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Zhu Y, Ali A, Mulinari Dos Santos G, Franciscon JPS, de Molon RS, Goh C, Erovolino E, Theodoro LH, Shrestha A. A Chitosan-based Hydrogel to Modulate Immune Cells and Promote Periodontitis Healing in the High-Fat Diet-induced Periodontitis Rat Model. Acta Biomater 2025:S1742-7061(25)00358-7. [PMID: 40379118 DOI: 10.1016/j.actbio.2025.05.034] [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: 02/03/2025] [Revised: 05/06/2025] [Accepted: 05/12/2025] [Indexed: 05/19/2025]
Abstract
Periodontitis is a multifactorial inflammatory disease driven by prolonged, dysregulated inflammation between dysbiotic microbiota and the host immune system. Risk factors such as metabolic syndrome exacerbate periodontitis progression through systemic inflammation. Current treatments primarily focus on removing pathogenic dental plaque, but subsequent healing relies mainly on the host immune response. Modulating the local immune environment, particularly dendritic cells (DCs) and T-cells, in periodontitis complicated by metabolic syndrome could enhance the healing process. The objective of this study is to develop a biomaterial-based adjuvant therapy to immunomodulate DCs and T-cells and promote healing in periodontitis complicated by metabolic syndrome. We developed and characterized a chitosan-based thermosensitive injectable self-assembled hydrogel (TISH), which exhibited an interconnected porous structure conducive to cell migration and adhesion. TISH was loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) and resveratrol (TISH(GR)), enabling sustained release over time. Mechanistically, TISH(GR) suppressed inflammatory signalling pathways (MAPKs and NF-κB) downstream of Toll-like receptor-4 in DCs. In a high-fat diet-induced periodontitis rat model, TISH(GR) administered as an adjuvant to SRP significantly alleviated periodontal inflammation and tissue destruction compared to SRP alone. TISH(GR) treatment was associated with decreased TH17 cell infiltration and elevated expression of the Tregs-associated cytokine IL-10 in the periodontium. In conclusion, TISH(GR) was developed and optimized as an injectable immunomodulatory hydrogel targeting DCs and T-cells. It demonstrated promising potential to attenuate inflammation and enhance periodontal healing, particularly in immunocompromised patients with metabolic syndrome. STATEMENT OF SIGNIFICANCE: Current treatments for periodontitis primarily focus on dental plaque removal, with healing heavily dependent on the host immune system. However, metabolic diseases can dysregulate the local immune response, exacerbating periodontal inflammation and impairing post-treatment healing. In this study, we developed a chitosan-based hydrogel designed to immunomodulate dendritic cells and T-cells, polarizing them toward an anti-inflammatory phenotype that promotes tissue repair. When administered as an adjuvant to scaling and root planing, this combination therapy significantly enhanced periodontal healing and reduced tissue damage in a high-fat diet complicated periodontitis model. These findings highlight the clinical potential of this hydrogel formulation to improve treatment outcomes, particularly in challenging clinical cases involving metabolic comorbidities.
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Affiliation(s)
- Yi Zhu
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada
| | - Aiman Ali
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada
| | - Gabriel Mulinari Dos Santos
- Department of Diagnostic and Surgery, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - João Paulo Soares Franciscon
- Department of Diagnostic and Surgery, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - Rafael Scaf de Molon
- Department of Diagnostic and Surgery, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - Cynthia Goh
- Department of Chemistry, University of Toronto, 80 George Street, Toronto, ON, M5S 3H6, Canada; Department of Materials Science and Engineering, University of Toronto, 84 College Street, Suite 140. Toronto, Ontario M5S 3E4 Canada
| | - Edilson Erovolino
- Department of Basic Science, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - Leticia Helena Theodoro
- Department of Diagnostic and Surgery, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - Annie Shrestha
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
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Weng J, Ross C, Baker J, Alfuraih S, Shamloo K, Sharma A. Diabetes-Associated Hyperglycemia Causes Rapid-Onset Ocular Surface Damage. Invest Ophthalmol Vis Sci 2023; 64:11. [PMID: 37938936 PMCID: PMC10637200 DOI: 10.1167/iovs.64.14.11] [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: 04/03/2023] [Accepted: 10/16/2023] [Indexed: 11/10/2023] Open
Abstract
Purpose The metabolic alterations due to chronic hyperglycemia are well-known to cause diabetes-associated complications. Short-term hyperglycemia has also been shown to cause many acute changes, including hemodynamic alterations and osmotic, oxidative, and inflammatory stress. The present study was designed to investigate whether diabetes-associated hyperglycemia can cause rapid-onset detrimental effects on the tear film, goblet cells, and glycocalyx and can lead to activation of an inflammatory cascade or cellular stress response in the cornea. Methods Mouse models of type 1 and type 2 diabetes were used. Tear film volume, goblet cell number, and corneal glycocalyx area were measured on days 7, 14, and 28 after the onset of hyperglycemia. Transcriptome analysis was performed to quantify changes in 248 transcripts of genes involved in inflammatory, apoptotic, and stress response pathways. Results Our data demonstrate that type 1 and type 2 diabetes-associated hyperglycemia caused a significant decrease in the tear film volume, goblet cell number, and corneal glycocalyx area. The decrease in tear film and goblet cell number was noted as early as 7 days after onset of hyperglycemia. The severity of ocular surface injury was significantly more in type 1 compared to type 2 diabetes. Diabetes mellitus also caused an increase in transcripts of genes involved in the inflammatory, apoptotic, and cellular stress response pathways. Conclusions The results of the present study demonstrate that diabetes-associated hyperglycemia causes rapid-onset damage to the ocular surface. Thus, short-term hyperglycemia in patients with diabetes mellitus may also play an important role in causing ocular surface injury and dry eye.
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Affiliation(s)
- Judy Weng
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Christopher Ross
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Jacob Baker
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Saleh Alfuraih
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Kiumars Shamloo
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Ajay Sharma
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
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Cohen CD, De Blasio MJ, Farrugia GE, Dona MS, Hsu I, Prakoso D, Kiriazis H, Krstevski C, Nash DM, Li M, Gaynor TL, Deo M, Drummond GR, Ritchie RH, Pinto AR. Mapping the cellular and molecular landscape of cardiac non-myocytes in murine diabetic cardiomyopathy. iScience 2023; 26:107759. [PMID: 37736052 PMCID: PMC10509303 DOI: 10.1016/j.isci.2023.107759] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/01/2023] [Accepted: 08/25/2023] [Indexed: 09/23/2023] Open
Abstract
Diabetes is associated with a significantly elevated risk of heart failure. However, despite extensive efforts to characterize the phenotype of the diabetic heart, the molecular and cellular protagonists that underpin cardiac pathological remodeling in diabetes remain unclear, with a notable paucity of data regarding the impact of diabetes on non-myocytes within the heart. Here we aimed to define key differences in cardiac non-myocytes between spontaneously type-2 diabetic (db/db) and healthy control (db/h) mouse hearts. Single-cell transcriptomic analysis revealed a concerted diabetes-induced cellular response contributing to cardiac remodeling. These included cell-specific activation of gene programs relating to fibroblast hyperplasia and cell migration, and dysregulation of pathways involving vascular homeostasis and protein folding. This work offers a new perspective for understanding the cellular mediators of diabetes-induced cardiac pathology, and pathways that may be targeted to address the cardiac complications associated with diabetes.
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Affiliation(s)
- Charles D. Cohen
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - Miles J. De Blasio
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, Australia
| | - Gabriella E. Farrugia
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Baker Department of Cardiovascular Research and Implementation, La Trobe University, Melbourne, VIC, Australia
| | - Malathi S.I. Dona
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
| | - Ian Hsu
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
| | - Darnel Prakoso
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Helen Kiriazis
- Preclinical Cardiology, Microsurgery and Imaging Platform, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, Australia
| | - Crisdion Krstevski
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - David M. Nash
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Mandy Li
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Taylah L. Gaynor
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - Minh Deo
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Grant R. Drummond
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - Rebecca H. Ritchie
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
| | - Alexander R. Pinto
- Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, Australia
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Starr CR, Gorbatyuk MS. Posttranslational modifications of proteins in diseased retina. Front Cell Neurosci 2023; 17:1150220. [PMID: 37066080 PMCID: PMC10097899 DOI: 10.3389/fncel.2023.1150220] [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: 01/23/2023] [Accepted: 03/13/2023] [Indexed: 04/03/2023] Open
Abstract
Posttranslational modifications (PTMs) are known to constitute a key step in protein biosynthesis and in the regulation of protein functions. Recent breakthroughs in protein purification strategies and current proteome technologies make it possible to identify the proteomics of healthy and diseased retinas. Despite these advantages, the research field identifying sets of posttranslationally modified proteins (PTMomes) related to diseased retinas is significantly lagging, despite knowledge of the major retina PTMome being critical to drug development. In this review, we highlight current updates regarding the PTMomes in three retinal degenerative diseases-namely, diabetic retinopathy (DR), glaucoma, and retinitis pigmentosa (RP). A literature search reveals the necessity to expedite investigations into essential PTMomes in the diseased retina and validate their physiological roles. This knowledge would accelerate the development of treatments for retinal degenerative disorders and the prevention of blindness in affected populations.
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Affiliation(s)
| | - Marina S. Gorbatyuk
- Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, AL, United States
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Lee HH, Jeong GW, Ye BJ, Yoo EJ, Son KS, Kim DK, Park HK, Kang BH, Lee-Kwon W, Kwon HM, Choi SY. TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling. Diabetes 2022; 71:2557-2571. [PMID: 36170666 PMCID: PMC9862453 DOI: 10.2337/db21-1099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 09/20/2022] [Indexed: 02/05/2023]
Abstract
The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell-specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet-induced obesity but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced proinflammatory phenotype of metabolically activated macrophages, decreased expression of inflammatory factors related to insulin resistance, and enhanced insulin sensitivity. TonEBP expression was elevated in the ATMs of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance-related genes and promoted induction of insulin sensitivity-related genes under obesity-mimicking conditions and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity.
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Affiliation(s)
- Hwan Hee Lee
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Gyu Won Jeong
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Byeong Jin Ye
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Eun Jin Yoo
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Keoung Sun Son
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye-Kyung Park
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Byoung Heon Kang
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Whaseon Lee-Kwon
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Hyug Moo Kwon
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
- Corresponding author: Soo Youn Choi, , or Hyug Moo Kwon,
| | - Soo Youn Choi
- School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
- Department of Biology, Jeju National University, Jeju, Republic of Korea
- Corresponding author: Soo Youn Choi, , or Hyug Moo Kwon,
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Schmidt S, Vogt Weisenhorn DM, Wurst W. Chapter 5 – “Parkinson's disease – A role of non-enzymatic posttranslational modifications in disease onset and progression?”. Mol Aspects Med 2022; 86:101096. [PMID: 35370007 DOI: 10.1016/j.mam.2022.101096] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/04/2022] [Accepted: 03/14/2022] [Indexed: 12/14/2022]
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Şimşek Tanin Ö, Kara M, Engin-Üstün Y, Göçmen AY, Yalvaç ES. Comparison of glucose degradation product and receptor levels in diabetic and normal pregnancy. J Turk Ger Gynecol Assoc 2021; 22:127-131. [PMID: 32517435 PMCID: PMC8187971 DOI: 10.4274/jtgga.galenos.2020.2020.0051] [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: 04/04/2020] [Accepted: 06/04/2020] [Indexed: 02/04/2023] Open
Abstract
Objective The aim of this study was to assess the diagnostic values of new biochemical markers that may be an alternative to the oral glucose tolerance test (OGTT) and determine the differences in these markers among three groups of women with varying degrees of glucose homeostasis dysregulation. Material and Methods This was a prospective study. All women were screened with 50 gram (g) oral glucose and a 100 g OGTT for gestational diabetes mellitus (GDM). The patients were divided into three groups depending on the result of the tests: no evidence of glucose metabolism abnormality (controls); impaired glucose tolerance (IGT); and GDM. All three groups were evaluated for serum human advanced glycation end-products (AGEs) concentrations, carboxymethyl lysine (CML) concentration and receptor for advanced glycation end-product concentrations (RAGE/AGER), body mass index (BMI), age, fasting glucose levels, obstetrical parameters and gestational age. Results The study included 180 women divided into 59 (32.8%) GDM, 50 (27.8%) IGT and 71 (39.4%) controls. Age was similar among the three groups. Whereas fasting glucose levels and BMI in the three groups was significantly different, AGEs, CML, RAGE/AGER levels were found as significantly different between the groups (p<0.001). Conclusion In this study the use of AGEs, CML, and RAGE/AGER concentrations for the diagnosis and screening of gestational diabetes was investigated. It was found that advanced glycation products were significantly elevated in pregnancies with both IGT and GDM. These biochemical markers of glucose homeostasis dysregulation may have potential for GDM screening in the future.
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Affiliation(s)
- Özlem Şimşek Tanin
- Clinic of Obstetrics and Gynecology, Boğazlıyan State Hospital, Yozgat, Turkey
| | - Mustafa Kara
- Department of Obstetrics and Gynecology, Kırşehir Ahi Evran University Faculty of Medicine, Kırşehir, Turkey
| | - Yaprak Engin-Üstün
- Department of Obstetrics and Gynecology, University of Health Sciences Turkey, Ankara Etlik Zübeyde Hanım Women’s Health and Research Center, Ankara, Turkey
| | - Ayşe Yeşim Göçmen
- Department of Medical Biochemistry, Yozgat Bozok University Faculty of Medicine, Yozgat, Turkey
| | - Ethem Serdar Yalvaç
- Department of Obstetrics and Gynecology, Yozgat Bozok University Faculty of Medicine, Yozgat, Turkey
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Zhou Y, Chen X, Zheng Y, Shen R, Sun S, Yang F, Min J, Bao L, Zhang Y, Zhao X, Wang J, Wang Q. Long Non-coding RNAs and mRNAs Expression Profiles of Monocyte-Derived Dendritic Cells From PBMCs in AR. Front Cell Dev Biol 2021; 9:636477. [PMID: 33644074 PMCID: PMC7906227 DOI: 10.3389/fcell.2021.636477] [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: 12/01/2020] [Accepted: 01/19/2021] [Indexed: 11/18/2022] Open
Abstract
Objective The objective of this study is to explore the long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) expression profiles of monocyte-derived dendritic cells (DCs) obtained from peripheral blood mononuclear cells (PBMCs). DCs are known to play a major role in the regulating function of allergic rhinitis (AR). Methods PBMCs were separately isolated from the human peripheral blood of patients with AR and normal person (NP). The mixed lymphocyte reaction (MLR) assay was used to evaluate the function of DCs. Flow cytometry was used to determine the immune regulatory function of immature DCs (imDCs) and mature DCs (mDCs). lncRNAs and mRNAs in the NP group (DCs isolated from NP) and the test group (DCs isolated from patients with AR) were identified via chip technology and bioinformatic analyses. Moreover, bioinformatic analyses were employed to identify the related biological functions of monocyte-derived DCs and construct the functional networks of lncRNAs and mRNAs that are differentially expressed (DE) in imDCs and mDCs. Results MLR was significantly higher in the mDCs group than that in the imDCs group. CD14 was highly expressed in imDCs, whereas HLA-DR, CD80, and CD86 were highly expressed in mDCs (p < 0.001). We identified 962 DE lncRNAs and 308 DE mRNAs in the imDCs of NP and patients with AR. Additionally, there were 601 DE lncRNAs and 168 DE mRNAs in the mDCs in the NP and test groups. Quantitative RT-qPCR was used to study the significant fold changes of lncRNAs and mRNAs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found 16 significant regulated pathways in imDCs and 10 significant regulated pathways in mDCs, including the phagosome, cell adhesion signaling pathway, and inflammatory mediator regulation of TRP channels pathway. Conclusion Our research studied the lncRNA and mRNA expression profiles of monocyte-derived DCs and demonstrated the functional networks that are involved in monocyte-derived DCs-mediated regulation in AR. These results provided possible molecular mechanisms of monocyte-derived DCs in the immunoregulating function and laid the foundation for the molecular therapeutic targets of AR.
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Affiliation(s)
- Yumei Zhou
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xuemei Chen
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yanfei Zheng
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Rongmin Shen
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Shuxian Sun
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Fei Yang
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jiayu Min
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Lei Bao
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yan Zhang
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoshan Zhao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Ji Wang
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Qi Wang
- National Institute of TCM Constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Budge K, Dellepiane S, Yu SMW, Cravedi P. Complement, a Therapeutic Target in Diabetic Kidney Disease. Front Med (Lausanne) 2021; 7:599236. [PMID: 33553201 PMCID: PMC7858668 DOI: 10.3389/fmed.2020.599236] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/21/2020] [Indexed: 01/15/2023] Open
Abstract
Currently available treatments of diabetic kidney disease (DKD) remain limited despite improved understanding of DKD pathophysiology. The complement system is a central part of innate immunity, but its dysregulated activation is detrimental and results in systemic diseases with overt inflammation. Growing evidence suggests complement activation in DKD. With existent drugs and clinical success of treating other kidney diseases, complement inhibition has emerged as a potential novel therapy to halt the progression of DKD. This article will review DKD, the complement system's role in diabetic and non-diabetic disease, and the potential benefits of complement targeting therapies especially for DKD patients.
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Affiliation(s)
- Kelly Budge
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Sergio Dellepiane
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Samuel Mon-Wei Yu
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Paolo Cravedi
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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10
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Giurdanella G, Lupo G, Gennuso F, Conti F, Furno DL, Mannino G, Anfuso CD, Drago F, Salomone S, Bucolo C. Activation of the VEGF-A/ERK/PLA2 Axis Mediates Early Retinal Endothelial Cell Damage Induced by High Glucose: New Insight from an In Vitro Model of Diabetic Retinopathy. Int J Mol Sci 2020; 21:7528. [PMID: 33065984 PMCID: PMC7589177 DOI: 10.3390/ijms21207528] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/08/2020] [Accepted: 10/11/2020] [Indexed: 12/18/2022] Open
Abstract
Early blood retinal barrier (BRB) dysfunction induced by hyperglycemia was related to increased pro-inflammatory activity of phospholipase A2 (PLA2) and the upregulation of vascular endothelial growth factor A (VEGF-A). Here, we tested the role of VEGF-A in high glucose (HG)-induced damage of human retinal endothelial cells (HRECs) mediated by Ca++-dependent (cPLA2) and Ca++-independent (iPLA2) PLA2s. HRECs were treated with normal glucose (5 mM, NG) or high glucose (25 mM, HG) for 48 h with or without the VEGF-trap Aflibercept (Afl, 40 µg/mL), the cPLA2 inhibitor arachidonoyl trifluoromethyl ketone (AACOCF3; 15 µM), the iPLA2 inhibitor bromoenol lactone (BEL; 5 µM), or VEGF-A (80 ng/mL). Both Afl and AACOCF3 prevented HG-induced damage (MTT and LDH release), impairment of angiogenic potential (tube-formation), and expression of VEGF-A mRNA. Furthermore, Afl counteracted HG-induced increase of phospho-ERK and phospho-cPLA2 (immunoblot). VEGF-A in HG-medium increased glucose toxicity, through upregulation of phospho-ERK, phospho-cPLA2, and iPLA2 (about 55%, 45%, and 50%, respectively); immunocytochemistry confirmed the activation of these proteins. cPLA2 knockdown by siRNA entirely prevented cell damage induced by HG or by HG plus VEGF-A, while iPLA2 knockdown produced a milder protective effect. These data indicate that VEGF-A mediates the early glucose-induced damage in retinal endothelium through the involvement of ERK1/2/PLA2 axis activation.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Salvatore Salomone
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, via S.Sofia 97, 95123 Catania, Italy; (G.G.); (G.L.); (F.G.); (F.C.); (D.L.F.); (G.M.); (C.D.A.); (F.D.); (C.B.)
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Moscardó V, Herrero P, Reddy M, Hill NR, Georgiou P, Oliver N. Assessment of Glucose Control Metrics by Discriminant Ratio. Diabetes Technol Ther 2020; 22:719-726. [PMID: 32163723 PMCID: PMC7591377 DOI: 10.1089/dia.2019.0415] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Objective: Increasing use of continuous glucose monitoring (CGM) data has created an array of glucose metrics for glucose variability, temporal patterns, and times in ranges. However, a gold standard metric has not been defined. We assess the performance of multiple glucose metrics to determine their ability to detect intra- and interperson variability to determine a set of recommended metrics. Methods: The Juvenile Diabetes Research Foundation data set, a randomized controlled study of CGM and self-monitored blood glucose conducted in children and adults with type 1 diabetes (T1D), was used. To determine the ability of the evaluated glycemic metrics to discriminate between different subjects and attenuate the effect of within-subject variation, the discriminant ratio was calculated and compared for each metric. Then, the findings were confirmed using data from two other recent randomized clinical trials. Results: Mean absolute glucose (MAG) has the highest discriminant ratio value (2.98 [95% confidence interval {CI} 1.64-3.67]). In addition, low blood glucose index and index of glycemic control performed well (1.93 [95% CI 1.15-3.44] and 1.92 [95% CI 1.27-2.93], respectively). For percentage times in glucose target ranges, the optimal discriminator was percentage time in glucose target 70-180 mg/dL. Conclusions: MAG is the optimal index to differentiate glucose variability in people with T1D, and may be a complementary therapeutic monitoring tool in addition to glycated hemoglobin and a measure of hypoglycemia. Percentage time in glucose target 70-180 mg/dL is the optimal percentage time in range to report.
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Affiliation(s)
- Vanessa Moscardó
- Instituto Universitario de Automática e Informática Industrial, Universitat Politècnica de València, València, Spain
| | - Pau Herrero
- Department of Electrical and Electronic Engineering, Imperial College London, London, United Kingdom
| | - Monika Reddy
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom
| | - Nathan R. Hill
- Harris Manchester College, Mansfield Road, University of Oxford, United Kingdom
| | - Pantelis Georgiou
- Department of Electrical and Electronic Engineering, Imperial College London, London, United Kingdom
| | - Nick Oliver
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom
- Address correspondence to: Nick Oliver, FRCP, Division of Diabetes, Endocrinology and Metabolic Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom
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Takahashi N, Harada M, Azhary JMK, Kunitomi C, Nose E, Terao H, Koike H, Wada-Hiraike O, Hirata T, Hirota Y, Koga K, Fujii T, Osuga Y. Accumulation of advanced glycation end products in follicles is associated with poor oocyte developmental competence. Mol Hum Reprod 2020; 25:684-694. [PMID: 31504800 DOI: 10.1093/molehr/gaz050] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 07/14/2019] [Accepted: 08/12/2019] [Indexed: 12/13/2022] Open
Abstract
Advanced glycation end products (AGEs) affect the follicular microenvironment. The close relationship between AGEs, proinflammatory cytokine production and activation of the unfolded protein response (UPR), which involves activating transcription factor 4 (ATF4), is crucial for regulation of various cellular functions. We examined whether accumulation of AGEs in follicles was associated with proinflammatory cytokine production and activation of the UPR in granulosa cells and decreased oocyte developmental competence. Concentrations of AGEs, soluble receptor for AGE (sRAGE), interleukin (IL)-6 and IL-8 in follicular fluid (FF) were examined by ELISAs in 50 follicles. mRNA expression of ATF4, IL-6 and IL-8 in cumulus cells (CCs) were examined by quantitative RT-PCR in 77 samples. Cultured human granulosa-lutein cells (GLCs) were treated with AGE-bovine serum albumin (BSA) alone or following transfection of ATF4-targeting small interfering RNA. The AGE concentration and the AGE/sRAGE ratio in FF were significantly higher in follicles containing oocytes that developed into poor-morphology embryos (group I) than those with good-morphology embryos (group II). When compared with sibling follicles from the same patients, the AGE/sRAGE and concentrations of IL-6 and IL-8 in FF, as well as ATF4, IL-6 and IL-8 mRNA expression in CCs, were significantly higher in group I follicles than group II. AGE treatment increased mRNA expression of ATF4, IL-6 and IL-8 in cultured GLCs. Knockdown of ATF4 abrogated the stimulatory effects of AGE on mRNA expression and protein secretion of IL-6 and IL-8. Our findings support the idea that accumulation of AGEs in follicles reduces oocyte competence by triggering inflammation via activation of ATF4 in the follicular microenvironment.
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Affiliation(s)
- Nozomi Takahashi
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Miyuki Harada
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Jerilee M K Azhary
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Chisato Kunitomi
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Emi Nose
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Hiromi Terao
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Hiroshi Koike
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Osamu Wada-Hiraike
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Tetsuya Hirata
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Yasushi Hirota
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Kaori Koga
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Tomoyuki Fujii
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan
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Thyroxine restores severely impaired cutaneous re-epithelialisation and angiogenesis in a novel preclinical assay for studying human skin wound healing under "pathological" conditions ex vivo. Arch Dermatol Res 2020; 313:181-192. [PMID: 32572565 PMCID: PMC7935818 DOI: 10.1007/s00403-020-02092-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 02/14/2020] [Accepted: 03/28/2020] [Indexed: 01/18/2023]
Abstract
Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, defective innervation, and hyperglycaemia. Since organ-cultured human skin already represents a denervated and impaired perfusion state, we sought to further mimic “pathological” wound healing conditions by culturing experimentally wounded, healthy full-thickness frontotemporal skin from three healthy female subjects for three days in either serum-free supplemented Williams’ E medium or in unsupplemented medium under “pathological” conditions (i.e. hypoxia [5% O2], oxidative damage [10 mM H2O2], absence of insulin, excess glucose). Under these “pathological” conditions, dermal–epidermal split formation and dyskeratosis were prominent in organ-cultured human skin, and epidermal reepithelialisation was significantly impaired (p < 0.001), associated with reduced keratinocyte proliferation (p < 0.001), cytokeratin 6 expression (p < 0.001) and increased apoptosis (p < 0.001). Moreover, markers of intracutaneous angiogenesis (CD31 immunoreactivity and the number of of CD31 positive cells and CD31 positive vessel lumina) were significantly reduced. Since we had previously shown that thyroxine promotes wound healing in healthy human skin ex vivo, we tested whether this in principle also occurs under “pathological” wound healing conditions. Indeed, thyroxine administration sufficed to rescue re-epithelialisation (p < 0.001) and promoted both epidermal keratinocyte proliferation (p < 0.01) and angiogenesis in terms of CD31 immunoreactivity and CD31 positive cells under “pathological” conditions (p < 0.001) ex vivo. This demonstrates the utility of this pragmatic short-term ex vivo model, which recapitulates some key parameters of impaired human skin wound healing, for the preclinical identification of promising wound healing promoters.
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Soave I, Occhiali T, Assorgi C, Marci R, Caserta D. Environmental toxin exposure in polycystic ovary syndrome women and possible ovarian neoplastic repercussion. Curr Med Res Opin 2020; 36:693-703. [PMID: 32046531 DOI: 10.1080/03007995.2020.1729108] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Purpose: Over the last two decades, increasing attention has been paid to environmental toxins and their effects on the female reproductive system. Endocrine disrupting chemicals (EDCs) are exogenous substances or mixtures that can mimic the action of steroid hormones and interfere with their metabolism. Advanced glycation end products (AGEs) are proinflammatory molecules that can interact with cell surface receptors and mediate the triggering of proinflammatory pathways and oxidative stress. The purpose of this review is to explore the effects of environmental toxin exposure in the pathogenesis of both polycystic ovary syndrome (PCOS) and OC (ovarian cancer), considered separately, and also to evaluate possible neoplastic ovarian repercussion after exposure in patients diagnosed with PCOS.Materials and methods: We searched PubMed for articles published in the English language with the use of the following MeSH search terms: "polycystic ovary syndrome" and "ovarian cancer" combined with "endocrine disruptors". Titles and abstracts were examined and full articles that met the selection criteria were retrieved. A manual search of review articles and cross-references completed the search.Results: Extensive data from different studies collected in recent years concerning the effects of EDC/AGE exposure have confirmed their role in the pathophysiology of both PCOS and OC. They favor PCOS/OC development through different mechanisms that finally lead to hormonal and metabolic disruption and epigenetic modifications.Conclusions: Environmental toxin exposure in PCOS women could favor neoplastic transformation by exacerbating and potentiating some PCOS features. Further research, although difficult, is needed in order to prevent further diffusion of these substances in the environment, or at least to provide adequate information to the population considered at risk.
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Affiliation(s)
- Ilaria Soave
- Department of Surgical and Clinical Sciences and Translational Medicine, S. Andrea Hospital, "Sapienza" University of Rome, Rome, Italy
| | - Tommaso Occhiali
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy
| | - Chiara Assorgi
- Department of Surgical and Clinical Sciences and Translational Medicine, S. Andrea Hospital, "Sapienza" University of Rome, Rome, Italy
| | - Roberto Marci
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy
| | - Donatella Caserta
- Department of Surgical and Clinical Sciences and Translational Medicine, S. Andrea Hospital, "Sapienza" University of Rome, Rome, Italy
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Postoperative hyperglycemia predicts symptomatic intracranial hemorrhage after endovascular treatment in patients with acute anterior circulation large artery occlusion. J Neurol Sci 2020; 409:116588. [DOI: 10.1016/j.jns.2019.116588] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 01/04/2023]
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16
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Gui F, You Z, Fu S, Wu H, Zhang Y. Endothelial Dysfunction in Diabetic Retinopathy. Front Endocrinol (Lausanne) 2020; 11:591. [PMID: 33013692 PMCID: PMC7499433 DOI: 10.3389/fendo.2020.00591] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 07/20/2020] [Indexed: 12/21/2022] Open
Abstract
Diabetic retinopathy (DR) is a diabetic complication which affects retinal function and results in severe loss of vision and relevant retinal diseases. Retinal vascular dysfunction caused by multifactors, such as advanced glycosylation end products and receptors, pro-inflammatory cytokines and chemokines, proliferator-activated receptor-γ disruption, growth factors, oxidative stress, and microRNA. These factors promote retinal endothelial dysfunction, which results in the development of DR. In this review, we summarize the contributors in the pathophysiology of DR for a better understanding of the molecular and cellular mechanism in the development of DR with a special emphasis on retinal endothelial dysfunction.
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Stockert K. Allergie, Mikrobiom und weitere epigenetische Faktoren. ALLERGIEPRÄVENTION 2020. [PMCID: PMC7123400 DOI: 10.1007/978-3-662-58140-7_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Fei J, Ling YM, Zeng MJ, Zhang KW. Shixiang Plaster, a Traditional Chinese Medicine, Promotes Healing in a Rat Model of Diabetic Ulcer Through the receptor for Advanced Glycation End Products (RAGE)/Nuclear Factor kappa B (NF-κB) and Vascular Endothelial Growth Factor (VEGF)/Vascular Cell Adhesion Molecule-1 (VCAM-1)/Endothelial Nitric Oxide Synthase (eNOS) Signaling Pathways. Med Sci Monit 2019; 25:9446-9457. [PMID: 31825949 PMCID: PMC6925528 DOI: 10.12659/msm.918268] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Shixiang plaster is a traditional Chinese medicine has been used to treat chronic ulcers, including diabetic ulcers. Aminoguanidine is a hydrazine derivative that inhibits the formation of advanced glycosylation end products (AGEs). This study aimed to investigate the effects of shixiang plaster and aminoguanidine on wound healing in the streptozotocin-induced rat model of diabetes and the molecular mechanisms involved. Material/Methods Sprague-Dawley rats treated with intraperitoneal streptozotocin and given surgical wounds were divided into the untreated chronic ulcer group (n=10), the aminoguanidine group (n=10), the shixiang plaster group (n=10), and the control group with sham surgery (n=10). Granulation tissue samples underwent light microscopy to evaluate angiogenesis and immunohistochemistry to identify AGE, vascular endothelial growth factor (VEGF), and CD34 expression. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot measured mRNA and protein expression of receptor for advanced glycation end products (RAGE), vascular cell adhesion molecule-1 (VCAM-1), nuclear factor kappa B (NF-κB) and endothelial nitric oxide synthase (eNOS). Results The shixiang plaster group showed a significant increase in angiogenesis in ulcer granulation tissue, significantly reduced expression of AGEs and increased expression of VEGF and CD34 expression in granulation tissue compared with the untreated chronic ulcer group (p<0.05). The shixiang plaster group showed significantly down-regulated expression of RAGE and VCAM-1 compared with the untreated chronic ulcer group (p<0.05). Shixiang plaster promoted angiogenesis by activating the NF-κB p65 associated pathway and eNOS activation. Conclusions Shixiang plaster promoted healing in a rat model of diabetic ulcer through the RAGE/NF-κB and VEGF/VCAM-1/eNOS signaling pathways.
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Affiliation(s)
- Ji Fei
- Department of Orthopedics, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China (mainland)
| | - Yi-Ming Ling
- Department of Orthopedics, Shaoxing Hospital of Traditional Chinese Medicine, Shaoxing, Zhejiang, China (mainland)
| | - Man-Jie Zeng
- Department of Orthopedics, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China (mainland)
| | - Kai-Wei Zhang
- Department of Orthopedics, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China (mainland)
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Abstract
Redox proteomics is a field of proteomics that is concerned with the characterization of the oxidation state of proteins to gain information about their modulated structure, function, activity, and involvement in different physiological pathways. Oxidative modifications of proteins have been shown to be implicated in normal physiological processes of cells as well as in pathomechanisms leading to the development of cancer, diabetes, neurodegenerative diseases, and some rare hereditary metabolic diseases, like classic galactosemia. Reactive oxygen species generate a variety of reversible and irreversible modifications in amino acid residue side chains and within the protein backbone. These oxidative post-translational modifications (Ox-PTMs) can participate in the activation of signal transduction pathways and mediate the toxicity of harmful oxidants. Thus the application of advanced redox proteomics technologies is important for gaining insights into molecular mechanisms of diseases. Mass-spectrometry-based proteomics is one of the most powerful methods that can be used to give detailed qualitative and quantitative information on protein modifications and allows us to characterize redox proteomes associated with diseases. This Review illustrates the role and biological consequences of Ox-PTMs under basal and oxidative stress conditions by focusing on protein carbonylation and S-glutathionylation, two abundant modifications with an impact on cellular pathways that have been intensively studied during the past decade.
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Affiliation(s)
- Atef Mannaa
- Borg AlArab Higher Institute of Engineering and Technology , New Borg AlArab City , Alexandria , Egypt
| | - Franz-Georg Hanisch
- Institute of Biochemistry II, Medical Faculty , University of Cologne , Joseph-Stelzmann-Str. 52 , 50931 Cologne , Germany
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Duwayri Y, Jordan WD. Diabetes, dysglycemia, and vascular surgery. J Vasc Surg 2019; 71:701-711. [PMID: 31327619 DOI: 10.1016/j.jvs.2019.05.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 05/10/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Abnormalities in glucose metabolism are common in patients with arterial disease. Chronic hyperglycemia and insulin resistance contribute to the complexity of vascular disorders. They also overlap with the effects of perioperative hyperglycemia on adverse perioperative outcomes. We provide an overview of the pathophysiologic consequences of dysglycemia and the evidence behind glycemic control in patients undergoing vascular surgery. METHODS We searched the literature for major studies evaluating the pathophysiology of hyperglycemia in microvascular and macrovascular beds, randomized trials in perioperative populations, and meta-analyses. The literature was summarized to guide therapy in the population of vascular patients and for the perioperative period. RESULTS National standards for glycemic control after vascular interventions were not identified. Mounting evidence exists for the long-term consequences of poor glycemic control on the progression of vascular disease. Similarly, there is a large body of evidence supporting tight control of hyperglycemia after general and cardiac surgery during the critical perioperative period. The absolute glucose target remains controversial. Randomized controlled studies are lacking in vascular surgery patients, but the current evidence can be extrapolated to guide management after vascular interventions. Glycated hemoglobin is a biomarker for increased mortality and vascular morbidity after vascular surgery. CONCLUSIONS Hyperglycemia contributes to poor outcome in the vascular patient. Further vascular focused studies are required to determine the proper perioperative serum glucose target and the long-term glycated hemoglobin range.
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Affiliation(s)
- Yazan Duwayri
- Division of Vascular Surgery and Endovascular Therapies, Emory University School of Medicine, Atlanta, Ga
| | - William D Jordan
- Division of Vascular Surgery and Endovascular Therapies, Emory University School of Medicine, Atlanta, Ga.
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Feng Z, Hou X, Zhu C, Zhu J, Jiang C. Retracted: Epigallocatechin gallate ameliorates morphological changes of pancreatic islets in diabetic mice and downregulates blood sugar level by inhibiting the accumulation of AGE-RAGE. J Cell Biochem 2019; 120:8510-8520. [PMID: 30582209 DOI: 10.1002/jcb.28139] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 11/05/2018] [Indexed: 02/02/2023]
Abstract
This study aimed to elucidate the key mechanisms and effects of the functional component of green tea, epigallocatechin gallate (EGCG) on a diabetic mouse model. The detected relationship between compounds and genes recorded in the STITCH database highlighted an interaction network between the direct target genes of EGCG and the known diabetes-related genes, which was made apparent through the analysis of gene-gene interactions and signaling pathways, revealing that a key AGE-RAGE signaling pathway in diabetes was enriched in the network. By means of systematic supplementary analyses on diabetic mice, provided evidence suggested that EGCG could significantly enhance the morphology of pancreatic tissues in diabetic mice and downregulate the blood glucose level in a clear dose effect manner, and increased insulin receptor (IR), insulin receptor substrate (IRS1 and IRS2) expression in the liver. Through the detection of protein expression, EGCG was observed to possess the ability to downregulate the accumulation of AGE-RAGE in pancreatic tissues as well as in the transcription factor nuclear factor-κB (NF-κB), which represents a potentially significant method by which EGCG influences diabetes. The results of this study provided evidence indicating that EGCG can effectively improve the morphology of pancreatic tissues, but notably reduce blood glucose levels in diabetic mice, which may be related to its inhibition of AGE-RAGE signaling pathway and activation of transcription factor NF-κB pathway.
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Affiliation(s)
- Zhongtao Feng
- Department of Clinical Laboratory, Jining No.1 People's Hospital, Affiliated Jining NO. 1 People's Hospital of Jining Medical University, Jining Medical University, Shandong Province, China
| | - Xiumei Hou
- Nursing Department, Jining Psychiatric Hospital, Jining, China
| | - Chuanan Zhu
- Department of Clinical Laboratory, Jining No. 1 People's Hospital, Jining, China
| | - Jiabin Zhu
- Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Chunxiao Jiang
- Department of Clinical Laboratory, Jining No. 1 People's Hospital, Jining, China
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22
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Omidian M, Djalali M, Javanbakht MH, Eshraghian MR, Abshirini M, Omidian P, Alvandi E, Mahmoudi M. Effects of vitamin D supplementation on advanced glycation end products signaling pathway in T2DM patients: a randomized, placebo-controlled, double blind clinical trial. Diabetol Metab Syndr 2019; 11:86. [PMID: 31673295 PMCID: PMC6814978 DOI: 10.1186/s13098-019-0479-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 10/09/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Several researches have recommended vitamin D possible health benefits on diabetic complications development, but a few number of studies have been accomplished on the molecular and cellular mechanisms. Certain cellular pathways modification and also some transcription factors activation may protect cells from hyperglycemia condition induced damages. This study purpose was to determine the vitamin D supplementation effect on some key factors [advanced glycation end products (AGEs) signaling pathway] that were involved in the diabetic complications occurrence and progression for type-2 diabetes participants. METHODOLOGY 48 type-2 diabetic patients (T2DM) randomly divided into two groups (n = 24 per group), receiving: 100-µg vitamin D or placebo for 3 months. At this study beginning and the end, the receptor expression for advanced glycation end products (RAGE) and glyoxalase I (GLO1) enzyme from peripheral blood mononuclear cells (PBMCs) and AGEs and tumor necrosis factor-α (TNF-α) serum levels were measured by the use of real-time PCR and ELISA methods, respectively. RESULTS This study results demonstrated that vitamin D supplementation could down-regulate RAGE mRNA [fold change = 0.72 in vitamin D vs. 0.95 in placebo) P = 0.001)]. In addition, no significant changes were observed for GLO1 enzyme expression (P = 0.06). This study results also indicated that vitamin D serum level significantly increased in vitamin D group (P < 0.001). Moreover, AGES and TNF-α serum levels significantly reduced in vitamin D group, but they were remained unchanged in the placebo group. CONCLUSION In conclusion, vascular complications are more frequent in diabetic patients, and vitamin D treatment may prevent or delay the complications onset in these patients by AGEs serum level and RAGE gene expression reducing.Trial registration NCT03008057. Registered December 2016.
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Affiliation(s)
- Mahsa Omidian
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Poorsina Street, Enghelab Avenue, PO Box: 14155-6446, Tehran, Iran
| | - Mahmoud Djalali
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Poorsina Street, Enghelab Avenue, PO Box: 14155-6446, Tehran, Iran
| | - Mohammad Hassan Javanbakht
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Poorsina Street, Enghelab Avenue, PO Box: 14155-6446, Tehran, Iran
| | - Mohammad Reza Eshraghian
- Department of Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Abshirini
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Omidian
- Rasoul Akram Complex Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Ehsan Alvandi
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Poorsina Street, Enghelab Avenue, PO Box: 14155-6446, Tehran, Iran
| | - Maryam Mahmoudi
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Poorsina Street, Enghelab Avenue, PO Box: 14155-6446, Tehran, Iran
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Zhao P, Wu H, Zhong Z, Zhang Q, Zhong W, Li B, Li C, Liu Z, Yang M. Expression profiles of long noncoding RNAs and mRNAs in peripheral blood mononuclear cells of patients with acute myocardial infarction. Medicine (Baltimore) 2018; 97:e12604. [PMID: 30313048 PMCID: PMC6203524 DOI: 10.1097/md.0000000000012604] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Acute myocardial infarction (AMI) is the most serious type of coronary atherosclerotic diseases. The incidence of AMI in some countries increases year by year, and shows younger trend. Some study indicated that abnormal expression of lncRNAs was closely related to cardiovascular disease. The aim of this study was to examine the lncRNA expression profiles in peripheral blood mononuclear cells (PBMCs) of patients with AMI through controlled studies.In the present study, we examined the lncRNA and mRNA expression profiles in 8 patients with AMI, with 7 NCA (noncoronary artery) subjects as controls using RNA sequencing protocol (RNA-seq) on the Illumina HiSeq 4000 platform. The differentially expressed lncRNAs were selected for bioinformatic analysis including gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG). Quantitative real time PCR (qRT-PCR) was used to confirm the differential expression of lncRNAs.We kept about 11.29 gigabase (Gb) high-quality sequence data while the Q30 ranged from 94.39% to 95.19% for each sample. Compared to the lncRNA expression profiles of NCA controls, a total of 106 differentially expressed lncRNAs were discriminated in AMI patients, including 40 upregulated lncRNAs and 66 downregulated lncRNAs (P < .05). Among the genes corresponding to the identified mRNAs, 2905 genes are involved in biological processes, 339 in cellular components, and 501 in molecular functions. Based on the KEGG pathway analysis, the most enriched pathways corresponding to the differentially expressed lncRNAs were associated with systemic lupus erythematosus, alcoholism, oxidative phosphorylation, Parkinson's disease and viral carcinogenesis, and so on. Further, 3 upregulated and 3 downregulated lncRNAs were randomly selected for qRT-PCR verification and the results of qRT-PCR were consistent with the findings obtained from RNA sequencing analysis.As a result, differential expression profiles of lncRNAs in AMI were identified in our study. The results suggested that lncRNAs may play important roles in the biological and pathological processes of AMI. These findings may provide useful reference for the early diagnosis and risk stratification of AMI patients. To enlarge the sample size in the next step will be needed for further research to confirm our results.
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Affiliation(s)
- Pingsen Zhao
- Clinical Core Laboratory
- Center for Precision Medicine
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Major Genetic Disorders, Meizhou, PR China
| | - Heming Wu
- Clinical Core Laboratory
- Center for Precision Medicine
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Major Genetic Disorders, Meizhou, PR China
| | - Zhixiong Zhong
- Center for Cardiovascular Diseases, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
| | - Qifeng Zhang
- Center for Cardiovascular Diseases, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
| | - Wei Zhong
- Center for Cardiovascular Diseases, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
| | - Bin Li
- Center for Cardiovascular Diseases, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
| | - Cunren Li
- Center for Cardiovascular Diseases, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
| | - Zhidong Liu
- Center for Cardiovascular Diseases, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
| | - Min Yang
- Center for Cardiovascular Diseases, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases
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Hyperglycemia induces inflammatory mediators in the human chorionic villous. Cytokine 2018; 111:41-48. [PMID: 30114628 DOI: 10.1016/j.cyto.2018.07.020] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 05/21/2018] [Accepted: 07/16/2018] [Indexed: 12/19/2022]
Abstract
This study was based on the hypothesis that IL-1β and its central regulator, the inflammasome, may play a role in the inflammatory condition exhibited by placental tissues from mothers with different gestational hyperglycemia levels. Pregnant women were classified according to the glycemic reference as non-diabetic (n = 15), mild gestational hyperglycemia (n = 15), gestational diabetes mellitus (n = 15) and type 2 diabetes mellitus (n = 15). We investigated levels of pro-inflammatory factors in maternal plasma and placental tissues (by ELISA or immunohistochemistry) and, NFKB activity (by electrophoretic mobility shift assay) and inflammasome protein expression (by Western blot) in chorionic villous. Maternal plasma and placental levels of inflammatory factors (IL-1β, IL-6, and MCP-1) were increased during all hyperglycemic conditions. Villous stroma cells showed strong immunoreactivity to CD68. In addition, with syncytiotrophoblast, the villous stroma cells were also stained to detect iNOS, MCP-1, TLR2, and TLR4. Although the levels of protein had fluctuated in the groups, NLRP1, NLRP3, ASC, and Caspase 1 were up-regulated in all hyperglycemic groups suggesting the inflammasome may be assembled in these pregnant women. The NFKB activity also exhibited higher levels in hyperglycemic groups, which might imply in pro-inflammatory cytokines production. In summary, increased maternal glucose levels during pregnancy changed systemic and placental inflammatory patterns, which occurred in parallel with the expression of inflammasome factors and processing and secretion of the pro-inflammatory cytokine IL-1β. These results suggest an inflammatory condition in all gestational hyperglycemic conditions, even in hyperglycemia that is less severe than gestational or overt diabetes, likely associated with inflammasome activation and inflammatory cytokine secretion. Inflammasome activation as a possible source of inflammatory factors may be an important target to be considered while managing hyperglycemia and preventing adverse pregnancy outcomes.
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25
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Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J, Manna P. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol 2018; 833:472-523. [DOI: 10.1016/j.ejphar.2018.06.034] [Citation(s) in RCA: 175] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 06/15/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
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Owens DR, Monnier L, Hanefeld M. A review of glucagon-like peptide-1 receptor agonists and their effects on lowering postprandial plasma glucose and cardiovascular outcomes in the treatment of type 2 diabetes mellitus. Diabetes Obes Metab 2017; 19:1645-1654. [PMID: 28474401 PMCID: PMC5697665 DOI: 10.1111/dom.12998] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 04/28/2017] [Accepted: 04/28/2017] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular (CV) comorbidities, with CV disease being the most common cause of death in adults with T2DM. Although glucocentric therapies may improve glycaemic control (as determined by glycated haemoglobin levels), evidence suggests that this approach alone has limited beneficial effects on CV outcomes relative to improvements in lipid and blood pressure control. This may be explained in part by the fact that current antidiabetic treatment regimens primarily address overall glycaemia and/or fasting plasma glucose, but not the postprandial plasma glucose (PPG) excursions that have a fundamental causative role in increasing CV risk. This literature review evaluates the relationship between PPG and the risk of CV disease, discusses the treatment of T2DM with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and examines the associated CV outcomes. The literature analysis suggests that exaggerated PPG excursions are a risk factor for CV disease because of their adverse pathophysiologic effects on the vasculature, resulting in increased all-cause and CV-related mortality. Although GLP-1 RAs are well established in the current T2DM treatment paradigm, a subgroup of these compounds has a particularly pronounced, persistent and short-lived effect on gastric emptying and, hence, lower PPG substantially. However, current long-term data on CV outcomes with GLP-1 RAs are contradictory, with both beneficial and adverse effects having been reported. This review explores the opportunity to direct treatment towards controlling PPG excursions, thereby improving not only overall glycaemic control but also CV outcomes.
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Affiliation(s)
- David R. Owens
- Diabetes Research Group, Institute of Life Sciences College of MedicineSwansea UniversitySwanseaUK
| | - Louis Monnier
- Laboratory of Human Nutrition and Atherosclerosis, Institute of Clinical ResearchUniversity of MontpellierMontpellierFrance
| | - Markolf Hanefeld
- Study Centre “Professor Hanefeld”GWT‐Technical University DresdenDresdenGermany
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27
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Collaborative Power of Nrf2 and PPAR γ Activators against Metabolic and Drug-Induced Oxidative Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:1378175. [PMID: 28928902 PMCID: PMC5591982 DOI: 10.1155/2017/1378175] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 07/25/2017] [Indexed: 12/30/2022]
Abstract
Mammalian cells have evolved a unique strategy to protect themselves against oxidative damage induced by reactive oxygen species (ROS). Especially, two transcription factors, nuclear factor erythroid 2p45-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor γ (PPARγ), have been shown to play key roles in establishing this cellular antioxidative defense system. Recently, several researchers reported ameliorating effects of pharmacological activators for these Nrf2 and PPARγ pathways on the progression of various metabolic disorders and drug-induced organ injuries by oxidative stress. In this review, general features of Nrf2 and PPARγ pathways in the context of oxidative protection will be summarized first. Then, a number of successful applications of natural and synthetic Nrf2 and PPARγ activators to the alleviation of pathological and drug-related oxidative damage will be discussed later.
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28
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Testa R, Bonfigli AR, Prattichizzo F, La Sala L, De Nigris V, Ceriello A. The "Metabolic Memory" Theory and the Early Treatment of Hyperglycemia in Prevention of Diabetic Complications. Nutrients 2017; 9:nu9050437. [PMID: 28452927 PMCID: PMC5452167 DOI: 10.3390/nu9050437] [Citation(s) in RCA: 161] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 04/20/2017] [Accepted: 04/24/2017] [Indexed: 12/12/2022] Open
Abstract
Several epidemiological and prospective studies suggest that an early intensive control of hyperglycaemia is able to decrease the risk of diabetic micro- and macro-vascular complications. A growing body of experimental evidence supports the concept that the risk for diabetes complications may be linked to oxidative stress, non-enzymatic glycation of proteins, epigenetic changes, and chronic inflammation, laying the foundation for the “metabolic memory” theory. From a clinical point of view, this theory supports the need for a very early aggressive treatment, with the goal of normalizing metabolic control as soon as possible. It may also prove beneficial to introduce therapeutic agents that are able to reduce reactive species and glycation, in addition to presenting better control of glucose levels in patients with diabetes, in order to minimize long-term diabetes complications. In this review, we evaluate the effect of glucose intake and metabolism in the light of this theory.
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Affiliation(s)
- Roberto Testa
- Experimental Models in Clinical Pathology, INRCA-IRCCS National Institute, Ancona I-60127, Italy.
| | - Anna Rita Bonfigli
- Scientific Direction, INRCA-IRCCS National Institute, Ancona I-60127, Italy.
| | - Francesco Prattichizzo
- Department of Cardiovascular and Metabolic Diseases, IRCCS Multimedica, Sesto San Giovanni I-20099, Italy.
| | - Lucia La Sala
- Department of Cardiovascular and Metabolic Diseases, IRCCS Multimedica, Sesto San Giovanni I-20099, Italy.
| | - Valeria De Nigris
- Insititut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/Rosselló, 149-153, Barcelona 08036, Spain.
| | - Antonio Ceriello
- Department of Cardiovascular and Metabolic Diseases, IRCCS Multimedica, Sesto San Giovanni I-20099, Italy.
- Insititut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/Rosselló, 149-153, Barcelona 08036, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
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29
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Chao KC, Chen SH, Chang CC, Lee YC, Wang CM, Chang JS. Effects of ferric citrate supplementation on advanced glycation end products in a rat model of streptozotocin/nicotinamide-induced diabetes. Mol Nutr Food Res 2017; 61. [PMID: 27862990 DOI: 10.1002/mnfr.201600753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/20/2016] [Accepted: 11/03/2016] [Indexed: 12/30/2022]
Abstract
SCOPE Diabetes is associated with the increased risks of anemia and activation of advanced glycation end products (AGEs) and the receptor for AGEs (RAGE). However, the effects of pharmacological doses of iron supplementation on AGE metabolism are less clear. The aim was to investigate the effect of ferric citrate supplementation on AGE metabolism. METHODS AND RESULTS Diabetes was induced in overnight starved rats by intraperitoneal injections of 40 mg/kg streptozotocin and 120 mg/kg nicotinamide. Diabetic rats were fed a standard diet or pharmacological doses of ferric citrate (0.5, 1, 2, and 3 g of ferric iron/kg diet) for 10 weeks. Ferric citrate supplementation showed a dose-related effect on the hepatic steatosis score, malondialdehyde, cathepsin D, and glyoxalase I. A Western blot analysis revealed that >1 g of ferric iron suppressed hepatic AGE receptor 1 and high-mobility group-box 1 expressions but increased heme oxygenase-1 and RAGE expressions. Further analysis showed that high doses of ferric iron triggered sterol regulatory element-binding protein 1c, p38-mitogen-activated protein kinase, and nuclear factor-κB protein expressions. CONCLUSION Overall, the present results suggest a dose-related effect of ferric citrate supplementation on AGE metabolism, and this effect was more evident at high iron doses (>1 g of ferric iron/kg diet).
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Affiliation(s)
- Kuo-Ching Chao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Seu-Hwa Chen
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chun-Chao Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yu-Chieh Lee
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chi-Mei Wang
- Department of Nutrition, MacKay Memorial Hospital, Hsinchu Branch, Hsinchu, Taiwan
| | - Jung-Su Chang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan.,Nutrition Research Centre, Taipei Medical University Hospital, Taipei, Taiwan
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30
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Toxicological potential of acyl glucuronides and its assessment. Drug Metab Pharmacokinet 2017; 32:2-11. [DOI: 10.1016/j.dmpk.2016.11.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 11/08/2016] [Accepted: 11/09/2016] [Indexed: 12/22/2022]
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31
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Son WR, Nam MH, Hong CO, Kim Y, Lee KW. Plantamajoside from Plantago asiatica modulates human umbilical vein endothelial cell dysfunction by glyceraldehyde-induced AGEs via MAPK/NF-κB. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:66. [PMID: 28109289 PMCID: PMC5251346 DOI: 10.1186/s12906-017-1570-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 01/07/2017] [Indexed: 01/25/2023]
Abstract
Background Plantago asiatica has been traditionally used for traditional medicine around East Asia. Plantamajoside (PM), which is isolated from this plant, is known for biological properties including anti-inflammation and antioxidant activity. To demonstrate the biological activity of PM against endothelial dysfunction induced by advanced glycation end-products (AGEs), a cellular inflammatory mechanism system was evaluated in human umbilical vein endothelial cells (HUVECs). Methods We obtained PM through previous research in our laboratory. We formed the AGEs from bovine serum albumin with glyceraldehyde in the dark for seven days. To confirm the modulation of the inflammatory mechanism in endothelial dysfunction, we quantified the various pro-inflammatory cytokines and endothelial dysfunction-related proteins in the HUVECs with Western blotting and with real-time and quantitative real-time polymerase chain reactions. Results Co-treatment with PM and AGEs significantly suppressed inflammatory cytokines and adhesion molecule expression. Moreover, the PM treatment for down-regulated inflammatory signals and blocked monocyte adhesion on the HUVECs. Conclusions Theses results demonstrated that PM, as a potential natural compound, protects AGE-induced endothelial cells against inflammatory cellular dysfunction. Electronic supplementary material The online version of this article (doi:10.1186/s12906-017-1570-1) contains supplementary material, which is available to authorized users.
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Dáňová K, Grohová A, Strnadová P, Funda DP, Šumník Z, Lebl J, Cinek O, Průhová Š, Koloušková S, Obermannová B, Petruželková L, Šedivá A, Fundová P, Buschard K, Špíšek R, Palová-Jelínková L. Tolerogenic Dendritic Cells from Poorly Compensated Type 1 Diabetes Patients Have Decreased Ability To Induce Stable Antigen-Specific T Cell Hyporesponsiveness and Generation of Suppressive Regulatory T Cells. THE JOURNAL OF IMMUNOLOGY 2016; 198:729-740. [PMID: 27927966 DOI: 10.4049/jimmunol.1600676] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 09/29/2016] [Indexed: 12/15/2022]
Abstract
Tolerogenic dendritic cells (tolDCs) may offer an interesting intervention strategy to re-establish Ag-specific tolerance in autoimmune diseases, including type 1 diabetes (T1D). T1D results from selective destruction of insulin-producing β cells leading to hyperglycemia that, in turn, specifically affects a patient's immune system. In this study, we prepared monocyte-derived tolDCs modulated by dexamethasone and vitamin D2 from 31 T1D patients with optimal glycemic control and 60 T1D patients with suboptimal glycemic control and assessed their tolerogenic properties in correlation with metabolic state of patients. tolDCs differentiated from both groups of patients acquired a regulatory phenotype and an anti-inflammatory profile. Interestingly, tolDCs from well-controlled patients expressed higher levels of inhibitory molecules IL-T3 and PD-L1. Additionally, glutamic acid decarboxylase (GAD)65-loaded tolDCs from well-controlled patients decreased significantly primary Th1/Th17 responses, induced stable GAD65-specific T cell hyporesponsiveness, and suppressed markedly control DC-induced GAD65-specific T cell activation compared with poorly controlled patients. The ability of tolDCs from poorly controlled patients to induce durable GAD65-specific T cell hyporesponsiveness was reversed once the control of glycemia improved. In both groups of patients, tolDCs were able to induce regulatory T cells from autologous naive CD4+ T cells. However, regulatory T cells from well-controlled patients had better suppressive abilities. The functionality of tolDCs was confirmed in the adoptive transfer model of NOD-SCID mice where tolDCs delayed diabetes onset. These results suggest that metabolic control of T1D affects the functional characteristics of tolDCs and subsequent effector T cell responses. Metabolic control may be relevant for refining inclusion criteria of clinical trials in the settings of T1D.
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Affiliation(s)
- Klára Dáňová
- Sotio a.s., 170 00 Prague, Czech Republic.,Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic
| | - Anna Grohová
- Sotio a.s., 170 00 Prague, Czech Republic.,Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic
| | | | - David P Funda
- Department of Immunology and Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague, Czech Republic
| | - Zdeněk Šumník
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and
| | - Jan Lebl
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and
| | - Ondřej Cinek
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and
| | - Štěpánka Průhová
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and
| | - Stanislava Koloušková
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and
| | - Barbora Obermannová
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and
| | - Lenka Petruželková
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and
| | - Anna Šedivá
- Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic
| | - Petra Fundová
- Department of Immunology and Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague, Czech Republic
| | - Karsten Buschard
- The Bartholin Institute, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Radek Špíšek
- Sotio a.s., 170 00 Prague, Czech Republic.,Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic
| | - Lenka Palová-Jelínková
- Sotio a.s., 170 00 Prague, Czech Republic; .,Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic
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Parvaresh Rizi E, Baig S, Shabeer M, Teo Y, Mok SF, Loh TP, Magkos F, Virtue S, Vidal-Puig A, Tai ES, Khoo CM, Toh SA. Meal rich in carbohydrate, but not protein or fat, reveals adverse immunometabolic responses associated with obesity. Nutr J 2016; 15:100. [PMID: 27903298 PMCID: PMC5131405 DOI: 10.1186/s12937-016-0219-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 11/24/2016] [Indexed: 12/18/2022] Open
Abstract
Background Obesity-related insulin resistance is linked to inflammation. Immunometabolic function differs between lean and obese subjects, but whether macronutrient composition of ingested meals affects these responses is not well known. We examined the effects of a single meal rich in fat, protein, or carbohydrate on immunometabolic responses. Methods Nine lean insulin sensitive (LIS) men and 9 obese insulin resistant (OIR) men ingested high-carbohydrate (HC), high-fat (HF) or high-protein (HP) mixed meals in random order. We assessed plasma glucose, insulin, and cytokine responses and cytokine gene expression in circulating mononuclear cells (MNC) at fasting and postprandial states (up to 6-h). Results Expression of NF-κB and TNFα genes were greater; whereas that of TGFβ and IL-6 genes were lower, in the OIR compared to the LIS individuals. The differences were significantly greater after the HC meal, but not after the HP or HF meal. Similar results were obtained for plasma concentrations of TNFα and IL-6. Conclusions Our findings indicate that a single HC meal has a distinct adverse effect on immunometabolic responses in the OIR individuals. The cumulative effect of such adverse responses to meals rich in carbohydrate may predispose the OIR individuals to a higher risk of cardiovascular disease. Electronic supplementary material The online version of this article (doi:10.1186/s12937-016-0219-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ehsan Parvaresh Rizi
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, 117599, Singapore, Singapore.,Department of Medicine, National University Health System, Singapore, Singapore
| | - Sonia Baig
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, 117599, Singapore, Singapore
| | - Muhammad Shabeer
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, 117599, Singapore, Singapore
| | - Yvonne Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, 117599, Singapore, Singapore
| | - Shao Feng Mok
- Department of Medicine, National University Health System, Singapore, Singapore
| | - Tze Ping Loh
- Department of Laboratory Medicine, National University Health System, Singapore, Singapore
| | - Faidon Magkos
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Singapore Institute of Clinical Sciences (SICS), A*STAR, Singapore, Singapore
| | - Sam Virtue
- University of Cambridge Metabolic Research Laboratories, Cambridge, UK
| | | | - E Shyong Tai
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, 117599, Singapore, Singapore.,Department of Medicine, National University Health System, Singapore, Singapore.,DUKE-National University of Singapore Medical School, Singapore, Singapore
| | - Chin Meng Khoo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, 117599, Singapore, Singapore.,Department of Medicine, National University Health System, Singapore, Singapore.,DUKE-National University of Singapore Medical School, Singapore, Singapore
| | - Sue-Anne Toh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, 117599, Singapore, Singapore. .,Department of Medicine, National University Health System, Singapore, Singapore. .,DUKE-National University of Singapore Medical School, Singapore, Singapore. .,Perelman School of Medicine, University of Pennsylvania, Pennsylvania, USA.
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Rutkowska AZ, Diamanti-Kandarakis E. Polycystic ovary syndrome and environmental toxins. Fertil Steril 2016; 106:948-58. [PMID: 27559705 DOI: 10.1016/j.fertnstert.2016.08.031] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 08/15/2016] [Accepted: 08/15/2016] [Indexed: 11/19/2022]
Abstract
Polycystic ovary syndrome (PCOS) is the most common, heterogeneous, and multifactorial endocrine disorder in premenopausal women. The pathophysiology of this endocrinopathy is still unclear; however, the heterogeneity of its features within ethnic races, geographic location, and families suggests that environment and lifestyle are of prime importance. This work is mainly focused on the possible role of the most common and studied environmental toxins for this syndrome in the pathogenesis of PCOS. Plasticizers, such as bisphenol A (BPA) or phthalates, which belong to the categories of endocrine disrupting chemicals (EDCs) and advanced glycation end products (AGEs), affect humans' health in everyday, industrialized life; therefore special attention should be paid to such exposure. Timing of exposure to EDCs is crucial for the intensity of adverse health effects. It is now evident that fetuses, infants, and/or young children are the most susceptible groups, especially in the early development periods. Prenatal exposure to EDCs that mimic endogenous hormones may contribute to the altered fetal programming and in consequence lead to PCOS and other adverse health effects, potentially transgenerationally. Acute or prolonged exposure to EDCs and AGEs through different life cycle stages may result in destabilization of the hormonal homeostasis and lead to disruption of reproductive functions. They may also interfere with metabolic alterations such as obesity, insulin resistance, and compensatory hyperinsulinemia that can exacerbate the PCOS phenotype and contribute to PCOS consequences such as type 2 diabetes and cardiovascular disease. Since wide exposure to environmental toxins and their role in the pathophysiology of PCOS are supported by extensive data derived from diverse scientific models, protective strategies and strong recommendations should be considered to reduce human exposure to protect present and future generations from their adverse health effects.
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Affiliation(s)
| | - Evanthia Diamanti-Kandarakis
- Department of Endocrinology and Diabetes Center of Excellence, Medical School University of Athens, EUROCLINIC, Athens, Greece.
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Targeting advanced glycation with pharmaceutical agents: where are we now? Glycoconj J 2016; 33:653-70. [PMID: 27392438 DOI: 10.1007/s10719-016-9691-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/11/2016] [Accepted: 05/26/2016] [Indexed: 02/06/2023]
Abstract
Advanced glycation end products (AGEs) are the final products of the Maillard reaction, a complex process that has been studied by food chemists for a century. Over the past 30 years, the biological significance of advanced glycation has also been discovered. There is mounting evidence that advanced glycation plays a homeostatic role within the body and that food-related Maillard products, intermediates such as reactive α-dicarbonyl compounds and AGEs, may influence this process. It remains to be understood, at what point AGEs and their intermediates become pathogenic and contribute to the pathogenesis of chronic diseases that inflict current society. Diabetes and its complications have been a major focus of AGE biology due to the abundance of excess sugar and α-dicarbonyls in this family of diseases. While further temporal information is required, a number of pharmacological agents that inhibit components of the advanced glycation pathway have already showed promising results in preclinical models. These therapies appear to have a wide range of mechanistic actions to reduce AGE load. Some of these agents including Alagebrium, have translated successfully to clinical trials, while others such as aminoguanidine, have had undesirable side-effect profiles. This review will discuss different pharmacological agents that have been used to reduce AGE burden in preclinical models of disease with a focus on diabetes and its complications, compare outcomes of those therapies that have reached clinical trials, and provide further rationale for the use of inhibitors of the glycation pathway in chronic diseases.
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De Matteis L, Bertoni G, Lombardelli R, Wellnitz O, Van Dorland HA, Vernay MCMB, Bruckmaier RM, Trevisi E. Acute phase response in lactating dairy cows during hyperinsulinemic hypoglycaemic and hyperinsulinemic euglycaemic clamps and after intramammary LPS challenge. J Anim Physiol Anim Nutr (Berl) 2016; 101:511-520. [PMID: 27079943 DOI: 10.1111/jpn.12463] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 12/04/2015] [Indexed: 01/04/2023]
Abstract
The link between energy availability, turnover of energy substrates and the onset of inflammation in dairy cows is complex and poorly investigated. To clarify this, plasma inflammatory variables were measured in mid-lactating dairy cows allocated to three groups: hyperinsulinemic hypoglycaemic clamp, induced by insulin infusion (HypoG, n = 5); hyperinsulinemic euglycaemic clamp, induced by insulin and glucose infusion (EuG; n = 6); control, receiving a saline solution infusion (NaCl; n = 6). At 48 h after the start of i.v. infusions, two udder quarters per cow were challenged with 200 μg of E. coli lipopolysaccharide (LPS). Individual blood samples were taken before clamps, before LPS challenge (i.e. 48 h after clamps) and 6.5 h after. At 48 h, positive acute phase proteins (posAPP) did not differ among groups, whereas albumin and cholesterol (index of lipoproteins), negative APP (negAPP), were lower (p < 0.05) in EuG compared to NaCl and HypoG. The concentration of IL-6 was greater in EuG (p < 0.05) but only vs. HypoG. At 6.5 h following LPS challenge, IL-6 increased in the NaCl and EuG clamps (p < 0.05), while TNF-α increased (p < 0.05) in the EuG only. Among the posAPP, haptoglobin markedly increased in EuG (p < 0.05), but not in NaCl (p = 0.76) and in HypoG; ceruloplasmin tended to decline during LPS challenge, the reduction was significant when all animals were considered (p < 0.05). Conversely, all the negAPP showed a marked reduction 6.5 h after LPS challenge in the three groups. In conclusion, EuG caused an inflammatory status after 48-h infusion (i.e. decrease of negAPP) and induced a quicker acute phase response (e.g. marked rise of TNF-α, IL-6) after the intramammary LPS challenge. These data suggest that the simultaneous high availability of glucose and insulin at the tissue-level makes dairy cows more susceptible to inflammatory events. In contrast, HypoG seems to attenuate the inflammatory response.
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Affiliation(s)
- L De Matteis
- Istituto di Zootecnica, Facoltà di Scienze Agrarie, Alimentari ed Ambientali, Università Cattolica del Sacro Cuore, Piacenza, Italy
| | - G Bertoni
- Istituto di Zootecnica, Facoltà di Scienze Agrarie, Alimentari ed Ambientali, Università Cattolica del Sacro Cuore, Piacenza, Italy
| | - R Lombardelli
- Istituto di Zootecnica, Facoltà di Scienze Agrarie, Alimentari ed Ambientali, Università Cattolica del Sacro Cuore, Piacenza, Italy
| | - O Wellnitz
- Veterinary Physiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - H A Van Dorland
- Veterinary Physiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - M C M B Vernay
- Veterinary Physiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - R M Bruckmaier
- Veterinary Physiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - E Trevisi
- Istituto di Zootecnica, Facoltà di Scienze Agrarie, Alimentari ed Ambientali, Università Cattolica del Sacro Cuore, Piacenza, Italy
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Lee JH, Yoon SR, Na GY, Jun M, Ahn MR, Cha JK, Kim OY. Fasting Glucose is a Useful Indicator for Cerebrovascular Risk in Non-Diabetic Koreans: Association With Oxidative Stress and Inflammation. Clin Nutr Res 2016; 5:33-42. [PMID: 26839875 PMCID: PMC4731860 DOI: 10.7762/cnr.2016.5.1.33] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 01/12/2016] [Accepted: 01/13/2016] [Indexed: 11/21/2022] Open
Abstract
Diabetes and impaired fasting glucose are associated with incidence of cerebro-/cardio-vascular diseases. This study hypothesized that fasting glycemic status may reflect cerebrovascular risk in non-diabetic Koreans. Fasting glycemic status, lipid profiles, oxidative stress, and inflammation markers were measured in non-diabetic subjects (healthy controls, n = 112 and stroke n = 41). Systolic blood pressure, fasting glucose, glycated hemoglobin (HbA1C), triglycerides, high sensitivity C-reactive protein (hs-CPR), interleukin-6, and tumor necrosis factor-alpha were higher, and high density lipoprotein (HDL)-cholesterols were lower in patients with stroke than healthy controls. Fasting glucose positively correlated with hs-CRP, interleukin-6, tumor necrosis factor-alpha, oxidized low density lipoprotein (LDL) and malondialdehyde. The significances continued or at least turned to a trend after adjustments for confounding factors. Multiple regression analyses revealed that fasting glucose was mainly associated with cerebrovascular risk (β'-coefficient = 0.284, p < 0.0001) together with age, systolic blood pressure, total cholesterol, hs-CRP, body mass index, dietary poly unsaturated fatty acid/saturated fatty acid (PUFA/SFA), and HbA1C (r2 = 0.634, p = 0.044). The subjects were subdivided by their fasting glucose levels [normal fasting glucose: 70-99 mg/dL, n = 91 [NFG-control] and n = 27 [NFG-stroke]; higher fasting glucose: 100-125 mg/dL, n = 21 [HFG-control] and n = 14 [HFG-stroke]). In both controls and stroke patients, HFG groups show higher triglyceride, total- and LDL-cholesterol and lower HDL-cholesterol than NFG groups. Control-HFG group showed significantly higher levels of oxidative stress and inflammation than control-NFG group. Stroke-HFG group also showed significantly higher inflammatory levels than stroke-NFG group, moreover the highest among the groups. Additionally, stroke-NFG group consumed higher PUFA/SFA than stroke-HFG group. Fasting glucose may be a useful indicator for cerebrovascular risk in non-diabetic individuals which may be mediated by oxidative stress and inflammation status.
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Affiliation(s)
- Jae Hyang Lee
- Department of Food Science Nutrition, Brain Busan 21 project, Dong-A University, Busan, 49315 Korea.; Department of Neurology, Busan-Ulsan Regional Cardiocerebrovascular Center, Dong-A University Hospital, College of Medicine, Busan, 49201 Korea
| | - So Ra Yoon
- Department of Food Science Nutrition, Brain Busan 21 project, Dong-A University, Busan, 49315 Korea
| | - Ga Yoon Na
- Department of Food Science Nutrition, Brain Busan 21 project, Dong-A University, Busan, 49315 Korea
| | - Mira Jun
- Department of Food Science Nutrition, Brain Busan 21 project, Dong-A University, Busan, 49315 Korea
| | - Mok-Ryeon Ahn
- Department of Food Science Nutrition, Brain Busan 21 project, Dong-A University, Busan, 49315 Korea
| | - Jae-Kwan Cha
- Department of Neurology, Busan-Ulsan Regional Cardiocerebrovascular Center, Dong-A University Hospital, College of Medicine, Busan, 49201 Korea
| | - Oh Yoen Kim
- Department of Food Science Nutrition, Brain Busan 21 project, Dong-A University, Busan, 49315 Korea
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Chung J, An SH, Kang SW, Kwon K. Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting RAGE Signaling in Diabetic Atherosclerosis. PLoS One 2016; 11:e0147839. [PMID: 26807573 PMCID: PMC4726772 DOI: 10.1371/journal.pone.0147839] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 01/08/2016] [Indexed: 11/30/2022] Open
Abstract
A naturally occurring bile acid, ursodeoxycholic acid (UDCA), is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, the detailed action mechanisms of UDCA in atherosclerosis are not fully understood. In this study, we demonstrated whether UDCA exerts anti-atherogenic activity in diabetic atherosclerosis by targeting ER stress and “receptor for advanced glycation endproduct” (RAGE) signaling. UDCA markedly reduced ER stress, RAGE expression, and pro-inflammatory responses [including NF-κB activation and reactive oxygen species (ROS) production] induced in endothelial cells (ECs) by high glucose (HG). In particular, UDCA inhibited HG-induced ROS production by increasing the Nrf2 level. In macrophages, UDCA also blocked HG-induced RAGE and pro-inflammatory cytokine expression and inhibited foam cell formation via upregulation of the ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1. In the diabetic mouse model, UDCA inhibited atheromatous plaque formation by decreasing ER stress, and the levels of RAGE and adhesion molecules. In conclusion, UDCA exerts an anti-atherogenic activity in diabetic atherosclerosis by targeting both ER stress and RAGE signaling. Our work implicates UDCA as a potential therapeutic agent for prevention or treatment of diabetic atherosclerosis.
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Affiliation(s)
- Jihwa Chung
- Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, Korea
| | - Shung Hyun An
- Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, Korea
| | - Sang Won Kang
- Center for Cell Signaling Research and Division of Molecular Life Sciences, Ewha Womans University, Seoul, Korea
| | - Kihwan Kwon
- Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, Korea
- Department of Internal Medicine, Cardiology Division and GT5 Program of Ewha Womans University School of Medicine, Seoul, Korea
- * E-mail:
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Reddy M, Godsland IF, Barnard KD, Herrero P, Georgiou P, Thomson H, Johnston DG, Oliver NS. Glycemic Variability and Its Impact on Quality of Life in Adults With Type 1 Diabetes. J Diabetes Sci Technol 2015; 10:60-6. [PMID: 26285951 PMCID: PMC4738216 DOI: 10.1177/1932296815601440] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND There is evidence suggesting that glycemic variability reduces quality of life (QoL) in people with type 2 diabetes, but this association has not been explored in type 1 diabetes. We aimed to assess whether glycemic variability has an impact on QoL in adults with established type 1 diabetes using multiple daily injections (MDI) of insulin or continuous subcutaneous insulin infusion (CSII). METHODS Participants wore a blinded continuous glucose monitor for up to 5 days and completed the diabetes quality of life (DQOL) questionnaire. Glycemic variability measures were calculated using the EasyGV version 9.0 software. A correlation analysis was performed to assess whether there was a relationship between glycemic variability and measures of QoL. RESULTS In all, 57 participants with type 1 diabetes (51% male, 65% on CSII, 35% on MDI, mean [SD] age 41 [13] years, duration of diabetes 21 [12] years, HbA1c 63 [12] mmol/mol [7.9% (1.1)], body mass index 25.2 [4.0] kg/m(2)) were included in the analysis. No significant associations between glycemic variability and DQOL total or subscale scores were demonstrated. The glycemic variability was significantly higher for MDI participants compared to CSII participants (P < .05 for all glycemic variability measures), but no significant difference in QoL between the 2 treatment modality groups was observed. CONCLUSIONS Treatment with CSII is associated with lower glycemic variability compared to MDI. Despite this, and contrary to findings in type 2 diabetes, this study did not find an association between glycemic variability and QoL in adults with relatively well-controlled type 1 diabetes, irrespective of whether they are on MDI or CSII.
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Affiliation(s)
- Monika Reddy
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Ian F Godsland
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Katharine D Barnard
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Pau Herrero
- Centre for Bio-Inspired Technology, Department of Electrical and Electronic Engineering, Institute of Biomedical Engineering, Imperial College London, London, UK
| | - Pantelis Georgiou
- Centre for Bio-Inspired Technology, Department of Electrical and Electronic Engineering, Institute of Biomedical Engineering, Imperial College London, London, UK
| | - Hazel Thomson
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Desmond G Johnston
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Nick S Oliver
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
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Sottero B, Gargiulo S, Russo I, Barale C, Poli G, Cavalot F. Postprandial Dysmetabolism and Oxidative Stress in Type 2 Diabetes: Pathogenetic Mechanisms and Therapeutic Strategies. Med Res Rev 2015; 35:968-1031. [PMID: 25943420 DOI: 10.1002/med.21349] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Postprandial dysmetabolism in type 2 diabetes (T2D) is known to impact the progression and evolution of this complex disease process. However, the underlying pathogenetic mechanisms still require full elucidation to provide guidance for disease prevention and treatment. This review focuses on the marked redox changes and inflammatory stimuli provoked by the spike in blood glucose and lipids in T2D individuals after meals. All the causes of exacerbated postprandial oxidative stress in T2D were analyzed, also considering the consequence of enhanced inflammation on vascular damage. Based on this in-depth analysis, current strategies of prevention and pharmacologic management of T2D were critically reexamined with particular emphasis on their potential redox-related rationale.
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Affiliation(s)
- Barbara Sottero
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Simona Gargiulo
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Isabella Russo
- Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Cristina Barale
- Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Giuseppe Poli
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Franco Cavalot
- Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
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41
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Resveratrol protects against methylglyoxal-induced hyperglycemia and pancreatic damage in vivo. Nutrients 2015; 7:2850-65. [PMID: 25884658 PMCID: PMC4425177 DOI: 10.3390/nu7042850] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 03/15/2015] [Accepted: 03/25/2015] [Indexed: 12/23/2022] Open
Abstract
Methylglyoxal (MG) has been found to cause inflammation and insulin resistance in vitro and in vivo in recent studies. Resveratrol has been proposed as an effective treatment that helps lower the risk of developing complications of diabetes. To study the significance of glycosylation-related stress on the pathology of diabetes, the effects of resveratrol were examined in a mouse model of diabetes induced by MG. Resveratrol was given via oral gavage in MG-treated mice, and diabetes-related tests and markers were assessed using biochemical and immunohistochemical analyses. Treatment with resveratrol markedly improved blood glucose level from the oral glucose tolerance test and promoted nuclear factor erythroid 2-related factor-2 (Nrf2) phosphorylation (p < 0.05) in the pancreas of MG-treated mice. However, these effects were abolished by retinoic acid, Nrf2 inhibitor, in resveratrol and retinoic acid-treated and MG-induced mice. These findings support that resveratrol may be useful in the treatment of type-2 diabetes by protecting against pancreatic cell dysfunction.
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43
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Smith LE, White MY. The role of post-translational modifications in acute and chronic cardiovascular disease. Proteomics Clin Appl 2015; 8:506-21. [PMID: 24961403 DOI: 10.1002/prca.201400052] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 05/27/2014] [Accepted: 06/17/2014] [Indexed: 12/22/2022]
Abstract
Cardiovascular disease (CVD) in one of the leading causes of mortality and morbidity worldwide, accounting for both primary diseases of the heart and vasculature and arising as a co-morbidity with numerous pathologies, including type 2 diabetes mellitus (T2DM). There has been significant emphasis on the role of the genome in CVD, aiding in the definition of 'at-risk' patients. The extent of disease penetrance however, can be influenced by environmental factors that are not detectable by investigating the genome alone. By targeting the transcriptome in response to CVD, the interplay between genome and environment is more apparent, however this implies the level of protein expression without reference to proteolytic turnover, or potentially more importantly, without defining the role of PTMs in the development of disease. Here, we discuss the role of both brief and irreversible PTMs in the setting of myocardial ischemia/reperfusion injury. Key proteins involved in calcium regulation have been observed as differentially modified by phosphorylation/O-GlcNAcylation or phosphorylation/redox modifications, with the level of interplay dependent on the physiological or pathophysiological state. The ability to modify crucial sites to produce the desired functional output is modulated by the presence of other PTMs as exemplified in the T2DM heart, where hyperglycemia results in aberrant O-GlcNAcylation and advanced glycation end products. By using the signalling events predicted to be critical to post-conditioning, an intervention with great promise for the cardioprotection of the ischemia/reperfusion injured heart, as an example, we discuss the level of PTMs and their interplay. The inability of post-conditioning to protect the diabetic heart may be regulated by aberrant PTMs influencing those sites necessary for protection.
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Affiliation(s)
- Lauren E Smith
- Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
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44
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Schmidt R, Böhme D, Singer D, Frolov A. Specific tandem mass spectrometric detection of AGE-modified arginine residues in peptides. JOURNAL OF MASS SPECTROMETRY : JMS 2015; 50:613-624. [PMID: 25800199 DOI: 10.1002/jms.3569] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 12/30/2014] [Accepted: 01/07/2015] [Indexed: 06/04/2023]
Abstract
Glycation is a non-enzymatic reaction of protein amino and guanidino groups with reducing sugars or dicarbonyl products of their oxidative degradation. Modification of arginine residues by dicarbonyls such as glyoxal and methylglyoxal results in formation of advanced glycation end-products (AGEs). In mammals, these modifications impact in diabetes mellitus, uremia, atherosclerosis and ageing. However, due to the low abundance of individual AGE-peptides in enzymatic digests, these species cannot be efficiently detected by LC-ESI-MS-based data-dependent acquisition (DDA) experiments. Here we report an analytical workflow that overcomes this limitation. We describe fragmentation patterns of synthetic AGE-peptides and assignment of modification-specific signals required for unambiguous structure retrieval. Most intense signals were those corresponding to unique fragment ions with m/z 152.1 and 166.1, observed in the tandem mass spectra of peptides, containing glyoxal- and methylglyoxal-derived hydroimidazolone AGEs, respectively. To detect such peptides, specific and sensitive precursor ion scanning methods were established for these signals. Further, these precursor ion scans were incorporated in conventional bottom-up proteomic approach based on data-dependent acquisition (DDA) LC-MS/MS experiments. The method was successfully applied for the analysis of human serum albumin (HSA) and human plasma protein tryptic digest with subsequent structure confirmation by targeted LC-MS/MS (DDA). Altogether 44 hydroimidazolone- and dihydroxyimidazolidine-derived peptides representing 42 AGE-modified proteins were identified in plasma digests obtained from type 2 diabetes mellitus (T2DM) patients.
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Affiliation(s)
- Rico Schmidt
- Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Center for Biotechnology and Biomedicine (BBZ), Universität Leipzig, Leipzig, Germany
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45
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Greifenhagen U, Frolov A, Hoffmann R. Oxidative degradation of N(ε)-fructosylamine-substituted peptides in heated aqueous systems. Amino Acids 2015; 47:1065-76. [PMID: 25712730 DOI: 10.1007/s00726-015-1940-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 02/11/2015] [Indexed: 10/23/2022]
Abstract
Glycation, or non-enzymatic glycosylation, is a common protein modification formed by reactions between reducing sugars (i.e. aldoses and ketoses) with protein amino groups. Resulting Amadori and Heyns compounds, respectively, can be oxidatively degraded yielding a structurally heterogeneous group of advanced glycation end-products. We have studied this process in aqueous conditions at 95 °C in terms of appearing products and their formation kinetics in the presence or absence of reactive oxygen species (ROS)-generating systems (iron(II) sulfate). RP-HPLC-ESI-MS revealed 20 products, 12 of which were confirmed after synthesis by identical retention times and fragmentation patterns. These products accumulated during the incubation period of 4 h (N(ε)-carboxymethyl-, N(ε)-formyl- and N(ε)-methyl lysine) or appeared intermediately (2-aminoadipic semialdehyde, N(ε)-ethanalyl lysine). Acidic and basic amino acid residues near the glycation site and elevated ROS levels in the reaction mixture had significant effects on both product formation and degradation kinetics.
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Affiliation(s)
- Uta Greifenhagen
- Faculty of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Universität Leipzig, Deutscher Platz 5, 04103, Leipzig, Germany
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Chandna AR, Nair M, Chang C, Pennington PR, Yamamoto Y, Mousseau DD, Campanucci VA. RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions. Eur J Neurosci 2014; 41:341-51. [PMID: 25431195 DOI: 10.1111/ejn.12795] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 10/27/2014] [Accepted: 10/28/2014] [Indexed: 12/11/2022]
Abstract
Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities and premature death. It was recently proposed that autonomic dysfunction is triggered by oxidation-mediated inactivation of neuronal nicotinic acetylcholine receptors (nAChRs), impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure. We investigated whether the receptor for advanced glycation end products (RAGE) and its role in the generation of reactive oxygen species (ROS) could be contributing to the events that initiate sympathetic malfunction under high glucose conditions. Using biochemical, live imaging and electrophysiological tools we demonstrated that exposure of sympathetic neurons to high glucose increases RAGE expression and oxidative markers, and that incubation with RAGE ligands (e.g. AGEs, S100 and HMGB1) mimics both ROS elevation and nAChR inactivation. In contrast, co-treatment with either antioxidants or an anti-RAGE IgG prevented the inactivation of nAChRs. Lastly, a role for RAGE in this context was corroborated by the lack of sensitivity of sympathetic neurons from RAGE knock-out mice to high glucose. These data define a pivotal role for RAGE in initiating the events associated with exposure of sympathetic neurons to high glucose, and strongly support RAGE signaling as a potential therapeutic target in the autonomic complications associated with diabetes.
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Affiliation(s)
- Andrew R Chandna
- Department of Physiology, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan, S7N 5E5, Canada
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47
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Zhu T, Meng Q, Ji J, Lou X, Zhang L. Toll-like receptor 4 and tumor necrosis factor-alpha as diagnostic biomarkers for diabetic peripheral neuropathy. Neurosci Lett 2014; 585:28-32. [PMID: 25445373 DOI: 10.1016/j.neulet.2014.11.020] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 10/04/2014] [Accepted: 11/14/2014] [Indexed: 12/13/2022]
Abstract
Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes, but currently no protein biomarkers have been introduced into clinical diagnosis, especially among early-stage diabetic patients. Our previous study in animal model showed Toll-like receptor (TLR) 4 and its downstream signaling molecules were associated with DPN. To assess the diagnostic values of TLR4, TNF-α, and IL-6 as biomarkers, here we detected their expressions in peripheral blood from normal controls, type 2 diabetic and DPN subjects. Both TLR4 mRNA and protein expressions increased significantly in DPN compare with both diabetic and control subjects. The protein levels of TNF-α and IL-6 were also raised significantly and correlated with TLR4 expression. Receiver operating characteristics (ROC) analysis suggested TLR4 and TNF-α had great potential advantages to predict the progression of neuropathy, the risks of DPN were increased in subjects with higher TLR4 (odds ratio: 5.27; 95% CI: 1.02-26.40) and TNF-α (odds ratio: 12.67; 95% CI: 2.35-68.22). These findings demonstrated TLR4 and TNF-α could be potential sensitive diagnostic biomarkers for DPN in both general population and type 2 diabetic subjects.
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Affiliation(s)
- Tao Zhu
- Department of Anesthesia, Songjiang Branch, Shanghai First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China.
| | | | - Jian Ji
- Department of Anesthesia, Songjiang Branch, Shanghai First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Xiaoli Lou
- Central Laboratory, Songjiang Branch, Shanghai First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Lijuan Zhang
- Department of Endocrinology, Songjiang Branch, Shanghai First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
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Fernández-Velasco M, Ruiz-Hurtado G, Gómez AM, Rueda A. Ca(2+) handling alterations and vascular dysfunction in diabetes. Cell Calcium 2014; 56:397-407. [PMID: 25218935 DOI: 10.1016/j.ceca.2014.08.007] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 07/30/2014] [Accepted: 08/07/2014] [Indexed: 12/12/2022]
Abstract
More than 65% of patients with diabetes mellitus die from cardiovascular disease or stroke. Hyperglycemia, due to either reduced insulin secretion or reduced insulin sensitivity, is the hallmark feature of diabetes mellitus. Vascular dysfunction is a distinctive phenotype found in both types of diabetes and could be responsible for the high incidence of stroke, heart attack, and organ damage in diabetic patients. In addition to well-documented endothelial dysfunction, Ca(2+) handling alterations in vascular smooth muscle cells (VSMCs) play a key role in the development and progression of vascular complications in diabetes. VSMCs provide not only structural integrity to the vessels but also control myogenic arterial tone and systemic blood pressure through global and local Ca(2+) signaling. The Ca(2+) signalosome of VSMCs is integrated by an extensive number of Ca(2+) handling proteins (i.e. channels, pumps, exchangers) and related signal transduction components, whose function is modulated by endothelial effectors. This review summarizes recent findings concerning alterations in endothelium and VSMC Ca(2+) signaling proteins that may contribute to the vascular dysfunction found in the diabetic condition.
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Affiliation(s)
| | - Gema Ruiz-Hurtado
- Unidad de Hipertensión, Instituto de Investigación imas12, Hospital 12 de Octubre, Madrid, Spain; Instituto Pluridisciplinar, Facultad de Farmacia, Universidad Complutense de Madrid, Spain
| | - Ana M Gómez
- Inserm, UMR S769, Faculté de Pharmacie, Université Paris Sud, Labex LERMIT, DHU TORINO, Châtenay-Malabry, France
| | - Angélica Rueda
- Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, Mexico.
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49
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Acute Insulin Resistance Mediated by Advanced Glycation Endproducts in Severely Burned Rats. Crit Care Med 2014; 42:e472-80. [DOI: 10.1097/ccm.0000000000000314] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Strilka RJ, Armen SB, Indeck MC. Qualitative analysis of subcutaneous Lispro and regular insulin injections for stress hyperglycemia: a pilot numerical study. J Theor Biol 2014; 356:192-200. [PMID: 24769252 DOI: 10.1016/j.jtbi.2014.04.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 04/12/2014] [Accepted: 04/16/2014] [Indexed: 11/15/2022]
Abstract
Increased glucose variability (GV) is an independent risk factor for mortality in the critically ill; unfortunately, the optimal insulin therapy that minimizes GV is not known. We simulate the glucose-insulin feedback system to study how stress hyperglycemia (SH) states, taken to be a non-uniform group of physiologic disorders with varying insulin resistance (IR) and similar levels of hyperglycemia, respond to the type and dose of subcutaneous (SQ) insulin. Two groups of 100 virtual patients are studied: those receiving and those not receiving continuous enteral feeds. Stress hyperglycemia was facilitated by doubling the gluconeogenesis rate and IR was stepwise varied from a borderline to a high value. Lispro and regular insulin were simulated with dosages that ranged from 0 to 6 units; the resulting GV was analyzed after each insulin injection. The numerical model used consists of a set of non-linear differential equations with two time delays and five adjustable parameters. The results show that regular insulin decreased GV in both patient groups and rarely caused hypoglycemia. With continuous enteral feeds and borderline to mild IR, Lispro showed minimal effect on GV; however, rebound hyperglycemia that increased GV occurred when the IR was moderate to high. Without a nutritional source, Lispro worsened GV through frequent hypoglycemia episodes as the injection dose increased. The inferior performance of Lispro is a result of its rapid absorption profile; half of its duration of action is similar to the glucose ultradian period. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units, and if such dynamics are present, their clinical effects should be evaluated.
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Affiliation(s)
- Richard J Strilka
- Division of Trauma, Acute Care and Critical Care Surgery, Pennsylvania State College of Medicine, 500 University Drive, UPC II, Suite 3100, Hershey, PA 17033, United States.
| | - Scott B Armen
- Division of Trauma, Acute Care and Critical Care Surgery, Pennsylvania State College of Medicine, 500 University Drive, UPC II, Suite 3100, Hershey, PA 17033, United States
| | - Matthew C Indeck
- Division of Trauma, Acute Care and Critical Care Surgery, Pennsylvania State College of Medicine, 500 University Drive, UPC II, Suite 3100, Hershey, PA 17033, United States
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