral vasculature, chronic inflammation and endothelial dysfunction can be proposed to explain the additive mechanisms through which renal dysfunction leads to cerebral SVD and other cerebrovascular events. Genetic epidemiology also can help identify new pathological pathways which wire kidney dysfunction and cerebral vascular pathology together. The need for identifying additional pathological mechanisms underlying kidney and cerebrovascular disease is attested to by the limited effect of current therapeutic options in preventing cerebrovascular disease in patients with kidney impairment.
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Affiliation(s)
- Sandro Marini
- Department of Neurology, Boston Medical Center, Boston University School of Medicine, Boston, MA, United States
| | - Marios K Georgakis
- Institute for Stroke and Dementia Research, University Hospital of LMU Munich, Munich, Germany.,McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, United States.,Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
| | - Christopher D Anderson
- McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, United States.,Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States.,Department of Neurology, Brigham and Women's Hospital, Boston, MA, United States
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33
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Hansen L, Joseph G, Valdivia A, Taylor WR. Satellite Cell Expression of RAGE (Receptor for Advanced Glycation end Products) Is Important for Collateral Vessel Formation. J Am Heart Assoc 2021; 10:e022127. [PMID: 34689598 PMCID: PMC8751830 DOI: 10.1161/jaha.120.022127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background The growth and remodeling of vascular networks is an important component of the prognosis for patients with peripheral artery disease. One protein that has been previously implicated to play a role in this process is RAGE (receptor for advanced glycation end products). This study sought to determine the cellular source of RAGE in the ischemic hind limb and the role of RAGE signaling in this cell type. Methods and Results Using a hind limb ischemia model of vascular growth, this study found skeletal muscle satellite cells to be a novel major cellular source of RAGE in ischemic tissue by both staining and cellular sorting. Although wild-type satellite cells increased tumor necrosis factor-α and monocyte chemoattractant protein-1 production in response to ischemia in vivo and a RAGE ligand in vitro, satellite cells from RAGE knockout mice lacked the increase in cytokine production both in vivo in response to ischemia and in vitro after stimuli with the RAGE ligand high-mobility group box 1. Furthermore, encapsulated wild-type satellite cells improved perfusion after hind limb ischemia surgery by both perfusion staining and vessel quantification, but RAGE knockout satellite cells provided no improvement over empty capsules. Conclusions Thus, RAGE expression and signaling in satellite cells is crucial for their response to stimuli and angiogenic and arteriogenic functions.
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Affiliation(s)
- Laura Hansen
- Division of Cardiology Department of Medicine Emory University Atlanta GA.,Division of Cardiology Atlanta Veterans Affairs Medical Center Decatur GA
| | - Giji Joseph
- Division of Cardiology Department of Medicine Emory University Atlanta GA
| | - Alejandra Valdivia
- Division of Cardiology Department of Medicine Emory University Atlanta GA
| | - W Robert Taylor
- Division of Cardiology Department of Medicine Emory University Atlanta GA.,Division of Cardiology Atlanta Veterans Affairs Medical Center Decatur GA.,The Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory University Atlanta GA
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34
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Dozio E, Massaccesi L, Corsi Romanelli MM. Glycation and Glycosylation in Cardiovascular Remodeling: Focus on Advanced Glycation End Products and O-Linked Glycosylations as Glucose-Related Pathogenetic Factors and Disease Markers. J Clin Med 2021; 10:jcm10204792. [PMID: 34682915 PMCID: PMC8539574 DOI: 10.3390/jcm10204792] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/15/2021] [Accepted: 10/16/2021] [Indexed: 02/07/2023] Open
Abstract
Glycation and glycosylation are non-enzymatic and enzymatic reactions, respectively, of glucose, glucose metabolites, and other reducing sugars with different substrates, such as proteins, lipids, and nucleic acids. Increased availability of glucose is a recognized risk factor for the onset and progression of diabetes-mellitus-associated disorders, among which cardiovascular diseases have a great impact on patient mortality. Both advanced glycation end products, the result of non-enzymatic glycation of substrates, and O-linked-N-Acetylglucosaminylation, a glycosylation reaction that is controlled by O-N-AcetylGlucosamine (GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), have been shown to play a role in cardiovascular remodeling. In this review, we aim (1) to summarize the most recent data regarding the role of glycation and O-linked-N-Acetylglucosaminylation as glucose-related pathogenetic factors and disease markers in cardiovascular remodeling, and (2) to discuss potential common mechanisms linking these pathways to the dysregulation and/or loss of function of different biomolecules involved in this field.
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Affiliation(s)
- Elena Dozio
- Laboratory of Clinical Pathology, Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (L.M.); (M.M.C.R.)
- Correspondence: ; Tel.: +39-02-50-315-342
| | - Luca Massaccesi
- Laboratory of Clinical Pathology, Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (L.M.); (M.M.C.R.)
| | - Massimiliano Marco Corsi Romanelli
- Laboratory of Clinical Pathology, Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (L.M.); (M.M.C.R.)
- Service of Laboratory Medicine1-Clinical Pathology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy
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35
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Linkens AMA, Houben AJHM, Kroon AA, Schram MT, Berendschot TTJM, Webers CAB, van Greevenbroek M, Henry RMA, de Galan B, Stehouwer CDA, Eussen SJMP, Schalkwijk CG. Habitual intake of dietary advanced glycation end products is not associated with generalized microvascular function-the Maastricht Study. Am J Clin Nutr 2021; 115:444-455. [PMID: 34581759 PMCID: PMC8827096 DOI: 10.1093/ajcn/nqab302] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/24/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat. OBJECTIVES We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort. METHODS In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors. RESULTS Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned. CONCLUSIONS We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions.
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Affiliation(s)
- Armand M A Linkens
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Alfons J H M Houben
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Abraham A Kroon
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Miranda T Schram
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Tos T J M Berendschot
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, Netherlands
| | - Carroll A B Webers
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, Netherlands
| | - Marleen van Greevenbroek
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Ronald M A Henry
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands,Heart and Vascular Center, Maastricht University Medical Center, Maastricht, Netherlands
| | - Bastiaan de Galan
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Coen D A Stehouwer
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Simone J M P Eussen
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands,Department of Epidemiology, Maastricht University, Maastricht, Netherlands,CAPHRI School for Care and Public Health Research Unit, Maastricht University, Maastricht, Netherlands
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Renfeng Q, Shuxiao C, Peixian G, Kun L, Xuedong F, Hai Y, Xuejun W, Gang L. ADAM10 attenuates the development of abdominal aortic aneurysms in a mouse model. Mol Med Rep 2021; 24:774. [PMID: 34490486 PMCID: PMC8456315 DOI: 10.3892/mmr.2021.12414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 07/23/2021] [Indexed: 01/24/2023] Open
Abstract
An abdominal aortic aneurysm (AAA) is a life-threatening disease associated with a high mortality rate. At present, surgery or minimally invasive interventions are used in clinical treatment, especially for small aneurysms. However, the benefits of surgical repair are not obvious, and AAA ruptures can be prevented by aneurysm therapy to inhibit the growth of small aneurysms. Therefore, evaluating effective drugs to treat small AAAs is urgently required. Chronic inflammation is the main pathological feature of aneurysmal tissues. The aim of the present study was to investigate the protective role and underlying mechanism of ADAM metallopeptidase domain 10 (ADAM10). In the present study, a mouse model of AAA was established via porcine pancreatic elastase perfusion for 5 min per day for 14 days. ADAM10 (6 mg/kg) was injected intraperitoneally following 3 days of porcine pancreatic elastase perfusion in the ADAM10 group and the treatment continued for 10 days. The maximum inner luminal diameters of the infrarenal abdominal aortas were measured using an animal ultrasound system. The levels of high mobility group box 1 (HMGB1) and soluble receptor for advanced glycosylation end products in serum samples were measured by ELISA. Hematoxylin and eosin and elastin van Gieson staining were performed to observe morphology, integrity of the elastin layers and elastin degradation. CD68 expression was detected by immunohistochemical staining. Reverse transcription-quantitative PCR and western blotting were used for detection of mRNA and protein levels. The gelatinolytic activities of MMP-2 and MMP-9 were quantified via gelatin zymography analysis. These results showed that ADAM10 inhibited HMGB1/RAGE/NF-κB signaling and MMP activity in the pathogenesis of pancreatic elastase-induced AAA, which provide insight into the molecular mechanism of AAA and suggested that ADAM10 may be a potential therapeutic target for AAA.
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Affiliation(s)
- Qiu Renfeng
- Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
| | - Chen Shuxiao
- Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
| | - Gao Peixian
- Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
| | - Luo Kun
- Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
| | - Feng Xuedong
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Yuan Hai
- Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
| | - Wu Xuejun
- Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
| | - Li Gang
- Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
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Azegami T, Nakayama T, Hayashi K, Hishikawa A, Yoshimoto N, Nakamichi R, Itoh H. Vaccination Against Receptor for Advanced Glycation End Products Attenuates the Progression of Diabetic Kidney Disease. Diabetes 2021; 70:2147-2158. [PMID: 34155040 DOI: 10.2337/db20-1257] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 06/14/2021] [Indexed: 11/13/2022]
Abstract
Effective treatment of diabetic kidney disease (DKD) remains a large unmet medical need. Within the disease's complicated pathogenic mechanism, activation of the advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis plays a pivotal role in the development and progression of DKD. To provide a new therapeutic strategy against DKD progression, we developed a vaccine against RAGE. Three rounds of immunization of mice with the RAGE vaccine successfully induced antigen-specific serum IgG antibody titers and elevated antibody titers were sustained for at least 38 weeks. In addition, RAGE vaccination significantly attenuated the increase in urinary albumin excretion in streptozotocin-induced diabetic mice (type 1 diabetes model) and leptin-receptor-deficient db/db mice (type 2 diabetes model). In microscopic analyses, RAGE vaccination suppressed glomerular hypertrophy and mesangial expansion in both diabetic models and significantly reduced glomerular basement membrane thickness in streptozotocin-induced diabetic mice. Results of an in vitro study indicated that the serum IgG antibody elicited by RAGE vaccination suppressed the expression of AGE-induced vascular cell adhesion molecule 1 and intracellular adhesion molecule 1 in endothelial cells. Thus, our newly developed RAGE vaccine attenuated the progression of DKD in mice and is a promising potential therapeutic strategy for patients with DKD.
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Affiliation(s)
- Tatsuhiko Azegami
- Keio University Health Center, Kanagawa, Japan
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takashin Nakayama
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Kaori Hayashi
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Akihito Hishikawa
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Norifumi Yoshimoto
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Ran Nakamichi
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Itoh
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Hansda AK, Goswami R. 17-β estradiol signalling affects cardiovascular and cancer pathogenesis by regulating the crosstalk between transcription factors and EC-miRNAs. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Prasad K. Current Status of Primary, Secondary, and Tertiary Prevention of Coronary Artery Disease. Int J Angiol 2021; 30:177-186. [PMID: 34776817 PMCID: PMC8580611 DOI: 10.1055/s-0041-1731273] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Fifty percent of all death from cardiovascular diseases is due to coronary artery disease (CAD). This is avoidable if early identification is made. Preventive health care has a major role in the fight against CAD. Atherosclerosis and atherosclerotic plaque rupture are involved in the development of CAD. Modifiable risk factors for CAD are dyslipidemia, diabetes, hypertension, cigarette smoking, obesity, chronic renal disease, chronic infection, high C-reactive protein, and hyperhomocysteinemia. CAD can be prevented by modification of risk factors. This paper defines the primary, secondary, and tertiary prevention of CAD. It discusses the mechanism of risk factor-induced atherosclerosis. This paper describes the CAD risk score and its use in the selection of individuals for primary prevention of CAD. Guidelines for primary, secondary, and tertiary prevention of CAD have been described. Modification of risk factors and use of guidelines for prevention of CAD would prevent, regress, and slow down the progression of CAD, improve the quality of life of patient, and reduce the health care cost.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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40
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Palmer TM, Salt IP. Nutrient regulation of inflammatory signalling in obesity and vascular disease. Clin Sci (Lond) 2021; 135:1563-1590. [PMID: 34231841 DOI: 10.1042/cs20190768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 06/10/2021] [Accepted: 06/28/2021] [Indexed: 11/17/2022]
Abstract
Despite obesity and diabetes markedly increasing the risk of developing cardiovascular diseases, the molecular and cellular mechanisms that underlie this association remain poorly characterised. In the last 20 years it has become apparent that chronic, low-grade inflammation in obese adipose tissue may contribute to the risk of developing insulin resistance and type 2 diabetes. Furthermore, increased vascular pro-inflammatory signalling is a key event in the development of cardiovascular diseases. Overnutrition exacerbates pro-inflammatory signalling in vascular and adipose tissues, with several mechanisms proposed to mediate this. In this article, we review the molecular and cellular mechanisms by which nutrients are proposed to regulate pro-inflammatory signalling in adipose and vascular tissues. In addition, we examine the potential therapeutic opportunities that these mechanisms provide for suppression of inappropriate inflammation in obesity and vascular disease.
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Affiliation(s)
- Timothy M Palmer
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull HU6 7RX, United Kingdom
| | - Ian P Salt
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
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An Update on the Pathogenic Role of Macrophages in Adult-Onset Still's Disease and Its Implication in Clinical Manifestations and Novel Therapeutics. J Immunol Res 2021; 2021:8998358. [PMID: 34239943 PMCID: PMC8238602 DOI: 10.1155/2021/8998358] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/23/2021] [Accepted: 05/28/2021] [Indexed: 12/18/2022] Open
Abstract
Increasing evidence indicates a pivotal role of macrophages in innate immunity, which contributes to the pathogenesis of adult-onset Still's disease (AOSD). Despite the available reviews that summarized the pathogenic role of proinflammatory cytokines in AOSD, a systematic approach focusing on the crucial role of macrophages in this disease is still lacking. This review summarizes the updated functions of macrophages in AOSD and their implication in clinical manifestations and therapeutics. We searched the MEDLINE database using the PubMed interface and reviewed the English-language literature as of 31 March 2021, from 1971 to 2021. We focus on the existing evidence on the pathogenic role of macrophages in AOSD and its implication in clinical characteristics and novel therapeutics. AOSD is an autoinflammatory disease mainly driven by the innate immune response. Among the innate immune responses, macrophage activation is a hallmark of AOSD pathogenesis. The pattern recognition receptors (PRRs) on macrophages recognize pathogen-associated molecular patterns and damage-associated molecular patterns and subsequently cause overproduction of proinflammatory cytokines and recruit adaptive immunity. Some biomarkers, such as ferritin and gasdermin D, reflecting macrophage activation were elevated and correlated with AOSD activity. Given that macrophage activation with the overproduction of proinflammatory cytokines plays a pathogenic role in AOSD, these inflammatory mediators would be the therapeutic targets. Accordingly, the inhibitors to interleukin- (IL-) 1, IL-6, and IL-18 have been shown to be effective in AOSD treatment. Gaining insights into the pathogenic role of macrophages in AOSD can aid in identifying disease biomarkers and therapeutic agents for this disease.
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Linkens AM, Eussen SJ, Houben AJ, Kroon AA, Schram MT, Reesink KD, Dagnelie PC, Henry RM, van Greevenbroek M, Wesselius A, Stehouwer CD, Schalkwijk CG. Habitual Intake of Dietary Advanced Glycation End Products Is Not Associated with Arterial Stiffness of the Aorta and Carotid Artery in Adults: The Maastricht Study. J Nutr 2021; 151:1886-1893. [PMID: 33982103 PMCID: PMC8245866 DOI: 10.1093/jn/nxab097] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/17/2021] [Accepted: 03/15/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Advanced glycation end products (AGEs), a heterogeneous group of bioactive compounds, are thought to contribute to arterial stiffness, which in turn is a causal factor in the pathogenesis of stroke, myocardial infarction, and heart failure. Whether AGEs derived from food also contribute to arterial stiffness is not clear. OBJECTIVES We investigated whether higher intake of dietary AGEs is associated with arterial stiffness. METHODS In this cross-sectional observational study in 2255 participants of The Maastricht Study (mean ± SD age: 60 ± 8 y, 51% male, mean ± SD BMI: 26.9 ± 4.4 kg/m2, n = 1326 normal glucose metabolism, n = 341 prediabetes, and n = 585 type 2 diabetes mellitus), we estimated intake of the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) by a validated FFQ coupled to our ultra-performance liquid chromatography tandem mass spectrometry dietary AGE database. Arterial stiffness was determined using carotid-femoral pulse wave velocity (cfPWV), carotid distensibility coefficient (DC), and carotid Young's elastic modulus (YEM). We performed multiple linear regression analyses adjusting for potential confounders (demographic, hemodynamic, cardiovascular, and dietary factors). RESULTS In the fully adjusted models we observed no statistically significant associations between intake of the dietary AGEs CML, CEL, and MG-H1 and arterial stiffness expressed as cfPWV, carotid DC, and carotid YEM. CONCLUSIONS In adults aged 40-75 y, habitual intake of the dietary AGEs CML, CEL, and MG-H1 is not associated with arterial stiffness measured as cfPWV, carotid DC, or carotid YEM.
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Affiliation(s)
- Armand Ma Linkens
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Simone Jmp Eussen
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands,Department of Epidemiology, Maastricht University, Maastricht, Netherlands
| | - Alfons Jhm Houben
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Abraham A Kroon
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Miranda T Schram
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands,Heart and Vascular Center, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Koen D Reesink
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands,Heart and Vascular Center, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Pieter C Dagnelie
- Department of Epidemiology, Maastricht University, Maastricht, Netherlands
| | - Ronald Ma Henry
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands,Heart and Vascular Center, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Marleen van Greevenbroek
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Anke Wesselius
- Department of Complex Genetics and Epidemiology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Coen Da Stehouwer
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands,CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
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Rojas A, Lindner C, Gonzàlez I, Morales MA. Advanced-glycation end-products axis: A contributor to the risk of severe illness from COVID-19 in diabetes patients. World J Diabetes 2021; 12:590-602. [PMID: 33995847 PMCID: PMC8107984 DOI: 10.4239/wjd.v12.i5.590] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/29/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products (RAGE) in orchestrating a plethora of proinflammatory cellular responses leading to many of the complications and end-organ damages reported in patients with diabetes mellitus (DM). During the coronavirus disease 2019 (COVID-19) pandemic, many clinical reports have pointed out that DM increases the risk of COVID-19 complications, hospitalization requirements, as well as the overall severe acute respiratory syndrome coronavirus 2 case-fatality rate. In the present review, we intend to focus on how the basal activation state of the RAGE axis in common preexisting conditions in DM patients such as endothelial dysfunction and hyperglycemia-related prothrombotic phenotype, as well as the contribution of RAGE signaling in lung inflammation, may then lead to the increased mortality risk of COVID-19 in these patients. Additionally, the cross-talk between the RAGE axis with either another severe acute respiratory syndrome coronavirus 2 receptor molecule different of angiotensin-converting enzyme 2 or the renin-angiotensin system imbalance produced by viral infection, as well as the role of this multi-ligand receptor on the obesity-associated low-grade inflammation in the higher risk for severe illness reported in diabetes patients with COVID-19, are also discussed.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Cristian Lindner
- Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Ileana Gonzàlez
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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Zhang Q, Yang Y, Lu Y, Cao Z. iTRAQ-based quantitative proteomic analyses the cycle chronic heat stress affecting liver proteome in yellow-feather chickens. Poult Sci 2021; 100:101111. [PMID: 33965807 PMCID: PMC8120948 DOI: 10.1016/j.psj.2021.101111] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/16/2020] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
Heat stress (HS) is one of the main environmental factors affecting the efficiency of poultry production. The yellow-feather chickens (YFC) as an indigenous strain of chicken is a popular poultry breed in China. Our previous study used the RNA-seq to analyze the gene expression profiles of male YFC under HS and showed that the lipid and energy metabolism pathways are activated in livers of YFC exposed to acute HS (38°C, 4 h and 25°C recovery 2 h). In this study, we used quantitative proteome analysis based on iTRAQ to study the liver response of YFC to cycle chronic HS (38 ± 1°C, 8 h/d, 7 d, CyCHS). The male YFCs treatment used the CyCHS from 22 to 28 days of age. The liver tissue samples were collected at 28 d old. A total of 39,327 unique peptides matches were detected using iTRAQ analysis and 4,571 proteins exhibited a false discovery rate of 1% or less. Forty-six significant differentially expressed proteins (DEPs) were detected in the CyCHS group compared with the control group for the liver samples, including up- and down-regulated DEPs were 18 and 28, respectively. We found that the enriched biological process terms of the DEPs expressed in the liver were related to DNA metabolic process, oxidation-reduction process, oxidative stress and gluconeogenesis. In KEGG pathway analysis. Most of the hepatic DEPs were annotated to glutathione metabolism and TCA cycle in response to CyCHS. The up-regulation of 5 DEPs (GPX1, GSTT1, GSTT1L, RRM2, and LOC100859645) in the glutathione metabolism pathway likely reflects an attempt to deal with oxidative damage by CyCHS. The down-regulation of 3 DEPs (Isocitrate dehydrogenase [IDH3A], IDH3B, and phosphoenolpyruvate carboxykinase 1) in the TCA cycle pathway contributes to the regulation mechanism of energy metabolism and probably to cope with the balance of heat production and dissipation during CyCHS in order to adapt to high temperature environments. Our results provide insights into the potential molecular mechanism in heat-induced oxidative stress and energy in YFCs and future studies will investigate the functional genes associated with the response to HS.
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Affiliation(s)
- Quan Zhang
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China.
| | - YuZe Yang
- Beijing General Station of Animal Husbandry, Beijing, China
| | - YongQiang Lu
- Beijing General Station of Animal Husbandry, Beijing, China
| | - ZiWen Cao
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China
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Huang HL, Kuo CS, Chang TY, Chou RH, Chen IC, Yang FC, Chen NJ, Lin SJ, Wu CC, Huang PH. An oral absorbent, AST-120, restores vascular growth and blood flow in ischemic muscles in diabetic mice via modulation of macrophage transition. J Mol Cell Cardiol 2021; 155:99-110. [PMID: 33713645 DOI: 10.1016/j.yjmcc.2021.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 02/06/2021] [Accepted: 03/04/2021] [Indexed: 10/21/2022]
Abstract
Background Diabetes has a pronounced effect on the peripheral vasculature. The accumulation of advanced glycation end products (AGEs) is regarded as the crucial mechanism responsible for vascular damage in diabetes, but it is not easy to be avoided from food. In this study, we aimed to investigate the effects of an oral absorbent, AST-120, on the accumulation of AGEs and changes in blood flow recovery in diabetic mice. Methods The mice were divided into four groups, wild-type (WT) mice without treatment, WT mice treated with 5% AST-120 mixed into pulverized chow, streptozotocin-induced diabetes mellitus (DM) mice, and DM mice treated with 5% AST-120. Six weeks after hind-limb ischemia surgery, blood flow reperfusion, histology, plasma AGE, and cytokine were examined. Bone marrow cells were cultured and derived into macrophages to evaluate the effects of AGEs on macrophage polarization. Results Plasma AGEs were significantly increased in diabetic mice. AST-120 could bind to AGEs and reduced their plasma concentrations. Histological analysis revealed fewer collateral vessels with corresponding impairment of blood flow recovery in diabetic mice. In these mice, AGE-positive and AGE receptor-positive macrophages were numerous in ischemic limbs compared with non- diabetic mice. In diabetic mice, macrophages in ischemic tissues demonstrated greater M1 polarization than M2 polarization; this pattern was reversed in the AST-120 treatment group. The change in macrophage polarization was associated with the corresponding expression of pro-inflammatory cytokines in the ischemic tissues. In cell cultures, AGEs triggered the transformation of bone marrow-derived macrophages into the M1 phenotype. The alterations in the polarization of macrophages were reversed after treatment with AST-120. Conclusions Oral administration of AST-120 decreased the serum levels of AGEs in diabetic mice and improved neovascularization of ischemic limbs. This benefit may be due to, at least partially, the alterations in macrophage polarization and the associated changes in inflammatory cytokines.
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Affiliation(s)
- Hsin-Lei Huang
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; National Taipei University of Nursing and Health Sciences, Taiwan
| | - Chin-Sung Kuo
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ting-Yung Chang
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Cardiovascular Research Center, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ruey-Hsing Chou
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Cardiovascular Research Center, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - I-Chun Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Fu-Chen Yang
- Institute of Microbiology and Immunology, School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Nien-Jung Chen
- Institute of Microbiology and Immunology, School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan; Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shing-Jong Lin
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; Cardiovascular Research Center, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Heart Center, Cheng-Hsin General Hospital, Taipei, Taiwan
| | - Chih-Cheng Wu
- National Tsing-Hua University, Institute of Biomedical Engineering, Hsinchu, Taiwan; Cardiovascular Center, National Taiwan University Hospital, Hsinchu Branch, Taipei, Taiwan; National Taiwan University Hospital, College of Medicine, Taipei, Taiwan; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
| | - Po-Hsun Huang
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Cardiovascular Research Center, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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46
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Abstract
Coronary artery atherosclerosis and atherosclerotic plaque rupture cause coronary artery disease (CAD). Advanced glycation end products (AGE) and its cell receptor RAGE, and soluble receptor (sRAGE) and endogenous secretory RAGE (esRAGE) may be involved in the development of atherosclerosis. AGE and its interaction with RAGE are atherogenic, while sRAGE and esRAGE have antiatherogenic effects. AGE-RAGE stress is a ratio of AGE/sRAGE. A high AGE-RAGE stress results in development and progression of CAD and vice-versa. AGE levels in serum and skin, AGE/sRAGE in patients with CAD, and expression of RAGE in animal model of atherosclerosis were higher, while serum levels of esRAGE were lower in patients with CAD compared with controls. Serum levels of sRAGE in CAD patients were contradictory, increased or decreased. This contradictory data may be due to type of patients used, because the sRAGE levels are elevated in diabetics and end-stage renal disease. AGE/sRAGE ratio is elevated in patients with reduced or elevated levels of serum sRAGE. It is to stress that AGE, RAGE, sRAGE, or esRAGE individually cannot serve as universal biomarker. AGE and sRAGE should be measured simultaneously to assess the AGE-RAGE stress. The treatment of CAD should be targeted at reduction in AGE levels, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of RAGE, elevation of sRAGE, and use of antioxidants. In conclusion, AGE-RAGE stress would initiate the development and progression of atherosclerosis. Treatment modalities would prevent, regress, and slow the progression of CAD.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Canada
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47
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Prantner D, Nallar S, Vogel SN. The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways. FASEB J 2020; 34:15659-15674. [PMID: 33131091 DOI: 10.1096/fj.202002136r] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/07/2020] [Accepted: 10/13/2020] [Indexed: 12/15/2022]
Abstract
Although the innate immune receptor protein, Receptor for Advanced Glycation End products (RAGE), has been extensively studied, there has been renewed interest in RAGE for its potential role in sepsis, along with a host of other inflammatory diseases of chronic, noninfectious origin. In contrast to other innate immune receptors, for example, Toll-like receptors (TLRs), that recognize ligands derived from pathogenic organisms that are collectively known as "pathogen-associated molecular patterns" (PAMPs) or host-derived "damage-associated molecular patterns" (DAMPs), RAGE has been shown to recognize a broad collection of DAMPs exclusively. Historically, these DAMPs have been shown to be pro-inflammatory in nature. Early studies indicated that the adaptor molecule, MyD88, might be important for this change. More recent studies have explored further the mechanisms underlying this inflammatory change. Overall, the newer results have shown that there is extensive crosstalk between RAGE and TLRs. The three canonical RAGE ligands, Advanced Glycation End products (AGEs), HMGB1, and S100 proteins, have all been shown to activate both TLRs and RAGE to varying degrees in order to induce inflammation in in vitro models. As with any field that delves deeply into innate signaling, obstacles of reagent purity may be a cause of some of the discrepancies in the literature, and we have found that commercial antibodies that have been widely used exhibit a high degree of nonspecificity. Nonetheless, the weight of published evidence has led us to speculate that RAGE may be physically interacting with TLRs on the cell surface to elicit inflammation via MyD88-dependent signaling.
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Affiliation(s)
- Daniel Prantner
- Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Shreeram Nallar
- Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Stefanie N Vogel
- Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD, USA
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48
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Abstract
Receptor for advanced glycation end products (RAGE) is an immunoglobulin-like receptor present on cell surface. RAGE binds to an array of structurally diverse ligands, acts as a pattern recognition receptor (PRR) and is expressed on cells of different origin performing different functions. RAGE ligation leads to the initiation of a cascade of signaling events and is implicated in diseases, such as inflammation, cancer, diabetes, vascular dysfunctions, retinopathy, and neurodegenerative diseases. Because of the significant involvement of RAGE in the progression of numerous diseases, RAGE signaling has been targeted through use of inhibitors and anti-RAGE antibodies as a treatment strategy and therapy. Here in this review, we have summarized the physical and physiological aspects of RAGE biology in mammalian system and the importance of targeting this molecule in the treatment of various RAGE mediated pathologies. Highlights Receptor for advanced glycation end products (RAGE) is a member of immunoglobulin superfamily of receptors and involved in many pathophysiological conditions. RAGE ligation with its ligands leads to initiation of distinct signaling cascades and activation of numerous transcription factors. Targeting RAGE signaling through inhibitors and anti-RAGE antibodies can be promising treatment strategy.
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Affiliation(s)
- Nitish Jangde
- Laboratory of Vascular Immunology, Institute of Life Sciences, Bhubaneswar, India.,Manipal Academy of Higher Education, Manipal, India
| | - Rashmi Ray
- Laboratory of Vascular Immunology, Institute of Life Sciences, Bhubaneswar, India
| | - Vivek Rai
- Laboratory of Vascular Immunology, Institute of Life Sciences, Bhubaneswar, India
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49
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Pestel J, Robert M, Corbin S, Vidal H, Eljaafari A. Involvement of glycated albumin in adipose-derived-stem cell-mediated interleukin 17 secreting T helper cell activation. World J Stem Cells 2020; 12:621-632. [PMID: 32843918 PMCID: PMC7415245 DOI: 10.4252/wjsc.v12.i7.621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/19/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Advanced glycation end products (AGE) are a marker of various diseases including diabetes, in which they participate to vascular damages such as retinopathy, nephropathy and coronaropathy. Besides those vascular complications, AGE are involved in altered metabolism in many tissues, including adipose tissue (AT) where they contribute to reduced glucose uptake and attenuation of insulin sensitivity. AGE are known to contribute to type 1 diabetes (T1D) through promotion of interleukin (IL)-17 secreting T helper (Th17) cells.
AIM To investigate whether lean adipose-derived stem cells (ASC) could be able to induce IL-17A secretion, with the help of AGE.
METHODS As we have recently demonstrated that ASC are involved in Th17 cell promotion when they are harvested from obese AT, we used the same co-culture model to measure the impact of glycated human serum albumin (G-HSA) on human lean ASC interacting with blood mononuclear cells. IL-17A and pro-inflammatory cytokine secretion were measured by ELISA. Receptor of AGE (RAGE) together with intercellular adhesion molecule 1 (ICAM-1), human leukocyte Antigen (HLA)-DR, cluster of differentiation (CD) 41, and CD62P surface expressions were measured by cytofluorometry. Anti-RAGE specific monoclonal antibody was added to co-cultures in order to evaluate the role of RAGE in IL-17A production.
RESULTS Results showed that whereas 1% G-HSA only weakly potentiated the production of IL-17A by T cells interacting with ASC harvested from obese subjects, it markedly increased IL-17A, but also interferon gamma and tumor necrosis factor alpha production in the presence of ASC harvested from lean individuals. This was associated with increased expression of RAGE and HLA-DR molecule by co-cultured cells. Moreover, RAGE blockade experiments demonstrated RAGE specific involvement in lean ASC-mediated Th-17 cell activation. Finally, platelet aggregation and ICAM-1, which are known to be induced by AGE, were not involved in these processes.
CONCLUSION Thus, our results demonstrated that G-HSA potentiated lean ASC-mediated IL-17A production in AT, suggesting a new mechanism by which AGE could contribute to T1D pathophysiology.
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Affiliation(s)
- Julien Pestel
- INSERM U1060 CarMen, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Faculty of Medicine, Université Claude Bernard Lyon 1, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
| | - Maud Robert
- INSERM U1060 CarMen, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Faculty of Medicine, Université Claude Bernard Lyon 1, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Department of Surgery in Gastro-enterology, Edouard Herriot Hospital, Lyon 69003, France
| | - Sara Corbin
- Public Health Department, Hospices Civils de Lyon, 1 quai des célestins Lyon 69002, France
| | - Hubert Vidal
- INSERM U1060 CarMen, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Faculty of Medicine, Université Claude Bernard Lyon 1, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
| | - Assia Eljaafari
- INSERM U1060 CarMen, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Faculty of Medicine, Université Claude Bernard Lyon 1, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- DO-IT Research Team, Hospices Civils de Lyon, 1 quai des célestins, Lyon 69002, France
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50
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Flynn MC, Kraakman MJ, Tikellis C, Lee MKS, Hanssen NMJ, Kammoun HL, Pickering RJ, Dragoljevic D, Al-Sharea A, Barrett TJ, Hortle F, Byrne FL, Olzomer E, McCarthy DA, Schalkwijk CG, Forbes JM, Hoehn K, Makowski L, Lancaster GI, El-Osta A, Fisher EA, Goldberg IJ, Cooper ME, Nagareddy PR, Thomas MC, Murphy AJ. Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis. Circ Res 2020; 127:877-892. [PMID: 32564710 DOI: 10.1161/circresaha.120.316653] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
RATIONALE Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. OBJECTIVE To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. METHODS AND RESULTS To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8, or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. CONCLUSIONS Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.
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Affiliation(s)
- Michelle C Flynn
- From the Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia (M.C.F., M.J.K., M.K.S.L., H.L.K., D.D., A.A.-S., F.H., G.I.L., A.J.M.), Monash University, Melbourne, Australia.,Department of Immunology (M.C.F., M.K.S.L., H.L.K., G.I.L., A.J.M.), Monash University, Melbourne, Australia
| | - Michael J Kraakman
- From the Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia (M.C.F., M.J.K., M.K.S.L., H.L.K., D.D., A.A.-S., F.H., G.I.L., A.J.M.), Monash University, Melbourne, Australia.,Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York (M.J.K.)
| | - Christos Tikellis
- Diabetes (C.T., R.J.P., A.E.-O., M.E.C., M.C.T.), Monash University, Melbourne, Australia
| | - Man K S Lee
- From the Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia (M.C.F., M.J.K., M.K.S.L., H.L.K., D.D., A.A.-S., F.H., G.I.L., A.J.M.), Monash University, Melbourne, Australia.,Department of Immunology (M.C.F., M.K.S.L., H.L.K., G.I.L., A.J.M.), Monash University, Melbourne, Australia
| | - Nordin M J Hanssen
- Department of Internal Medicine, CARIM, School of Cardiovascular Diseases, Maastricht University, the Netherlands (N.M.J.H., C.G.S.)
| | - Helene L Kammoun
- From the Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia (M.C.F., M.J.K., M.K.S.L., H.L.K., D.D., A.A.-S., F.H., G.I.L., A.J.M.), Monash University, Melbourne, Australia.,Department of Immunology (M.C.F., M.K.S.L., H.L.K., G.I.L., A.J.M.), Monash University, Melbourne, Australia
| | - Raelene J Pickering
- Diabetes (C.T., R.J.P., A.E.-O., M.E.C., M.C.T.), Monash University, Melbourne, Australia
| | - Dragana Dragoljevic
- From the Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia (M.C.F., M.J.K., M.K.S.L., H.L.K., D.D., A.A.-S., F.H., G.I.L., A.J.M.), Monash University, Melbourne, Australia
| | - Annas Al-Sharea
- From the Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia (M.C.F., M.J.K., M.K.S.L., H.L.K., D.D., A.A.-S., F.H., G.I.L., A.J.M.), Monash University, Melbourne, Australia
| | - Tessa J Barrett
- Division of Cardiology (T.J.B., E.A.F., I.J.G.), New York University School of Medicine
| | - Fiona Hortle
- From the Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia (M.C.F., M.J.K., M.K.S.L., H.L.K., D.D., A.A.-S., F.H., G.I.L., A.J.M.), Monash University, Melbourne, Australia
| | - Frances L Byrne
- Division of Endocrinology, Diabetes and Metabolism (F.L.B., E.O., K.H.), New York University School of Medicine
| | - Ellen Olzomer
- Division of Endocrinology, Diabetes and Metabolism (F.L.B., E.O., K.H.), New York University School of Medicine
| | - Domenica A McCarthy
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia (D.A.M., J.M.F.)
| | - Casper G Schalkwijk
- Department of Internal Medicine, CARIM, School of Cardiovascular Diseases, Maastricht University, the Netherlands (N.M.J.H., C.G.S.)
| | - Josephine M Forbes
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia (D.A.M., J.M.F.)
| | - Kyle Hoehn
- Division of Endocrinology, Diabetes and Metabolism (F.L.B., E.O., K.H.), New York University School of Medicine
| | - Liza Makowski
- Glycation and Diabetes Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia (L.M.)
| | - Graeme I Lancaster
- From the Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia (M.C.F., M.J.K., M.K.S.L., H.L.K., D.D., A.A.-S., F.H., G.I.L., A.J.M.), Monash University, Melbourne, Australia.,Department of Immunology (M.C.F., M.K.S.L., H.L.K., G.I.L., A.J.M.), Monash University, Melbourne, Australia
| | - Assam El-Osta
- Diabetes (C.T., R.J.P., A.E.-O., M.E.C., M.C.T.), Monash University, Melbourne, Australia.,Division of Hematology and Oncology, Department of Medicine, University of Tennessee Health Science Center, Memphis (A.E.-O.).,Department of Medicine and Therapeutics (A.E.-O.), The Chinese University of Hong Kong.,Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital (A.E.-O.), The Chinese University of Hong Kong.,Li Ka Shing Institute of Health Sciences (A.E.-O.), The Chinese University of Hong Kong
| | - Edward A Fisher
- Division of Cardiology (T.J.B., E.A.F., I.J.G.), New York University School of Medicine
| | - Ira J Goldberg
- Division of Cardiology (T.J.B., E.A.F., I.J.G.), New York University School of Medicine
| | - Mark E Cooper
- Diabetes (C.T., R.J.P., A.E.-O., M.E.C., M.C.T.), Monash University, Melbourne, Australia
| | | | - Merlin C Thomas
- Diabetes (C.T., R.J.P., A.E.-O., M.E.C., M.C.T.), Monash University, Melbourne, Australia
| | - Andrew J Murphy
- Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Australia (A.J.M.)
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