|
1
|
Zhu XZ, Qiu Z, Lei SQ, Leng Y, Li WY, Xia ZY. The Role of P53 in Myocardial Ischemia-Reperfusion Injury. Cardiovasc Drugs Ther 2025; 39:195-209. [PMID: 37389674 DOI: 10.1007/s10557-023-07480-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/09/2023] [Indexed: 07/01/2023]
Abstract
PURPOSE P53 is one of the key tumor suppressors. In normal cells, p53 is maintained at low levels by the ubiquitination of the ubiquitinated ligase MDM2. In contrast, under stress conditions such as DNA damage and ischemia, the interaction between p53 and MDM2 is blocked and activated by phosphorylation and acetylation, thereby mediating the trans-activation of p53 through its target genes to regulate a variety of cellular responses. Previous studies have shown that the expression of p53 is negligible in normal myocardium, tends to increase in myocardial ischemia and is maximally induced in ischemia-reperfused myocardium, demonstrating a possible key role of p53 in the development of MIRI. In this review, we detail and summarize recent studies on the mechanism of action of p53 in MIRI and describe the therapeutic agents targeting the relevant targets to provide new strategies for the prevention and treatment of MIRI. METHODS We collected 161 relevant papers mainly from Pubmed and Web of Science (search terms "p53" and "myocardial ischemia-reperfusion injury"). After that, we selected pathway studies related to p53 and classified them according to their contents. We eventually analyzed and summarized them. RESULTS AND CONCLUSION In this review, we detail and summarize recent studies on the mechanism of action of p53 in MIRI and validate its status as an important intermediate affecting MIRI. On the one hand, p53 is regulated and modified by multiple factors, especially non-coding RNAs; on the other hand, p53 regulates apoptosis, programmed necrosis, autophagy, iron death and oxidative stress in MIRI through multiple pathways. More importantly, several studies have reported medications targeting p53-related therapeutic targets. These medications are expected to be effective options for the alleviation of MIRI, but further safety and clinical studies are needed to convert them into clinical applications.
Collapse
Affiliation(s)
- Xi-Zi Zhu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China
| | - Zhen Qiu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China
| | - Shao-Qing Lei
- Department of Anesthesiology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China
| | - Yan Leng
- Department of Anesthesiology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China
| | - Wen-Yuan Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China
| | - Zhong-Yuan Xia
- Department of Anesthesiology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People's Republic of China.
| |
Collapse
|
|
2
|
Li J, Roshelli Baker J, Aglago EK, Zhao Z, Jiao L, Freisling H, Hughes DJ, Eriksen AK, Tjønneland A, Severi G, Katzke V, Kaaks R, Schulze MB, Masala G, Pala V, Pasanisi F, Tumino R, Padroni L, Vermeulen RCH, Gram IT, Braaten T, Jakszyn PG, Sánchez MJ, Gómez-Gómez JH, Moreno-Iribas C, Amiano P, Papier K, Weiderpass E, Huybrechts I, Heath AK, Schalkwijk C, Jenab M, Fedirko V. Pre-diagnostic plasma advanced glycation end-products and soluble receptor for advanced glycation end-products and mortality in colorectal cancer patients. Int J Cancer 2024; 155:1982-1995. [PMID: 39057841 DOI: 10.1002/ijc.35114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 04/22/2024] [Accepted: 05/10/2024] [Indexed: 07/28/2024]
Abstract
Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, Nε-[carboxy-methyl]lysine (CML), Nε-[carboxy-ethyl]lysine (CEL) and Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (Pinteraction = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HRQ5vs.Q1 = 1.67, 95% CI: 1.21-2.30, Ptrend = .02) or any cause (HRQ5vs.Q1 = 1.38, 95% CI: 1.05-1.83, Ptrend = .09). These associations tended to be stronger among cases with diabetes (Pinteraction = .03) and pre-diabetes (Pinteraction <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes.
Collapse
Affiliation(s)
- Jinze Li
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jacqueline Roshelli Baker
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Elom K Aglago
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Zhiwei Zhao
- Department of Biostatistics, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Li Jiao
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Heinz Freisling
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - David J Hughes
- Cancer Biology and Therapeutics Group, School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
| | - Anne Kirstine Eriksen
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Anne Tjønneland
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Gianluca Severi
- Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, CESP, Villejuif, France
- Department of Statistics, Computer Science, Applications "G. Parenti", University of Florence, Florence, Italy
| | - Verena Katzke
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Matthias B Schulze
- Department of Molecular Epidemiology, German Institute for Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Giovanna Masala
- Clinical Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network, Florence, Italy
| | - Valeria Pala
- Epidemiology and Prevention Unit Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
| | - Fabrizio Pasanisi
- Dipartimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy
| | - Rosario Tumino
- Hyblean Association for Epidemiological Research, AIRE ONLUS, Ragusa, Italy
| | - Lisa Padroni
- Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital, and Center for Cancer Prevention (CPO), Turin, Italy
| | - Roel C H Vermeulen
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | - Inger T Gram
- Faculty of Health Sciences, Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway
| | - Tonje Braaten
- Faculty of Health Sciences, Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway
| | - Paula Gabriela Jakszyn
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
| | - Maria-José Sánchez
- Escuela Andaluza de Salud Pública (EASP), Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
- CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Jesús-Humberto Gómez-Gómez
- CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia, Spain
| | - Conchi Moreno-Iribas
- CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Pilar Amiano
- CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain
- BioGipuzkoa (BioDonostia) Health Research Institute, Epidemiology of Chronic and Communicable Diseases Group, San Sebastián, Spain
| | - Keren Papier
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Elisabete Weiderpass
- International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Inge Huybrechts
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Alicia K Heath
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Casper Schalkwijk
- Laboratory of Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University Medical Center, The Netherlands
| | - Mazda Jenab
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Veronika Fedirko
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| |
Collapse
|
|
3
|
Oliveira JSE, Gomes JMG, Costa JDA, Oliveira LLD, Alfenas RDCG. Increased calcium intake from skimmed milk in energy-restricted diets reduces glycation markers in adults with type 2 diabetes and overweight: A secondary analysis of a randomized clinical trial. Nutr Res 2024; 127:40-52. [PMID: 38861793 DOI: 10.1016/j.nutres.2024.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 06/13/2024]
Abstract
The effect of calcium (Ca) on glycation markers is unknown. We hypothesized that increased Ca intake from skimmed milk associated with an energy-restricted diet intake will reduce glycation markers. This reduction will be associated with a greater improvement in markers of metabolic control in adults with type 2 diabetes, overweight, and low habitual Ca intake (<600 mg/d). In this secondary data analysis based on a crossover clinical trial, 14 adults were allocated into 2 groups: high calcium (shake containing 700 mg Ca/day) or low calcium (shake with 6.4 mg Ca/day), for 12 consecutive weeks per session. Energy-restricted diets were also prescribed (-500 kcal/d, 800 mg of dietary Ca/d) to all participants. Advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), glycemic control, and lipid profile were assessed at baseline and after 12 weeks. High-calcium serum AGE concentrations and AGE/sRAGE ratio were lower at the end of the study. ΔAGE and ΔAGE/sRAGE ratio were both positively associated with Δtriglycerides, Δtotal cholesterol, Δtriglyceride-glucose index and variations, and Δvisceral adiposity index. ΔAGE/sRAGE was positively associated with Δfructosamine and Δhigh-density lipoprotein-cholesterol, and negatively associated with male sex. Consumption of approximately 1200 mg/day of calcium (3 servings of skim milk) reduced serum AGEs concentrations and the AGE/sRAGE ratio in individuals with diabetes. In general, positive changes in glycation markers are associated with lipid profile, insulin resistance, and adiposity markers worsening. ΔAGEs/ΔsRAGE ratio seems to be a better marker of metabolic status than ΔAGEs and ΔsRAGE alone. Registered in ClinicalTrials.gov (NCT02377076).
Collapse
Affiliation(s)
- Julia Silva E Oliveira
- Departamento de Nutricao e Saude, Universidade Federal de Viçosa, 36570-900, Vicosa, Minas Gerais, Brazil.
| | - Júnia Maria Geraldo Gomes
- Instituto Federal de Educacao, Ciencia e Tecnologia do Sudeste de Minas Gerais, 36205-018, Barbacena, Minas Gerais, Brazil
| | - Jorge de Assis Costa
- Departamento de Ciencia Humana e Línguas, Universidade Estadual de Minas Gerais, 36500-000, Uba, Minas Gerais, Brazil
| | | | | |
Collapse
|
|
4
|
Bridglalsingh S, Archer-Hartmann S, Azadi P, Barbier de La Serre C, Remillard RL, Sunvold GD, Bartges JW. Association of four differently processed diets with plasma and urine advanced glycation end products and serum soluble receptor for advanced glycation end products concentration in healthy dogs. J Anim Physiol Anim Nutr (Berl) 2024; 108:735-751. [PMID: 38279966 PMCID: PMC11327896 DOI: 10.1111/jpn.13927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 12/12/2023] [Accepted: 01/06/2024] [Indexed: 01/29/2024]
Abstract
Advanced glycation end products (AGEs), formed via the Maillard reaction (MR) during processing of foods, have been implicated in inflammatory and degenerative diseases in human beings. Cellular damage is primarily caused by AGE binding with the receptor for AGEs (RAGE) on cell membranes. An isoform of RAGE, soluble RAGE (sRAGE), acts as a decoy receptor binding circulating AGEs preventing cellular activation. Pet food manufacturing involves processing methods similar to human food processing that may increase dietary AGEs (dAGEs). We hypothesized that diet, plasma and urine AGEs, and serum sRAGE concentrations would differ between thermally processed diets. This study examined the association of four differently processed diets: ultra-processed canned wet food (WF); ultra-processed dry food (DF); moderately processed air-dried food (ADF) and minimally processed mildly cooked food (MF) on total plasma levels of the AGEs, carboxymethyllysine (CML), carboxyethyllysine (CEL), methylglyoxal hydroimidazolone-1, glyoxal hydroimidazolone-1, argpyrimidine, urine CML, CEL and lysinoalanine, and serum sRAGE concentration. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used to measure AGEs. sRAGE concentration was measured using a commercial canine-specific enzyme-linked immunosorbent assay kit. Total dAGEs (mg/100 kcal as fed) were higher in WF than in other diets. Plasma total AGEs (nM/50 μL) were significantly higher with WF, with no difference found between DF, ADF, and MF; however, ADF was significantly higher than MF. Urine CML (nmol AGEs/mmol creatinine) was significantly higher with DF than with WF and MF. There were no significant differences in total urine AGEs or serum sRAGE concentration between diets. In conclusion, different methods of processing pet foods are associated with varied quantities of AGEs influencing total plasma AGE concentration in healthy dogs. Serum sRAGE concentration did not vary across diets but differences in total AGE/sRAGE ratio were observed between MF and WF and, ADF and DF.
Collapse
Affiliation(s)
- Siobhan Bridglalsingh
- Department of Small Animal Medicine and Surgery, University of Georgia, Athens, Georgia, USA
| | - Stephanie Archer-Hartmann
- Analytical Services, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA
| | - Parastoo Azadi
- Analytical Services, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA
| | | | | | | | - Joseph W Bartges
- Department of Small Animal Medicine and Surgery, University of Georgia, Athens, Georgia, USA
| |
Collapse
|
|
5
|
Hiney K, Sypniewski L, DeSilva U, Pezeshki A, Rudra P, Goodarzi P, Willis E, McFarlane D. Fecal microbiota composition, serum metabolomics, and markers of inflammation in dogs fed a raw meat-based diet compared to those on a kibble diet. Front Vet Sci 2024; 11:1328513. [PMID: 38694479 PMCID: PMC11061498 DOI: 10.3389/fvets.2024.1328513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 03/13/2024] [Indexed: 05/04/2024] Open
Abstract
Introduction Despite the potential health risks associated with feeding raw and non-traditional diets, the use of these diets in dogs is increasing, yet the health outcomes associated with these diets is not well understood. This study investigates the effect of feeding dogs a kibble or raw meat-based diets on fecal microbiota composition, serum metabolomics and inflammatory markers. Methods Clinically healthy dogs with a history of consuming either kibble (KD, n = 27) or raw meat-based diets (RMBD, n = 28) for more than 1 year were enrolled. Dogs were fed a standardized diet of either a single brand of KD or RMBD for 28 days. Serum and fecal samples were collected for analysis of microbiota, metabolomics, and inflammatory markers. Multiple regression analysis was performed for each of the metabolites and inflammatory markers, with feed group, age and BCS included as independent variables. Results The fecal microbiota composition differed between the KD and RMBD groups. Beta-diversity and some indices of alpha-diversity (i.e., Shannon and Simpson) were different between the two diet groups. Sixty- three serum metabolites differed between KD and RMBD-fed dogs with the majority reflecting the differences in macronutrient composition of the two diets.Fecal IAP, IgG and IgA were significantly higher in RMBD dogs compared to KD dogs, while systemic markers of inflammation, including serum c-reactive protein (CRP), galectin, secretory receptor of advanced glycation end-products (sRAGE), haptoglobin, and serum IgG were similar in dogs fed either diet. Discussion Diet composition significantly affected fecal microbiota composition and metabolome. Although it had a potentially beneficial effect on local inflammatory markers, feeding RMBD had no impact on systemic inflammation. The influence of these changes on long term health outcomes provides an area for future study.
Collapse
Affiliation(s)
- Kris Hiney
- Department of Animal and Food Sciences, Ferguson College of Agriculture, Oklahoma State University, Stillwater, OK, United States
| | - Lara Sypniewski
- Department of Clinical Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, United States
| | - Udaya DeSilva
- Department of Animal and Food Sciences, Ferguson College of Agriculture, Oklahoma State University, Stillwater, OK, United States
| | - Adel Pezeshki
- Department of Animal and Food Sciences, Ferguson College of Agriculture, Oklahoma State University, Stillwater, OK, United States
| | - Pratyaydipta Rudra
- Department of Statistics, College of Arts and Sciences, Oklahoma State University, Stillwater, OK, United States
| | - Parniyan Goodarzi
- Department of Animal and Food Sciences, Ferguson College of Agriculture, Oklahoma State University, Stillwater, OK, United States
| | - Erin Willis
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, United States
| | - Dianne McFarlane
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, United States
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
| |
Collapse
|
|
6
|
Carrión-Barberà I, Triginer L, Tío L, Pérez-García C, Ribes A, Abad V, Pros A, Monfort J, Salman-Monte TC. Serum Advanced Glycation End Products and Their Soluble Receptor as New Biomarkers in Systemic Lupus Erythematosus. Biomedicines 2024; 12:610. [PMID: 38540223 PMCID: PMC10968350 DOI: 10.3390/biomedicines12030610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 11/11/2024] Open
Abstract
It has been postulated that advanced glycation end products (AGEs) and their soluble receptor (sRAGE) may play a relevant role as inducers in the chronic inflammatory pathway in various conditions, among them, in immune-mediated diseases such as systemic lupus erythematosus (SLE). However, previous studies show conflicting results about their association with SLE characteristics and their usefulness as disease biomarkers. We aimed to study the association of specific serum AGEs (pentosidine, Nξ-(carboxymethyl)lysine (CML), Nξ-(carboxyethyl)lysine (CEL)), sRAGE levels and AGEs (specific serum AGEs and skin AGEs) to sRAGE ratios with various disease parameters, in order to clarify their potential as new biomarkers in SLE and to study their relationship with cardiovascular disease (CVD). To this aim, serum pentosidine, CML, CEL and sRAGE were measured via ELISA, and skin AGEs levels were measured by skin autofluorescence. Correlations of pentosidine levels with demographic and clinical data, indexes of activity, accrual damage and patient-reported outcomes were analyzed through multiple linear regression models, while correlations of the rest of the AGEs, sRAGE and AGE to sRAGE ratios (non-normal) were analyzed using both an OLS regression model and a GML. All of the analyses were adjusted for confounders. A total of 119 SLE patients were recruited. Serum AGEs and sRAGEs were significantly associated with SLE activity indexes and/or demographic or disease characteristics: pentosidine with pulmonary manifestations; CML with anti-dsDNA antibodies, IL-6, disease duration and non-Caucasian ethnicities; CEL with anti-dsDNA antibodies, IL-6 and accumulated number of manifestations; and sRAGE with male gender, photosensitivity and being on specific immunosuppressants. These results suggest that the AGE-sRAGE axis may serve as a novel biomarker for managing and prognosticating this disease. Its correlation with certain antibodies, demographics and disease presentations may indicate a distinct clinical phenotype associated with varying levels of AGEs and/or sRAGE. The significance of specific AGE/sRAGE ratios, introduced in this study for the first time, warrants additional investigation in forthcoming research. Our study did not confirm the link between serum AGEs and CVD, which merits further exploration through studies designed for this specific purpose.
Collapse
Affiliation(s)
- Irene Carrión-Barberà
- Rheumatology Department, Hospital del Mar, 08003 Barcelona, Spain; (I.C.-B.)
- Medicine Department, Medicine Faculty, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Hospital del Mar Research Institute, 08003 Barcelona, Spain
- Clinical Expertise Unit (UEC) in Systemic Autoimmune Diseases and Vasculitis, 08003 Barcelona, Spain
| | - Laura Triginer
- Hospital del Mar Research Institute, 08003 Barcelona, Spain
| | - Laura Tío
- Hospital del Mar Research Institute, 08003 Barcelona, Spain
| | - Carolina Pérez-García
- Rheumatology Department, Hospital del Mar, 08003 Barcelona, Spain; (I.C.-B.)
- Hospital del Mar Research Institute, 08003 Barcelona, Spain
- Clinical Expertise Unit (UEC) in Systemic Autoimmune Diseases and Vasculitis, 08003 Barcelona, Spain
| | - Anna Ribes
- Hospital del Mar Research Institute, 08003 Barcelona, Spain
| | - Victoria Abad
- Rheumatology Department, Hospital del Mar, 08003 Barcelona, Spain; (I.C.-B.)
- Clinical Expertise Unit (UEC) in Systemic Autoimmune Diseases and Vasculitis, 08003 Barcelona, Spain
| | - Ana Pros
- Rheumatology Department, Hospital del Mar, 08003 Barcelona, Spain; (I.C.-B.)
- Clinical Expertise Unit (UEC) in Systemic Autoimmune Diseases and Vasculitis, 08003 Barcelona, Spain
| | - Jordi Monfort
- Rheumatology Department, Hospital del Mar, 08003 Barcelona, Spain; (I.C.-B.)
- Hospital del Mar Research Institute, 08003 Barcelona, Spain
- Clinical Expertise Unit (UEC) in Systemic Autoimmune Diseases and Vasculitis, 08003 Barcelona, Spain
| | - Tarek Carlos Salman-Monte
- Rheumatology Department, Hospital del Mar, 08003 Barcelona, Spain; (I.C.-B.)
- Hospital del Mar Research Institute, 08003 Barcelona, Spain
- Clinical Expertise Unit (UEC) in Systemic Autoimmune Diseases and Vasculitis, 08003 Barcelona, Spain
| |
Collapse
|
|
7
|
Rodríguez de Fonseca F, Medina-Paz F, Sapozhnikov M, Hurtado-Guerrero I, Rubio L, Martín-de-las-Heras S, Requena-Ocaña N, Flores-López M, Fernández-Arjona MDM, Rivera P, Serrano A, Serrano P, C. Zapico S, Suárez J. Plasma Concentrations of High Mobility Group Box 1 Proteins and Soluble Receptors for Advanced Glycation End-Products Are Relevant Biomarkers of Cognitive Impairment in Alcohol Use Disorder: A Pilot Study. TOXICS 2024; 12:190. [PMID: 38535924 PMCID: PMC10974976 DOI: 10.3390/toxics12030190] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 01/14/2025]
Abstract
Alcohol use disorder (AUD) is a major component in the etiology of cognitive decline and dementia. Underlying mechanisms by which long-term alcohol abuse causes cognitive dysfunction include excessive oxidative stress and inflammation in the brain, activated by increased reactive oxygen/nitrogen species (ROS/RNS), advanced glycation end-products (AGEs) and high-mobility group box 1 protein (HMGB1). In a pilot study, we examine the potential clinical value of circulating biomarkers of oxidative stress including ROS/RNS, HMGB1, the soluble receptor for AGE (sRAGE), the brain biomarker of aging apolipoprotein D (ApoD), and the antioxidant regulator nuclear factor erythroid 2-related factor 2 (NRF2) as predictive indices for cognitive impairment (CI) in abstinent patients with AUD (n = 25) compared to patients with established Alzheimer's disease (AD, n = 26) and control subjects (n = 25). Plasma concentrations of sRAGE were evaluated with immunoblotting; ROS/RNS with a fluorometric kit; and HMGB1, ApoD, and NRF2 by ELISA. Abstinent AUD patients had higher sRAGE, ROS/RNS (p < 0.05), and ApoD (p < 0.01) concentrations, similar to those of AD patients, and lower NRF2 (p < 0.01) concentrations, compared to controls. These changes were remarkable in AUD patients with CI. HMGB1, and sRAGE correlated positively with duration of alcohol use (rho = 0.398, p = 0.022; rho = 0.404, p = 0.018), whereas sRAGE correlated negatively with periods of alcohol abstinence (rho = -0.340, p = 0.045). A predictive model including ROS/RNS, HMGB1, sRAGE, alcohol use duration, and alcohol abstinence periods was able to differentiate AUD patients with CI (92.3% of correct predictions, ROC-AUC= 0.90) from those without CI. In conclusion, we propose ROS/RNS, HMGB1, and sRAGE as stress biomarkers capable of predicting cognitive impairment in AUD patients.
Collapse
Affiliation(s)
- Fernando Rodríguez de Fonseca
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- Servicio de Neurología, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Francisco Medina-Paz
- Department of Chemistry and Environmental Sciences, New Jersey Institute of Technology, Tiernan Hall 365, Newark, NJ 07102, USA; (F.M.-P.); (M.S.)
| | - Mira Sapozhnikov
- Department of Chemistry and Environmental Sciences, New Jersey Institute of Technology, Tiernan Hall 365, Newark, NJ 07102, USA; (F.M.-P.); (M.S.)
| | - Isaac Hurtado-Guerrero
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Facultad de Medicina, Universidad de Málaga, 29071 Málaga, Spain
| | - Leticia Rubio
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Facultad de Medicina, Universidad de Málaga, 29071 Málaga, Spain
| | - Stella Martín-de-las-Heras
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Facultad de Medicina, Universidad de Málaga, 29071 Málaga, Spain
| | - Nerea Requena-Ocaña
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - María Flores-López
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - María del Mar Fernández-Arjona
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- Servicio de Neurología, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Patricia Rivera
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Antonia Serrano
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Pedro Serrano
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- Servicio de Neurología, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Sara C. Zapico
- Department of Chemistry and Environmental Sciences, New Jersey Institute of Technology, Tiernan Hall 365, Newark, NJ 07102, USA; (F.M.-P.); (M.S.)
- Anthropology Department, National Museum of Natural History, Smithsonian Institution, 10th and Constitution Ave. NW, Washington, DC 20560, USA
| | - Juan Suárez
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (F.R.d.F.); (I.H.-G.); (L.R.); (S.M.-d.-l.-H.); (N.R.-O.); (M.F.-L.); (M.d.M.F.-A.); (P.R.); (A.S.); (P.S.)
- Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Facultad de Medicina, Universidad de Málaga, 29071 Málaga, Spain
| |
Collapse
|
|
8
|
Arivazhagan L, Popp CJ, Ruiz HH, Wilson RA, Manigrasso MB, Shekhtman A, Ramasamy R, Sevick MA, Schmidt AM. The RAGE/DIAPH1 axis: mediator of obesity and proposed biomarker of human cardiometabolic disease. Cardiovasc Res 2024; 119:2813-2824. [PMID: 36448548 PMCID: PMC11484493 DOI: 10.1093/cvr/cvac175] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 12/07/2023] Open
Abstract
Overweight and obesity are leading causes of cardiometabolic dysfunction. Despite extensive investigation, the mechanisms mediating the increase in these conditions are yet to be fully understood. Beyond the endogenous formation of advanced glycation endproducts (AGEs) in overweight and obesity, exogenous sources of AGEs accrue through the heating, production, and consumption of highly processed foods. Evidence from cellular and mouse model systems indicates that the interaction of AGEs with their central cell surface receptor for AGE (RAGE) in adipocytes suppresses energy expenditure and that AGE/RAGE contributes to increased adipose inflammation and processes linked to insulin resistance. In human subjects, the circulating soluble forms of RAGE, which are mutable, may serve as biomarkers of obesity and weight loss. Antagonists of RAGE signalling, through blockade of the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous-1 (DIAPH1), target aberrant RAGE activities in metabolic tissues. This review focuses on the potential roles for AGEs and other RAGE ligands and RAGE/DIAPH1 in the pathogenesis of overweight and obesity and their metabolic consequences.
Collapse
Affiliation(s)
- Lakshmi Arivazhagan
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Collin J Popp
- Center for Healthful Behavior Change, Department of Population Health, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Henry H Ruiz
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Robin A Wilson
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Michaele B Manigrasso
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY 12222, USA
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| | - Mary Ann Sevick
- Center for Healthful Behavior Change, Department of Population Health, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, Science Building, 435 E. 30th Street, New York, NY 10016, USA
| |
Collapse
|
|
9
|
Zhou J, Liu S, Bi S, Kong W, Qian R, Xie X, Zeng M, Jiang X, Liao Z, Shuai M, Liu W, Cheng L, Wu M. The RAGE signaling in osteoporosis. Biomed Pharmacother 2023; 165:115044. [PMID: 37354815 DOI: 10.1016/j.biopha.2023.115044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 06/26/2023] Open
Abstract
Osteoporosis (OP), characterized by an imbalance of bone remodeling between formation and resorption, has become a health issue worldwide. The receptor for advanced glycation end product (RAGE), a transmembrane protein in the immunoglobin family, has multiple ligands and has been involved in many chronic diseases, such as diabetes and OP. Increasing evidence shows that activation of the RAGE signaling negatively affects bone remodeling. Ligands, such as advanced glycation end products (AGEs), S100, β-amyloid (Aβ), and high mobility group box 1 (HMGB1), have been well documented that they may negatively regulate the proliferation and differentiation of osteoblasts and positively stimulate osteoclastogenesis by activating the expression of RAGE. In this review, we comprehensively discuss the structure of RAGE and its biological functions in the pathogenesis of OP. The research findings suggest that RAGE signaling has become a potential target for the therapeutic management of OP.
Collapse
Affiliation(s)
- Jianguo Zhou
- Department of Joint Surgery, Ganzhou People's Hospital, Ganzhou 341000, China.
| | - Shiwei Liu
- Department of Joint Surgery, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Shengrong Bi
- Department of Joint Surgery, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Weihao Kong
- Department of Joint Surgery, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Rui Qian
- Department of Joint Surgery, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Xunlu Xie
- Department of Pathology, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Ming Zeng
- Department of Orthopedics, Ruijin Traditional Chinese Medicine Hospital, Ruijin 342500, China
| | - Xiaowei Jiang
- Department of Joint Surgery, Ningdu County People's Hospital, Ningdu 342800, China
| | - Zhibin Liao
- Department of Joint Surgery, Ningdu County People's Hospital, Ningdu 342800, China
| | - Ming Shuai
- Department of Orthopedics, Chongyi County People's Hospital, Chongyi 341300, China
| | - Wei Liu
- Department of Orthopedics, Ningdu County Traditional Chinese Medicine Hospital, Ningdu 342800, China
| | - Long Cheng
- Department of Orthopedics, Ningdu County Traditional Chinese Medicine Hospital, Ningdu 342800, China
| | - Moujian Wu
- Department of Orthopedics, Xingguo County Traditional Chinese Medicine Hospital, Xingguo 342400, China
| |
Collapse
|
|
10
|
Li A, Yan J, Zhao Y, Yu Z, Tian S, Khan AH, Zhu Y, Wu A, Zhang C, Tian XL. Vascular Aging: Assessment and Intervention. Clin Interv Aging 2023; 18:1373-1395. [PMID: 37609042 PMCID: PMC10441648 DOI: 10.2147/cia.s423373] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 08/06/2023] [Indexed: 08/24/2023] Open
Abstract
Vascular aging represents a collection of structural and functional changes in a blood vessel with advancing age, including increased stiffness, vascular wall remodeling, loss of angiogenic ability, and endothelium-dependent vasodilation dysfunction. These age-related alterations may occur earlier in those who are at risk for or have cardiovascular diseases, therefore, are defined as early or premature vascular aging. Vascular aging contributes independently to cardio-cerebral vascular diseases (CCVDs). Thus, early diagnosis and interventions targeting vascular aging are of paramount importance in the delay or prevention of CCVDs. Here, we review the direct assessment of vascular aging by examining parameters that reflect changes in structure, function, or their compliance with age including arterial wall thickness and lumen diameter, endothelium-dependent vasodilation, arterial stiffness as well as indirect assessment through pathological studies of biomarkers including endothelial progenitor cell, lymphocytic telomeres, advanced glycation end-products, and C-reactive protein. Further, we evaluate how different types of interventions including lifestyle mediation, such as caloric restriction and salt intake, and treatments for hypertension, diabetes, and hyperlipidemia affect age-related vascular changes. As a single parameter or intervention targets only a certain vascular physiological change, it is recommended to use multiple parameters to evaluate and design intervention approaches accordingly to prevent systemic vascular aging in clinical practices or population-based studies.
Collapse
Affiliation(s)
- Ao Li
- Queen Mary School, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Jinhua Yan
- Department of Geriatrics, Institute of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Ya Zhao
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Zhenping Yu
- Institute of Translational Medicine, School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Shane Tian
- Department of Biochemistry/Chemistry, Ohio State University, Columbus, OH, USA
| | - Abdul Haseeb Khan
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Yuanzheng Zhu
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Andong Wu
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Cuntai Zhang
- Department of Geriatrics, Institute of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Xiao-Li Tian
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, Jiangxi, 330031, People’s Republic of China
| |
Collapse
|
|
11
|
Ragazzi E, Burlina S, Cosma C, Chilelli NC, Lapolla A, Sartore G. Anti-diabetic combination therapy with pioglitazone or glimepiride added to metformin on the AGE-RAGE axis: a randomized prospective study. Front Endocrinol (Lausanne) 2023; 14:1163554. [PMID: 37635976 PMCID: PMC10453795 DOI: 10.3389/fendo.2023.1163554] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 07/26/2023] [Indexed: 08/29/2023] Open
Abstract
Introduction The ratio between advanced glycation end products (AGEs) and soluble form of receptor (s-RAGE) has been proposed as a risk marker for renal and cardiovascular diseases. The aim of this study was to evaluate in the diabetes condition the influence of two different oral anti-diabetic treatments on the AGE/s-RAGE ratio, during a 5-year observation period. Methods Seventy-three patients with type 2 diabetes mellitus were randomly assigned to a drug therapy with pioglitazone or glimepiride, combined to metformin. Each subject was evaluated at baseline and after 5 years of treatment. Results In both groups s-RAGE levels did not significantly vary, while the levels of AGE and AGE/s-RAGE were both significantly reduced, basal compared to 5-year values. Within pioglitazone group, as well within glimepiride group, significant variations (Δ, as difference between 5 years of treatment minus basal) were observed for AGE (Δ= -21.1±13.4 µg/ml, P<0.001 for pioglitazone; Δ= -14.4±11.4 µg/ml, P<0.001 for glimepiride) and in AGE/s-RAGE (Δ= -0.037±0.022 µg/pg, P<0.001 for pioglitazone; Δ= -0.024±0.020µg/pg, P<0.001 for glimepiride), suggesting an average decrease of the parameters by more than 50% in both treatments. Pioglitazone was more effective than glimepiride in reducing AGE/s-RAGE ratio after 5 years of therapy. Conclusion These data can help to explain the benefits of oral anti-diabetic therapy in relation to the reduction of cardiovascular risk, as suggested by variations in AGE/s-RAGE ratio as biochemical marker of endothelial function; in particular, treatment with pioglitazone seems to offer greater long-term benefit on AGE-RAGE axis.
Collapse
Affiliation(s)
- Eugenio Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Silvia Burlina
- Department of Medicine – DIMED, University of Padova, Padova, Italy
| | - Chiara Cosma
- Department of Medicine – DIMED, University of Padova, Padova, Italy
| | | | | | - Giovanni Sartore
- Department of Medicine – DIMED, University of Padova, Padova, Italy
| |
Collapse
|
|
12
|
Garza-Campos A, Prieto-Correa JR, Domínguez-Rosales JA, Hernández-Nazará ZH. Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer. World J Diabetes 2023; 14:977-994. [PMID: 37547586 PMCID: PMC10401444 DOI: 10.4239/wjd.v14.i7.977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/31/2023] [Accepted: 04/17/2023] [Indexed: 07/12/2023] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are chronic pathologies with a high incidence worldwide. They share some pathological mechanisms, including hyperinsulinemia, the production and release of hormones, and hyperglycemia. The above, over time, affects other systems of the human body by causing tissue hypoxia, low-grade inflammation, and oxidative stress, which lay the pathophysiological groundwork for cancer. The leading causes of death globally are T2DM and cancer. Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death (i.e., damage-associated molecular patterns) such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products (RAGE) - a multiligand receptor involved in inflammatory and metabolic and neoplastic processes. This review analyzes the latest advanced reports on the role of RAGE in the development of obesity, T2DM, and cancer, with an aim to understand the intracellular signaling mechanisms linked with cancer initiation. This review also explores inflammation, oxidative stress, hypoxia, cellular senescence, RAGE ligands, tumor microenvironment changes, and the “cancer hallmarks” of the leading tumors associated with T2DM. The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.
Collapse
Affiliation(s)
- Andrea Garza-Campos
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Roberto Prieto-Correa
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Alfredo Domínguez-Rosales
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Zamira Helena Hernández-Nazará
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| |
Collapse
|
|
13
|
Gkavogiannakis NA, Tsoporis JN, Drosatos IA, Tsirebolos G, Izhar S, Sakadakis E, Triantafyllis AS, Parker TG, Kalogiros LA, Leong-Poi H, Rallidis LS, Rizos I. Emergent Inflammatory Markers and Echocardiographic Indices in Patients with Bronchial Asthma. Biomolecules 2023; 13:955. [PMID: 37371535 DOI: 10.3390/biom13060955] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 05/31/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Asthma is a heterogeneous disease, characterized by chronic inflammation and oxidative stress of the airways. Several inflammatory pathways including activation of the receptor for advanced glycation end products (RAGE) have been described in the course of the disease. DJ-1 is a redox-sensitive protein with multifaceted roles in mast cell homeostasis and an emerging role in the pathogenesis of asthma. Moreover, cardiac function abnormalities have been described via echocardiography in patients with asthma. The main aim of this study was to investigate the plasma levels of RAGE, its ligands and DJ-1 in asthmatic patients pre- and post-treatment along with echocardiographic indices of cardiovascular function. The study population was divided into two groups. Group A included 13 patients with newly diagnosed bronchial asthma who were free of treatment for at least two weeks and Group B included 12 patients without asthma. An echocardiography examination was performed on all patients. The plasma levels of RAGE, its ligands (AGEs, S100A12, S100B, S100A8/A9), the interleukins (IL-6, IL-1β) and DJ-1 were measured. No differences were noted among the two groups for baseline characteristics and echocardiographic indices of cardiac function. In Group A, 31% suffered from mild asthma, 54% from moderate asthma and 15% from severe asthma. Plasma levels of IL-6, AGEs and AGE/RAGE ratio were increased and those of S100A12 and DJ-1 were decreased in asthmatics. Pharmacotherapy with corticosteroids/β2-agonists decreased IL-6, and AGEs, and increased DJ-1. In search of novel approaches in diagnosing and treating patients with asthma, S100A12, ratio AGE/sRAGE, and DJ-1 in addition to IL-6 may prove to be useful tools.
Collapse
Affiliation(s)
- Nikolaos A Gkavogiannakis
- Allergy Unit "D. Kalogeromitros", Attikon University Hospital, 124 62 Athens, Greece
- Allergy & Clinical Immunology Department, 401 General Military Hospital of Athens, 115 27 Athens, Greece
| | - James N Tsoporis
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada
| | - Ioannis-Alexandros Drosatos
- Second Department of Cardiology, Attikon University Hospital, 124 62 Athens, Greece
- Department of Cardiology, 414 Military Hospital, P. Penteli, 152 36 Athens, Greece
| | - George Tsirebolos
- Second Department of Cardiology, Attikon University Hospital, 124 62 Athens, Greece
- Department of Cardiology, 401 General Military Hospital of Athens, 115 27 Athens, Greece
| | - Shehla Izhar
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada
| | | | | | - Thomas G Parker
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada
| | - Lampros A Kalogiros
- Allergy & Clinical Immunology Department, 401 General Military Hospital of Athens, 115 27 Athens, Greece
| | - Howard Leong-Poi
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada
| | - Loukianos S Rallidis
- Second Department of Cardiology, Attikon University Hospital, 124 62 Athens, Greece
| | - Ioannis Rizos
- Second Department of Cardiology, Attikon University Hospital, 124 62 Athens, Greece
| |
Collapse
|
|
14
|
Csiha S, Molnár I, Halmi S, Hutkai D, Lőrincz H, Somodi S, Katkó M, Harangi M, Paragh G, Nagy EV, Berta E, Bodor M. Advanced glycation end products and their soluble receptor (sRAGE) in patients with Hashimoto's thyroiditis on levothyroxine substitution. Front Endocrinol (Lausanne) 2023; 14:1187725. [PMID: 37305044 PMCID: PMC10250717 DOI: 10.3389/fendo.2023.1187725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 05/09/2023] [Indexed: 06/13/2023] Open
Abstract
Background Advanced glycation end products (AGEs) are heterogenous group of irreversible chemical moieties originated from non-enzymatic glycation and oxidation of proteins, nucleic acids, and lipids. The engagement of AGEs with their chief cellular receptor (RAGE) activates a myriad of signaling pathways contributing to the progression of chronic diseases like autoimmune thyroiditis, type 2 diabetes mellitus and its complications. Soluble RAGE (sRAGE) prevents AGE-RAGE interaction in a competitive manner. Objective We investigated the association between serum AGE, sRAGE and thyroid function in 73 Hashimoto thyroiditis patients (HT) on levothyroxine substitution, and in 83 age, BMI and gender-matched healthy controls. Methods The serum AGEs levels were determined by autofluorescence on a multi-mode microplate reader, and the serum sRAGE levels by ELISA method. Results Mean AGE level was lower (10.71 vs 11.45 AU/µg protein; p=0.046), while mean sRAGE level was higher (923 vs 755 pg/mL; p<0.0005) in the serum of HT patients than the controls. AGE correlated with age, while sRAGE correlated negatively with BMI in both groups. We found negative correlation between AGE and fT3 levels (r=-0.32; p=0.006) and sRAGE and TSH levels (r=-0.27; p=0.022) in HT patients, while we failed to find association between AGE, sRAGE and parameters of thyroid function in the control group. Median AGE/sRAGE ratio was lower in HT patients than in controls (2.4, IQR 1.9 - 3.1 vs 3.3, IQR 2.3 - 4.1 AU/pg; p < 0.001). In HT patients, the AGE/sRAGE ratio correlated positively with BMI and correlated negatively with fT3. Conclusion According to our results in HT patients lower TSH and higher fT3 levels within the reference range is accompanied by a favorable AGE/RAGE balance. Further investigations are needed to confirm these results.
Collapse
Affiliation(s)
- Sára Csiha
- Division of Endocrinology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Department of Clinical Basics, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
- Doctoral School of Health Sciences, University of Debrecen, Debrecen, Hungary
| | - István Molnár
- Department of Clinical Basics, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
- Doctoral School of Health Sciences, University of Debrecen, Debrecen, Hungary
- Division of Metabolism, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Sándor Halmi
- Division of Endocrinology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Health Sciences, University of Debrecen, Debrecen, Hungary
| | - Dávid Hutkai
- Division of Nephrology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
| | - Hajnalka Lőrincz
- Division of Metabolism, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Sándor Somodi
- Division of Metabolism, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Department of Emergency Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Mónika Katkó
- Division of Endocrinology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Mariann Harangi
- Division of Metabolism, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Institute of Health Studies, Faculty of Health Sciences, University of Debrecen, Debrecen, Hungary
| | - György Paragh
- Division of Metabolism, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Endre V. Nagy
- Division of Endocrinology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Eszter Berta
- Department of Clinical Basics, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
- Division of Metabolism, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Miklós Bodor
- Division of Endocrinology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Department of Clinical Basics, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
| |
Collapse
|
|
15
|
Liu J, Jin Z, Wang X, Jakoš T, Zhu J, Yuan Y. RAGE pathways play an important role in regulation of organ fibrosis. Life Sci 2023; 323:121713. [PMID: 37088412 DOI: 10.1016/j.lfs.2023.121713] [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: 02/22/2023] [Revised: 04/09/2023] [Accepted: 04/18/2023] [Indexed: 04/25/2023]
Abstract
Organ fibrosis is a pathological process of fibroblast activation and excessive deposition of extracellular matrix after persistent tissue injury and therefore is a common endpoint of many organ pathologies. Multiple cellular types and soluble mediators, including chemokines, cytokines and non-peptidic factors, are implicated in fibrogenesis and the remodeling of tissue architecture. The molecular basis of the fibrotic process is complex and consists of closely intertwined signaling networks. Research has strived for a better understanding of these pathological mechanisms to potentially reveal novel therapeutic targets for fibrotic diseases. In light of new knowledge, the receptor for advanced glycation end products (RAGE) emerged as an important candidate for the regulation of a wide variety of cellular functions related to fibrosis, including inflammation, cell proliferation, apoptosis, and angiogenesis. RAGE is a pattern recognition receptor that binds a broad range of ligands such as advanced glycation end products, high mobility group box-1, S-100 calcium-binding protein and amyloid beta protein. Although the link between RAGE and fibrosis has been established, the exact mechanisms need be investigated in further studies. The aim of this review is to collect all available information about the intricate function of RAGE and its signaling cascades in the pathogenesis of fibrotic diseases within different organs. In addition, to the major ligands and signaling pathways, we discuss potential strategies for targeting RAGE in fibrosis. We emphasize the functional links between RAGE, inflammation and fibrosis that may guide further studies and the development of improved therapeutic drugs.
Collapse
Affiliation(s)
- Jing Liu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University School of Pharmacy, Shanghai 201100, China.
| | - Zhedong Jin
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University School of Pharmacy, Shanghai 201100, China.
| | - Xiaolong Wang
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University School of Pharmacy, Shanghai 201100, China.
| | - Tanja Jakoš
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University School of Pharmacy, Shanghai 201100, China.
| | - Jianwei Zhu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University School of Pharmacy, Shanghai 201100, China.
| | - Yunsheng Yuan
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University School of Pharmacy, Shanghai 201100, China.
| |
Collapse
|
|
16
|
Robles-Rivera K, Rivera-Paredez B, Quezada-Sanchéz AD, Velázquez-Cruz R, Salmerón J. Advanced glycation end products are associated with cardiovascular risk in the Mexican population. Nutr Metab Cardiovasc Dis 2023; 33:826-834. [PMID: 36842957 DOI: 10.1016/j.numecd.2022.12.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 12/07/2022] [Accepted: 12/29/2022] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIMS Chronic exposure to hyperglycemia is a significant risk factor for cardiovascular disease (CVD). Advanced glycation end products (AGES) result from multiple sugar-dependent reactions interacting with proteins and their receptors, generating endothelial dysfunction and CVD. However, there is little epidemiological data about its impact on CVD risk. We aimed to assess the association between circulating AGES and CVD risk in the Mexican population. METHODS AND RESULTS We used longitudinal data from waves 2004-2006 and 2010-2012 of 1195 participants from the Health Workers Cohort Study. Circulating AGES were assessed by radioimmunoassay, and cardiovascular risk (CVR) was computed with the Framingham risk score. Linear and logistic fixed-effects regression models were used to assess the interest association, adjusting for confounding factors. An increase in 200 μU/ml of AGES was associated with a 0.18% increased risk of CVD (95% CI 0.05-0.31%). After adjusting for physical activity and smoking status, individuals who increased their AGES category had higher odds of middle-high CVR (low to medium AGES: OR 1.83, 95% CI 1.11-3.20; low to high AGES: OR 2.61, 95% CI 1.51-4.50). The associations remained statistically significant when we further adjusted for insulin resistance, dietary intake of AGES, and total daily calorie intake. CONCLUSION Our data show that circulating AGES are associated with the Framingham CVD risk score, independently of other major risk factors for CVD in the Mexican population.
Collapse
Affiliation(s)
- Karina Robles-Rivera
- Research Center in Policy, Population, and Health, School of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.
| | - Berenice Rivera-Paredez
- Research Center in Policy, Population, and Health, School of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.
| | - Amado D Quezada-Sanchéz
- Center for Evaluation and Surveys Research, National Institute of Public Health, Cuernavaca 62100, Mexico.
| | - Rafael Velázquez-Cruz
- Genomics of Bone Metabolism Laboratory, National Institute of Genomic Medicine (INMEGEN), Mexico City 14610, Mexico.
| | - Jorge Salmerón
- Research Center in Policy, Population, and Health, School of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico.
| |
Collapse
|
|
17
|
Tsirebolos G, Tsoporis JN, Drosatos IA, Izhar S, Gkavogiannakis N, Sakadakis E, Triantafyllis AS, Parker TG, Rallidis LS, Rizos I. Emerging markers of inflammation and oxidative stress as potential predictors of coronary artery disease. Int J Cardiol 2023; 376:127-133. [PMID: 36758863 DOI: 10.1016/j.ijcard.2023.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/20/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023]
Abstract
BACKGROUND AND AIMS The multi-ligand receptor for advanced glycation end products (RAGE) and its ligands AGEs and S100/calgranulin proteins are important mediators of inflammation and oxidative stress whereas the soluble form of RAGE (sRAGE) by acting as a decoy and the antioxidant PARK7/DJ-1 exert antiatherogenic effects. We examined whether sRAGE and its ligands AGEs, S100A8/A9, S100B, S100A12 and DJ-1 are associated with the presence of angiographic coronary artery disease (CAD) in asymptomatic patients with and without diabetes. METHODS AND RESULTS Plasma levels of RAGE ligands, sRAGE and DJ-1 were determined in 50 patients with angiographically proven CAD and in 50 age-matched healthy controls. In the whole cohort, lower levels of sRAGE and higher levels of interleukin-6 (IL-6), the RAGE ligands S100B, S100A12 and the AGEs/sRAGE ratio were associated with CAD. In patients without diabetes (n = 72), lower levels of sRAGE and DJ-1 and higher levels of IL-6 and AGEs/sRAGE ratio were associated with CAD. In multivariable analysis, AGEs/sRAGE ratio was an independent predictor of CAD both in the whole cohort (p = 0.034, OR = 1.247, [95%CI: 1.024, 1.0519]) and in the subgroup of patients without diabetes (p = 0.021, OR = 1.363, 95%CI [1.048, 1.771]) on top of established cardiovascular risk factors. CONCLUSION Alterations in plasma RAGE axis inflammatory mediators are associated with atherosclerosis, and higher levels of AGEs/sRAGE ratio are independently associated with CAD in asymptomatic patients and may act as a novel biomarker for predicting CAD. DJ-1 emerges as promising marker of oxidative stress in CAD patients without diabetes, a finding that deserves further study.
Collapse
Affiliation(s)
- George Tsirebolos
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece; Department of Cardiology, 401 General Military Hospital of Athens, Athens, Greece
| | - James N Tsoporis
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Ontario, Canada.
| | - Ioannis-Alexandros Drosatos
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece; Department of Cardiology, 414 Military Hospital, P.Penteli, Athens, Greece
| | - Shehla Izhar
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Ontario, Canada
| | - Nikolaos Gkavogiannakis
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece; Department of Cardiology, 401 General Military Hospital of Athens, Athens, Greece
| | | | | | - Thomas G Parker
- Department of Cardiology, 414 Military Hospital, P.Penteli, Athens, Greece
| | | | - Ioannis Rizos
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece
| |
Collapse
|
|
18
|
Martín-Carro B, Martín-Vírgala J, Fernández-Villabrille S, Fernández-Fernández A, Pérez-Basterrechea M, Navarro-González JF, Donate-Correa J, Mora-Fernández C, Dusso AS, Carrillo-López N, Panizo S, Naves-Díaz M, Fernández-Martín JL, Cannata-Andía JB, Alonso-Montes C. Role of Klotho and AGE/RAGE-Wnt/β-Catenin Signalling Pathway on the Development of Cardiac and Renal Fibrosis in Diabetes. Int J Mol Sci 2023; 24:5241. [PMID: 36982322 PMCID: PMC10049403 DOI: 10.3390/ijms24065241] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/03/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Fibrosis plays an important role in the pathogenesis of long-term diabetic complications and contributes to the development of cardiac and renal dysfunction. The aim of this experimental study, performed in a long-term rat model, which resembles type 1 diabetes mellitus, was to investigate the role of soluble Klotho (sKlotho), advanced glycation end products (AGEs)/receptor for AGEs (RAGE), fibrotic Wnt/β-catenin pathway, and pro-fibrotic pathways in kidney and heart. Diabetes was induced by streptozotocin. Glycaemia was maintained by insulin administration for 24 weeks. Serum and urine sKlotho, AGEs, soluble RAGE (sRAGE) and biochemical markers were studied. The levels of Klotho, RAGEs, ADAM10, markers of fibrosis (collagen deposition, fibronectin, TGF-β1, and Wnt/β-catenin pathway), hypertrophy of the kidney and/or heart were analysed. At the end of study, diabetic rats showed higher levels of urinary sKlotho, AGEs and sRAGE and lower serum sKlotho compared with controls without differences in the renal Klotho expression. A significant positive correlation was found between urinary sKlotho and AGEs and urinary albumin/creatinine ratio (uACR). Fibrosis and RAGE levels were significantly higher in the heart without differences in the kidney of diabetic rats compared to controls. The results also suggest the increase in sKlotho and sRAGE excretion may be due to polyuria in the diabetic rats.
Collapse
Affiliation(s)
- Beatriz Martín-Carro
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Julia Martín-Vírgala
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Sara Fernández-Villabrille
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | | | - Marcos Pérez-Basterrechea
- Unit of Cell Therapy and Regenerative Medicine, Hematology and Hemotherapy Service, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Juan F. Navarro-González
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Research Unit, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- Nephrology Service, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Javier Donate-Correa
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Research Unit, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Carmen Mora-Fernández
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Research Unit, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Adriana S. Dusso
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Natalia Carrillo-López
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Sara Panizo
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Manuel Naves-Díaz
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José L. Fernández-Martín
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jorge B. Cannata-Andía
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Medicine, Universidad de Oviedo, 33006 Oviedo, Spain
| | - Cristina Alonso-Montes
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Psychobiology, Universidad de Oviedo, 33003 Oviedo, Spain
| |
Collapse
|
|
19
|
The Patient's Physiological Status at the Start Determines the Success of the Inpatient Cardiovascular Rehabilitation Program. J Clin Med 2023; 12:jcm12051735. [PMID: 36902521 PMCID: PMC10003145 DOI: 10.3390/jcm12051735] [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: 01/19/2023] [Revised: 02/11/2023] [Accepted: 02/13/2023] [Indexed: 02/24/2023] Open
Abstract
Multidisciplinary inpatient rehabilitation plays an important role in the recovery of patients with cardiovascular diseases (CVDs). Lifestyle changes, achieved by exercise, diet, weight loss and patient education programs, are the first steps to a healthier life. Advanced glycation end products (AGEs) and their receptor (RAGE) are known to be involved in CVDs. Clarification on whether initial AGE levels can influence the rehabilitation outcome is important. Serum samples were collected at the beginning and end of the inpatient rehabilitation stay and analyzed for parameters: lipid metabolism, glucose status, oxidative stress, inflammation and AGE/RAGE-axis. As result, a 5% increase in the soluble isoform RAGE (sRAGE) (T0: 891.82 ± 44.97 pg/mL, T1: 937.17 ± 43.29 pg/mL) accompanied by a 7% decrease in AGEs (T0: 10.93 ± 0.65 µg/mL, T1: 10.21 ± 0.61 µg/mL) was shown. Depending on the initial AGE level, a significant reduction of 12.2% of the AGE activity (quotient AGE/sRAGE) was observed. We found that almost all measured factors improved. Summarizing, CVD-specific multidisciplinary rehabilitation positively influences disease-associated parameters, and thus provides an optimal starting point for subsequent disease-modifying lifestyle changes. Considering our observations, the initial physiological situations of patients at the beginning of their rehabilitation stay seem to play a decisive role regarding the assessment of rehabilitation success.
Collapse
|
|
20
|
Roguljić M, Vučković M, Gelemanović A, Kovačević K, Orešković J, Radić M, Božić D, Radić J. Risk factors of severe periodontitis in kidney transplant recipients: A case-control study. J Periodontol 2023. [PMID: 36700464 DOI: 10.1002/jper.22-0351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 09/23/2022] [Accepted: 01/12/2023] [Indexed: 01/27/2023]
Abstract
BACKGROUND Kidney transplant recipients (KTRs) represent a vulnerable group of patients who develop a number of comorbidities. Severe periodontitis (SP) is associated with the most common chronic systemic diseases including kidney diseases. The objective of this study was to explore the risk factors for SP in KTRs. METHODS In this study, KTRs were divided into those with or without periodontitis and in relation to the severity of periodontitis. A comprehensive medical and periodontal examination was performed and evaluated. Multivariate logistic regression was performed to examine possible risk factors for SP among KTRs. RESULTS A total of 100 KTRs were included in the analysis, of which 87% had periodontitis. Significant predictors of periodontitis were older age (OR = 1.07, 95% CI [1.01, 1.13], p = 0.016) and lower skeletal muscle mass (OR = 0.88, 95% CI [0.78, 0.99], p = 0.035). When examining periodontitis severity, predictors of SP (n = 21, 24%) were increased levels of uric acid (OR = 1.01, 95% CI [1.00, 1.02], p = 0.022) and dental plaque (OR = 1.04, 95% CI [1.01, 1.07], p = 0.013). In the subset analysis that included only KTRs with measured advanced glycation end products (AGE) (n = 47), 34% (n = 16) had SP. The predictors of SP were AGE (OR = 3.89, 95% CI [1.28, 11.82], p = 0.017) and dental plaque (OR = 1.07, 95% CI [1.01, 1.13], p = 0.028). CONCLUSIONS KTRs with SP had significantly higher uric acid levels and AGE, which may contribute to the systemic health status of this patient population.
Collapse
Affiliation(s)
- Marija Roguljić
- Department of Oral Medicine and Periodontology, School of Medicine, University of Split, Split, Croatia.,Department of Dental Medicine, University Hospital Centre Split, Split, Croatia
| | - Marijana Vučković
- Department of Nephrology and Dialysis, University Hospital Centre Split, Split, Croatia
| | | | | | | | - Mislav Radić
- Department of Clinical Immunology and Rheumatology, University Hospital Centre Split, Split, Croatia.,Department of Internal Medicine, University of Split, School of Medicine, Split, Croatia
| | - Darko Božić
- Department of Periodontology, School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Josipa Radić
- Department of Nephrology and Dialysis, University Hospital Centre Split, Split, Croatia.,Department of Internal Medicine, University of Split, School of Medicine, Split, Croatia
| |
Collapse
|
|
21
|
The Role of Advanced Glycation End Products on Dyslipidemia. Metabolites 2023; 13:metabo13010077. [PMID: 36677002 PMCID: PMC9862879 DOI: 10.3390/metabo13010077] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/28/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023] Open
Abstract
Disorders of lipoprotein metabolism and glucose homeostasis are common consequences of insulin resistance and usually co-segregate in patients with metabolic syndrome and type 2 diabetes mellitus (DM). Insulin-resistant subjects are characterized by atherogenic dyslipidemia, a specific lipid pattern which includes hypertriglyceridemia, reduced high-density lipoprotein cholesterol level, and increased proportion of small, dense low-density lipoprotein (LDL). Chronic hyperglycemia favors the processes of non-enzymatic glycation, leading to the increased production of advanced glycation end products (AGEs). Apart from direct harmful effects, AGEs are also potent inducers of oxidative stress and inflammation. In addition, increased AGEs' production may induce further qualitative modifications of small, dense LDL particles, converting them to glycated LDLs. These particles are even more atherogenic and may confer an increased cardiovascular risk. In this narrative review, we summarize the available evidence of the pathophysiological role and clinical importance of circulating AGEs and glycated LDLs in patients with dyslipidemia, particularly those with DM and related complications. In addition, we discuss recent advances and the issues that should be improved regarding laboratory assessment of AGEs and glycated LDLs, as well as the possibilities for their therapeutic modulation.
Collapse
|
|
22
|
Ailioaie LM, Ailioaie C, Litscher G. Biomarkers in Systemic Juvenile Idiopathic Arthritis, Macrophage Activation Syndrome and Their Importance in COVID Era. Int J Mol Sci 2022; 23:12757. [PMID: 36361547 PMCID: PMC9655921 DOI: 10.3390/ijms232112757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 08/30/2023] Open
Abstract
Systemic juvenile idiopathic arthritis (sJIA) and its complication, macrophage activation syndrome (sJIA-MAS), are rare but sometimes very serious or even critical diseases of childhood that can occasionally be characterized by nonspecific clinical signs and symptoms at onset-such as non-remitting high fever, headache, rash, or arthralgia-and are biologically accompanied by an increase in acute-phase reactants. For a correct positive diagnosis, it is necessary to rule out bacterial or viral infections, neoplasia, and other immune-mediated inflammatory diseases. Delays in diagnosis will result in late initiation of targeted therapy. A set of biomarkers is useful to distinguish sJIA or sJIA-MAS from similar clinical entities, especially when arthritis is absent. Biomarkers should be accessible to many patients, with convenient production and acquisition prices for pediatric medical laboratories, as well as being easy to determine, having high sensitivity and specificity, and correlating with pathophysiological disease pathways. The aim of this review was to identify the newest and most powerful biomarkers and their synergistic interaction for easy and accurate recognition of sJIA and sJIA-MAS, so as to immediately guide clinicians in correct diagnosis and in predicting disease outcomes, the response to treatment, and the risk of relapses. Biomarkers constitute an exciting field of research, especially due to the heterogeneous nature of cytokine storm syndromes (CSSs) in the COVID era. They must be selected with utmost care-a fact supported by the increasingly improved genetic and pathophysiological comprehension of sJIA, but also of CSS-so that new classification systems may soon be developed to define homogeneous groups of patients, although each with a distinct disease.
Collapse
Affiliation(s)
- Laura Marinela Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania
| | - Constantin Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania
| | - Gerhard Litscher
- Research Unit of Biomedical Engineering in Anesthesia and Intensive Care Medicine, Research Unit for Complementary and Integrative Laser Medicine, Traditional Chinese Medicine (TCM) Research Center Graz, Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 39, 8036 Graz, Austria
| |
Collapse
|
|
23
|
Ragavi R, Adole PS, Vinod KV, Pillai AA. Altered expression of a disintegrin and metalloproteinase 10 in peripheral blood mononuclear cells in type 2 diabetes mellitus patients with the acute coronary syndrome: a pilot study. Endocrine 2022; 77:461-468. [PMID: 35877008 DOI: 10.1007/s12020-022-03141-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 07/11/2022] [Indexed: 11/26/2022]
Abstract
PURPOSE Advanced glycation end products (AGEs) are responsible for the complications in type 2 diabetes mellitus (T2DM) patients by acting via its receptor (RAGE). The soluble form of RAGE (sRAGE) prevents the harmful effects of AGE-RAGE signalling. The sRAGE is produced either by alternate splicing (esRAGE) or proteolytic RAGE cleavage by a disintegrin and metalloproteinase 10 (ADAM10). Hence, the study aimed to compare the expression of ADAM10 in peripheral blood mononuclear cell (PBMC), serum sRAGE and esRAGE levels in T2DM patients with and without acute coronary syndrome (ACS). METHODS Forty-five T2DM patients with ACS and 45 age, gender and duration of DM-matched T2DM patients without ACS were recruited. Serum sRAGE and esRAGE levels were measured by enzyme-linked immunosorbent assay. The expression of ADAM10 in PBMC was determined by quantitative reverse transcription-polymerase chain reaction. RESULTS The expression of ADAM10 in PBMC and serum sRAGE levels were significantly lower in T2DM patients with ACS than in T2DM patients without ACS (p < 0.001). Serum sRAGE levels and expression of ADAM10 in PBMC were positively correlated with each other and negatively correlated with markers of cardiac injury and glycaemic status (p < 0.05). Simple logistic regression showed that the models containing the expression of ADAM10 and serum sRAGE level could predict the ACS risk among T2DM patients. ROC analysis showed that both might be used for ACS diagnosis in T2DM patients. CONCLUSION Reduced expression of ADAM10 in PBMC might be responsible for lower serum sRAGE levels, predisposing T2DM patients to high ACS risk.
Collapse
Affiliation(s)
- Ravindran Ragavi
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, 605006, India
| | - Prashant Shankarrao Adole
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, 605006, India.
| | - Kolar Vishwanath Vinod
- Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, 605006, India
| | - Ajith Ananthakrishna Pillai
- Department of Cardiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, 605006, India
| |
Collapse
|
|
24
|
Wu HP, Chuang LP, Liu PH, Chu CM, Yu CC, Lin SW, Kao KC, Li LF, Chuang DY. Decreased Monocyte HLA-DR Expression in Patients with Sepsis and Acute Kidney Injury. Medicina (B Aires) 2022; 58:medicina58091198. [PMID: 36143874 PMCID: PMC9506340 DOI: 10.3390/medicina58091198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
Background and objectives: Acute kidney injury (AKI) is common in critically ill patients, especially those with sepsis. Persistently low human leukocyte antigen (HLA)-DR expression in monocytes reflects the decreased function of antigen-presenting cells, contributing to poor outcomes in sepsis. This study aimed to establish an association between AKI and HLA-DR expression in monocytes of patients with sepsis. Materials and Methods: We detected HLA-DR expression in monocytes and measured plasma levels of S100A12, high-mobility group box 1 (HMGB1), advanced glycation end products (AGE), and soluble receptor for AGE (sRAGE) from septic patients and healthy controls. Results: HLA-DR expression in monocytes was decreased in patients with AKI than in those without AKI (29.8 ± 5.0% vs. 53.1 ± 5.8%, p = 0.005). Compared with AKI patients, the mean monocyte HLA-DR expression in patients with end-stage renal disease was increased without statistical significance. There were no differences in the AGE/sRAGE ratio and plasma levels of S100A12, HMGB1, AGE, and sRAGE between patients with and without AKI. Conclusions: Compared with septic patients without AKI, patients with AKI had significantly lower HLA-DR expression in monocytes. The role of hemodialysis in monocyte HLA-DR expression needs further studies to explore.
Collapse
Affiliation(s)
- Huang-Pin Wu
- Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Li-Pang Chuang
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Pulmonary and Critical Care Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Pi-Hua Liu
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Chien-Ming Chu
- Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Chung-Chieh Yu
- Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Shih-Wei Lin
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Pulmonary and Critical Care Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Kuo-Chin Kao
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Pulmonary and Critical Care Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Li-Fu Li
- Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Duen-Yau Chuang
- Department of Chemistry, National Chung-Hsing University, Taichung 40227, Taiwan
- Correspondence: ; Tel.: +886-4-22840411 (ext. 817); Fax: +886-4-22862547
| |
Collapse
|
|
25
|
Lee J, Yun JS, Ko SH. Advanced Glycation End Products and Their Effect on Vascular Complications in Type 2 Diabetes Mellitus. Nutrients 2022; 14:3086. [PMID: 35956261 PMCID: PMC9370094 DOI: 10.3390/nu14153086] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/22/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetes is well established as a chronic disease with a high health burden due to mortality or morbidity from the final outcomes of vascular complications. An increased duration of hyperglycemia is associated with abnormal metabolism. Advanced glycation end products (AGEs) are nonenzymatic glycated forms of free amino acids that lead to abnormal crosslinking of extra-cellular and intracellular proteins by disrupting the normal structure. Furthermore, the interaction of AGEs and their receptors induces several pathways by promoting oxidative stress and inflammation. In this review, we discuss the role of AGEs in diabetic vascular complications, especially type 2 DM, based on recent clinical studies.
Collapse
Affiliation(s)
- Jeongmin Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03391, Korea;
| | - Jae-Seung Yun
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Korea;
| | - Seung-Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Korea;
| |
Collapse
|
|
26
|
Prasad K, Khan AS, Bhanumathy KK. Does AGE-RAGE Stress Play a Role in the Development of Coronary Artery Disease in Obesity? Int J Angiol 2022; 31:1-9. [PMID: 35221846 PMCID: PMC8881108 DOI: 10.1055/s-0042-1742587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
This article deals with the role of AGE (advanced glycation end products)-RAGE (receptor for AGE) stress (AGE/sRAGE) in the development of coronary artery disease (CAD) in obesity. CAD is due to atherosclerosis in coronary artery. The serum/plasma levels of AGE and sRAGE are reduced, while AGE-RAGE stress and expression of RAGE are elevated in obese individuals. However, the levels of AGE are elevated in obese individuals with more than one metabolic syndrome. The increases in the AGE-RAGE stress would elevate the expression and production of atherogenic factors, including reactive oxygen species, nuclear factor-kappa B, cytokines, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecules, monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and growth factors. Low levels of sRAGE would also increase the atherogenic factors. The increases in the AGE-RAGE stress and decreases in the levels of sRAGE would induce development of atherosclerosis, leading to CAD. The therapeutic regimen for AGE-RAGE stress-induced CAD in obesity would include lowering of AGE intake, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of AGE-RAGE interaction, downregulation of sRAGE expression, and use of antioxidants. In conclusion, the data suggest that AGE-RAGE stress is involved in the development of CAD in obesity, and the therapeutic interventions to reduce AGE-RAGE would be helpful in preventing, regressing, and slowing the progression of CAD in obesity.
Collapse
Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada,Address for correspondence Kailash Prasad, MBBS, MD, PhD, DSc Department of Physiology (APP), College of Medicine, University of Saskatoon107 Wiggins Road, Saskatoon, SK, S7N 5E5Canada
| | - Amal S. Khan
- Community, Health and Epidemiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Kalpana K. Bhanumathy
- Division of Oncology, Cancer Cluster Unit, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| |
Collapse
|
|
27
|
Kim KS, Lee YJ, Ahn S, Chang YS, Choi Y, Lee HJ. Association between soluble forms of the receptor for advanced glycation end products and periodontal disease: a retrospective study. J Korean Assoc Oral Maxillofac Surg 2021; 47:445-453. [PMID: 34969018 PMCID: PMC8721412 DOI: 10.5125/jkaoms.2021.47.6.445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/18/2021] [Accepted: 11/24/2021] [Indexed: 11/10/2022] Open
Abstract
Objectives Periodontitis is the most common chronic disease that causes tooth loss and is related to systemic diseases such as cardiovascular disease and diabetes. An objective indicator of the current activity of periodontitis is necessary. Soluble forms of the receptor for advanced glycation end products (sRAGE) are markers that reflect the status of inflammatory diseases. In this study, the relationship between sRAGE and periodontitis was analyzed to determine whether it can be used to diagnose the current state of periodontitis. Patients and Methods Eighty-four patients without any systemic diseases were diagnosed with periodontitis using three classifications of periodontitis. Demographics and oral examination data such as plaque index (PI), bleeding on probing (BOP) index, and probing pocket depth (PPD) were analyzed according to each classification. In addition, correlation and partial correlation between sRAGE and the values indicating periodontitis were analyzed. Results In each classification, the level of sRAGE tended to decrease if periodontitis was present or severe, but this change was not statistically significant. sRAGE and periodontitis-related variables exhibited a weak correlation, among which the BOP index showed a relatively strong negative correlation (ρ=–0.20). Based on this, on analyzing the correlation between the BOP index and sRAGE in the group with more severe periodontitis (PPD≥5 mm group, severe group of AAP/CDC [American Academy of Periodontology/Centers for Disease Control and Prevention], periodontitis group of López), the correlation further increased (ρ=–0.23, –0.40, –0.50). Partial correlation analysis of the sRAGE and BOP index showed a stronger negative correlation (ρ=–0.36, –0.55, –0.45). Conclusion sRAGE demonstrated a tendency to decrease upon increased severity of periodontitis according to the classifications used. Above all, the correlation with the BOP index, which reflects the current state of periodontitis, was higher in the group with severe periodontitis. This indicates that the current status of periodontitis can be diagnosed through sRAGE.
Collapse
Affiliation(s)
- Keun-Suh Kim
- Department of Periodontology, Section of Dentistry, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yun Jong Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Soyeon Ahn
- Division of Statistics, Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yoon-Seok Chang
- Division of Statistics, Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Korea.,Division of Allergy and Clinical Immunology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yonghoon Choi
- Department of Conservative Dentistry, Section of Dentistry, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyo-Jung Lee
- Department of Periodontology, Section of Dentistry, Seoul National University Bundang Hospital, Seongnam, Korea
| |
Collapse
|
|
28
|
Miyagawa T, Iwata Y, Oshima M, Ogura H, Sato K, Nakagawa S, Yamamura Y, Kamikawa Y, Miyake T, Kitajima S, Toyama T, Hara A, Sakai N, Shimizu M, Furuichi K, Munesue S, Yamamoto Y, Kaneko S, Wada T. Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury. Biol Open 2021; 11:273473. [PMID: 34812852 PMCID: PMC8822355 DOI: 10.1242/bio.058852] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 11/11/2021] [Indexed: 11/20/2022] Open
Abstract
The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.
Collapse
Affiliation(s)
- Taro Miyagawa
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Yasunori Iwata
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.,Division of Infection Control, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Megumi Oshima
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Hisayuki Ogura
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Koichi Sato
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Shiori Nakagawa
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Yuta Yamamura
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Yasutaka Kamikawa
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Taito Miyake
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Shinji Kitajima
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Tadashi Toyama
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Akinori Hara
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Norihiko Sakai
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.,Division of Blood Purification, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Miho Shimizu
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Kengo Furuichi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan
| | - Seiichi Munesue
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Shuichi Kaneko
- Department of System Biology, Institute of Medical Pharmaceutical and Health Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
| |
Collapse
|
|
29
|
Role of Advanced Glycation End-Products and Other Ligands for AGE Receptors in Thyroid Cancer Progression. J Clin Med 2021; 10:jcm10184084. [PMID: 34575195 PMCID: PMC8470575 DOI: 10.3390/jcm10184084] [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: 07/15/2021] [Revised: 08/30/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
To date, thyroid cancers (TCs) remain a clinical challenge owing to their heterogeneous nature. The etiopathology of TCs is associated not only with genetic mutations or chromosomal rearrangements, but also non-genetic factors, such as oxidative-, nitrosative-, and carbonyl stress-related alterations in tumor environment. These factors, through leading to the activation of intracellular signaling pathways, induce tumor tissue proliferation. Interestingly, the incidence of TCs is often coexistent with various simultaneous mutations. Advanced glycation end-products (AGEs), their precursors and receptors (RAGEs), and other ligands for RAGEs are reported to have significant influence on carcinogenesis and TCs progression, inducing gene mutations, disturbances in histone methylation, and disorders in important carcinogenesis-related pathways, such as PI3K/AKT/NF-kB, p21/MEK/MPAK, or JAK/STAT, RAS/ERK/p53, which induce synthesis of interleukins, growth factors, and cytokines, thus influencing metastasis, angiogenesis, and cancer proliferation. Precursors of AGE (such as methylglyoxal (MG)) and selected ligands for RAGEs: AS1004, AS1008, and HMGB1 may, in the future, become potential targets for TCs treatment, as low MG concentration is associated with less aggressive anaplastic thyroid cancer, whereas the administration of anti-RAGE antibodies inhibits the progression of papillary thyroid cancer and anaplastic thyroid cancer. This review is aimed at collecting the information on the role of compounds, engaged in glycation process, in the pathogenesis of TCs. Moreover, the utility of these compounds in the diagnosis and treatment of TCs is thoroughly discussed. Understanding the mechanism of action of these compounds on TCs pathogenesis and progression may potentially be the grounds for the development of new treatment strategies, aiming at quality-of-life improvements.
Collapse
|
|
30
|
Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors. Int J Mol Sci 2021; 22:ijms22136904. [PMID: 34199060 PMCID: PMC8268101 DOI: 10.3390/ijms22136904] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 12/16/2022] Open
Abstract
Receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin superfamily. RAGE binds and mediates cellular responses to a range of DAMPs (damage-associated molecular pattern molecules), such as AGEs, HMGB1, and S100/calgranulins, and as an innate immune sensor, can recognize microbial PAMPs (pathogen-associated molecular pattern molecules), including bacterial LPS, bacterial DNA, and viral and parasitic proteins. RAGE and its ligands stimulate the activations of diverse pathways, such as p38MAPK, ERK1/2, Cdc42/Rac, and JNK, and trigger cascades of diverse signaling events that are involved in a wide spectrum of diseases, including diabetes mellitus, inflammatory, vascular and neurodegenerative diseases, atherothrombosis, and cancer. Thus, the targeted inhibition of RAGE or its ligands is considered an important strategy for the treatment of cancer and chronic inflammatory diseases.
Collapse
|
|
31
|
Sharifi-Zahabi E, Sharafabad FH, Abdollahzad H, Malekahmadi M, Rad NB. Circulating Advanced Glycation End Products and Their Soluble Receptors in Relation to All-Cause and Cardiovascular Mortality: A Systematic Review and Meta-analysis of Prospective Observational Studies. Adv Nutr 2021; 12:2157-2171. [PMID: 34139010 PMCID: PMC8634502 DOI: 10.1093/advances/nmab072] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/05/2021] [Accepted: 05/12/2021] [Indexed: 01/10/2023] Open
Abstract
Advanced glycation end products (AGEs) are involved in the development of several age-related complications. The protective role of soluble receptors for AGEs (sRAGE) against deleterious effects of AGEs has been indicated in several studies. However, findings on the association of AGEs or sRAGE with mortality are equivocal. In this meta-analysis we aimed to present a quantitative estimation of the association between circulating AGEs or sRAGE and all-cause or cardiovascular disease (CVD) mortality. A comprehensive literature search was performed to determine relevant publications through the online databases including PubMed, Scopus, and Web of Science up to 29 November 2020. Prospective observational studies assessing the association between circulating AGEs or sRAGE and all-cause or CVD mortality were included. Seven studies with a total of 3718 participants and 733 mortality cases (345 CVD deaths) were included in the meta-analysis for assessing the association between circulating AGEs and mortality. Our results showed that higher circulating AGEs were associated with increased risk of all-cause (pooled effect measure: 1.05; 95% CI: 1.01, 1.09; P = 0.018, I2 = 77.7%) and CVD mortality (pooled effect measure: 1.08; 95% CI: 1.01, 1.14; P = 0.015, I2 = 80.2%), respectively. The association between sRAGE and mortality was assessed in 14 studies with a total of 16,335 participants and 2844 mortality cases (419 CVD deaths). Serum concentrations of sRAGE were not associated with the risk of all-cause mortality (pooled effect measure: 1.01; 95% CI: 1.00, 1.01; P = 0.205, I2 = 75.5%), whereas there was a significant link between sRAGE and the risk of CVD mortality (pooled effect measure: 1.02; 95% CI: 1.00, 1.04; P = 0.02, I2 = 78.9%). Our findings showed that a higher serum AGE concentration was associated with increased risk of all-cause and CVD mortality. In addition, higher circulating sRAGE was related to increased risk of CVD mortality. This review was registered at PROSPERO as CRD42021236559.
Collapse
Affiliation(s)
- Elham Sharifi-Zahabi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | | | - Mahsa Malekahmadi
- Research Institute for Gastroenterology and Liver, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nadya Bahari Rad
- School of Nutritional Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| |
Collapse
|
|
32
|
Gomez-Cabrero D, Walter S, Abugessaisa I, Miñambres-Herraiz R, Palomares LB, Butcher L, Erusalimsky JD, Garcia-Garcia FJ, Carnicero J, Hardman TC, Mischak H, Zürbig P, Hackl M, Grillari J, Fiorillo E, Cucca F, Cesari M, Carrie I, Colpo M, Bandinelli S, Feart C, Peres K, Dartigues JF, Helmer C, Viña J, Olaso G, García-Palmero I, Martínez JG, Jansen-Dürr P, Grune T, Weber D, Lippi G, Bonaguri C, Sinclair AJ, Tegner J, Rodriguez-Mañas L. A robust machine learning framework to identify signatures for frailty: a nested case-control study in four aging European cohorts. GeroScience 2021; 43:1317-1329. [PMID: 33599920 PMCID: PMC8190217 DOI: 10.1007/s11357-021-00334-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Phenotype-specific omic expression patterns in people with frailty could provide invaluable insight into the underlying multi-systemic pathological processes and targets for intervention. Classical approaches to frailty have not considered the potential for different frailty phenotypes. We characterized associations between frailty (with/without disability) and sets of omic factors (genomic, proteomic, and metabolomic) plus markers measured in routine geriatric care. This study was a prevalent case control using stored biospecimens (urine, whole blood, cells, plasma, and serum) from 1522 individuals (identified as robust (R), pre-frail (P), or frail (F)] from the Toledo Study of Healthy Aging (R=178/P=184/F=109), 3 City Bordeaux (111/269/100), Aging Multidisciplinary Investigation (157/79/54) and InCHIANTI (106/98/77) cohorts. The analysis included over 35,000 omic and routine laboratory variables from robust and frail or pre-frail (with/without disability) individuals using a machine learning framework. We identified three protective biomarkers, vitamin D3 (OR: 0.81 [95% CI: 0.68-0.98]), lutein zeaxanthin (OR: 0.82 [95% CI: 0.70-0.97]), and miRNA125b-5p (OR: 0.73, [95% CI: 0.56-0.97]) and one risk biomarker, cardiac troponin T (OR: 1.25 [95% CI: 1.23-1.27]). Excluding individuals with a disability, one protective biomarker was identified, miR125b-5p (OR: 0.85, [95% CI: 0.81-0.88]). Three risks of frailty biomarkers were detected: pro-BNP (OR: 1.47 [95% CI: 1.27-1.7]), cardiac troponin T (OR: 1.29 [95% CI: 1.21-1.38]), and sRAGE (OR: 1.26 [95% CI: 1.01-1.57]). Three key frailty biomarkers demonstrated a statistical association with frailty (oxidative stress, vitamin D, and cardiovascular system) with relationship patterns differing depending on the presence or absence of a disability.
Collapse
Affiliation(s)
- David Gomez-Cabrero
- Translational Bioinformatics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain
| | - Stefan Walter
- Dept. of Medicine and Public Health, Rey Juan Carlos University, Alcorcon, Spain
| | | | | | | | - Lee Butcher
- Department of Biomedical Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Jorge D Erusalimsky
- Department of Biomedical Sciences, Cardiff Metropolitan University, Cardiff, UK
| | | | - José Carnicero
- Dept. of Geriatric Medicine, Complejo Hospitalario Universitario de Toledo (CHUT), Toledo, Spain
| | | | - Harald Mischak
- Mosaiques Diagnostics GmbH, Rotenburger Str. 20, 30659, Hannover, Germany
| | - Petra Zürbig
- Mosaiques Diagnostics GmbH, Rotenburger Str. 20, 30659, Hannover, Germany
| | - Matthias Hackl
- Evercyte GmbH; BOKU-University of Natural Resources and Life Sciences Vienna, Department of Biotechnology, Ludwig Boltzmann Institute of Experimental and Clinical Traumatology, Vienna, Austria
| | - Johannes Grillari
- Evercyte GmbH; BOKU-University of Natural Resources and Life Sciences Vienna, Department of Biotechnology, Ludwig Boltzmann Institute of Experimental and Clinical Traumatology, Vienna, Austria
| | - Edoardo Fiorillo
- Instituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy
| | - Francesco Cucca
- Instituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy
| | - Matteo Cesari
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | | | | | | | - Catherine Feart
- Univ. Bordeaux, Bordeaux Population Health Research Center, UMR 1219, F-33000, Bordeaux, France
| | - Karine Peres
- Univ. Bordeaux, Bordeaux Population Health Research Center, UMR 1219, F-33000, Bordeaux, France
| | - Jean-François Dartigues
- Univ. Bordeaux, Bordeaux Population Health Research Center, UMR 1219, F-33000, Bordeaux, France
| | - Catherine Helmer
- Univ. Bordeaux, Bordeaux Population Health Research Center, UMR 1219, F-33000, Bordeaux, France
| | - José Viña
- Freshage, University of Valencia, Valencia, Spain
| | - Gloria Olaso
- Freshage, University of Valencia, Valencia, Spain
| | | | | | - Pidder Jansen-Dürr
- Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria
| | - Tilman Grune
- German Institute for Human Nutrition, Potsdam, Germany
| | - Daniela Weber
- German Institute for Human Nutrition, Potsdam, Germany
| | - Giuseppe Lippi
- Clinical Biochemistry and Molecular Biology, Universita di Verona, Verona, Italy
| | - Chiara Bonaguri
- Laboratoy Medicine Technical Sciences, Parma University, Parma, Italy
| | | | - Jesper Tegner
- Dept. of Medicine, Karolinska Institute, Stockholm, Sweden
- Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Leocadio Rodriguez-Mañas
- CIBER of Frailty and Healthy Aging, Madrid, Spain.
- Dept. of Geriatric Medicine, Getafe University Hospital, Getafe, Spain.
| |
Collapse
|
|
33
|
Gasmi A, Chirumbolo S, Peana M, Mujawdiya PK, Dadar M, Menzel A, Bjørklund G. Biomarkers of Senescence during Aging as Possible Warnings to Use Preventive Measures. Curr Med Chem 2021; 28:1471-1488. [PMID: 32942969 DOI: 10.2174/0929867327999200917150652] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 08/09/2020] [Accepted: 08/18/2020] [Indexed: 11/22/2022]
Abstract
Human life expectancy is increasing significantly over time thanks to the improved possibility for people to take care of themselves and the higher availability of food, drugs, hygiene, services, and assistance. The increase in the average age of the population worldwide is, however, becoming a real concern, since aging is associated with the rapid increase in chronic inflammatory pathologies and degenerative diseases, very frequently dependent on senescent phenomena that occur alongside with senescence. Therefore, the search for reliable biomarkers that can diagnose the possible onset or predict the risk of developing a disease associated with aging is a crucial target of current medicine. In this review, we construct a synopsis of the main addressable biomarkers to study the development of aging and the associated ailments.
Collapse
Affiliation(s)
- Amin Gasmi
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Massimiliano Peana
- Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy
| | | | - Maryam Dadar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Alain Menzel
- Laboratoires Réunis, Junglinster, Luxembourg, Norway
| | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway
| |
Collapse
|
|
34
|
Serum biomarkers, skin autofluorescence and other methods. Which parameter better illustrates the relationship between advanced glycation end products and arterial stiffness in the general population? Hypertens Res 2021; 44:518-527. [PMID: 33437026 DOI: 10.1038/s41440-020-00601-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/20/2020] [Accepted: 11/06/2020] [Indexed: 01/29/2023]
Abstract
Stiffening of large arteries, clinically manifesting as increased aortic pulse wave velocity (PWV), is an inevitable outcome of aging. Among other mechanisms, impaired glucose metabolism plays an important role, leading to the deposition of advanced glycation end products (AGEs). This process is counterbalanced by the circulating soluble receptor for AGEs (sRAGE). We investigated the association between arterial stiffness on one side and multiple circulating biomarkers and the degree of skin deposition of AGEs on the other. In a cross-sectional design, 867 participants based on a general population sample (Czech post-MONICA studies) were examined. PWV was measured by SphygmoCor device (AtCor Medical Ltd.), while skin AGEs were measured using a dedicated autofluorescence method (AGE Reader mu®). To quantify the circulating status of AGEs, carboxymethyl lysine (CML) and sRAGE concentrations were assessed by ELISA, along with conventional glucose metabolism indicators. When analyzing the whole sample using multiple linear or logistic regression models and after adjustment for potential covariates, a significant association with PWV was found for fasting glycemia, HbA1c, sRAGE, skin AGEs, and the skin AGE-to-sRAGE ratio. Among these parameters, stepwise models identified the strongest association for the skin AGEs and AGE-to-sRAGE ratio, and this was also true when diabetic subjects were excluded. In contrast, neither CML nor its ratio relative to sRAGE showed any association with arterial stiffness. In conclusion, skin AGEs along with their ratio relative to sRAGE were closely associated with arterial stiffness and is a better indicator of the current status of deposited AGEs than other relevant factors.
Collapse
|
|
35
|
Luppi F, Kalluri M, Faverio P, Kreuter M, Ferrara G. Idiopathic pulmonary fibrosis beyond the lung: understanding disease mechanisms to improve diagnosis and management. Respir Res 2021; 22:109. [PMID: 33865386 PMCID: PMC8052779 DOI: 10.1186/s12931-021-01711-1] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 04/11/2021] [Indexed: 02/07/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disorder with an estimated median survival time of 3–5 years after diagnosis. This condition occurs primarily in elderly subjects, and epidemiological studies suggest that the main risk factors, ageing and exposure to cigarette smoke, are associated with both pulmonary and extrapulmonary comorbidities (defined as the occurrence of two or more disorders in a single individual). Ageing and senescence, through interactions with environmental factors, may contribute to the pathogenesis of IPF by various mechanisms, causing lung epithelium damage and increasing the resistance of myofibroblasts to apoptosis, eventually resulting in extracellular matrix accumulation and pulmonary fibrosis. As a paradigm, syndromes featuring short telomeres represent archetypal premature ageing syndromes and are often associated with pulmonary fibrosis. The pathophysiological features induced by ageing and senescence in patients with IPF may translate to pulmonary and extrapulmonary features, including emphysema, pulmonary hypertension, lung cancer, coronary artery disease, gastro-oesophageal reflux, diabetes mellitus and many other chronic diseases, which may lead to substantial negative consequences in terms of various outcome parameters in IPF. Therefore, the careful diagnosis and treatment of comorbidities may represent an outstanding chance to improve quality of life and survival, and it is necessary to contemplate all possible management options for IPF, including early identification and treatment of comorbidities.
Collapse
Affiliation(s)
- Fabrizio Luppi
- Respiratory Unit, University of Milano Bicocca, S. Gerardo Hospital, ASST Monza, Monza, Italy
| | - Meena Kalluri
- Division of Pulmonary Medicine, Department of Medicine, University of Alberta, 3-134 Clinical Sciences Building, 11304 83 Ave., Edmonton, AB, T6G 2G3, Canada
| | - Paola Faverio
- Respiratory Unit, University of Milano Bicocca, S. Gerardo Hospital, ASST Monza, Monza, Italy
| | - Michael Kreuter
- Centre for Interstitial and Rare Lung Diseases, Pneumology and Respiratory Critical Care Medicine, University of Heidelberg, German Center for Lung Research, ThoraxklinikHeidelberg, Germany
| | - Giovanni Ferrara
- Sensory Motor Adaptive Rehabilitation Technology (SMART) Network, University of Alberta, Edmonton, AB, Canada. .,Division of Pulmonary Medicine, Department of Medicine, University of Alberta, 3-134 Clinical Sciences Building, 11304 83 Ave., Edmonton, AB, T6G 2G3, Canada.
| |
Collapse
|
|
36
|
Contribution of Glycation and Oxidative Stress to Thyroid Gland Pathology-A Pilot Study. Biomolecules 2021; 11:biom11040557. [PMID: 33920190 PMCID: PMC8069218 DOI: 10.3390/biom11040557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 12/15/2022] Open
Abstract
The patho-mechanism of changes in the thyroid gland, including carcinogenesis, is a complex process, which involves oxidative stress. The goal of our investigation was to verify the extent of stress in the thyroid gland related to glycation. The study samples were comprised of blood sera, thyroid, and adipose tissue sections probed from 37 patients diagnosed with thyroid cancers and goiter. Using immuno-enzymatic and fluorometric assays we analyzed the content of advanced glycation end-products (AGEs), pentosidine, receptors for advanced glycation end-products (RAGE), scavenger receptor class (SR)-A, SR-B, glutathione, malondialdehyde and nitric oxide synthase. In addition to classic AGEs, a recent study detected the melibiose-derived glycation (MAGE) product. We demonstrated the presence of AGEs, MAGE and their receptors of the RAGE and SR-A. In addition, in the control samples of thyroid glands SR-B groups were detected as well as of pathological groups without noticeable tendency to antigen concentration in the area of carcinogenesis. Fluorescent AGEs correlate positively with glutathione, which supports the assumption that glycation stress leads to augmentation of oxidative stress and increase of the intensity of antioxidant mechanisms.
Collapse
|
|
37
|
Erusalimsky JD. The use of the soluble receptor for advanced glycation-end products (sRAGE) as a potential biomarker of disease risk and adverse outcomes. Redox Biol 2021; 42:101958. [PMID: 33839083 PMCID: PMC8113049 DOI: 10.1016/j.redox.2021.101958] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/21/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
The soluble receptor for advanced glycation end-products (sRAGE) has been classically considered a sink for pro-inflammatory RAGE ligands and as such has been associated with protection from inflammatory stress and disease. An alternative, though not mutually exclusive view is that high levels of sRAGE in circulation reflect the overstimulation of cell surface RAGE which if persistent, lead to the amplification of pro-inflammatory processes and the exacerbation of pathological states. With these two scenarios in mind this review focuses on the potential role of sRAGE as a prospective biomarker of disease risk and adverse outcomes.
The prognostic value of measuring sRAGE levels in blood is subjected to debate. Raised sRAGE levels may result from the overstimulation of cell surface RAGE. Raised sRAGE may reflect chronic inflammation and multimorbidity rather than a healthy state. sRAGE is a promising biomarker of disease risk and adverse outcomes.
Collapse
Affiliation(s)
- Jorge D Erusalimsky
- The Cellular Senescence and Pathophysiology Group, Cardiff Metropolitan University, Cardiff, UK.
| |
Collapse
|
|
38
|
Semchyshyn H. Is carbonyl/AGE/RAGE stress a hallmark of the brain aging? Pflugers Arch 2021; 473:723-734. [PMID: 33742308 DOI: 10.1007/s00424-021-02529-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 01/21/2021] [Accepted: 01/28/2021] [Indexed: 12/13/2022]
Abstract
Recent studies have linked carbonyl stress to many physiological processes. Increase in the levels of carbonyl compounds, derived from both endogenous and exogenous sources, is believed to accompany normal age-related decline as well as different pathologies. Reactive carbonyl species (RCS) are capable of damaging biomolecules via their involvement in a net of nonspecific reactions. In the advanced stages of RCS metabolism, variety of poorly degraded adducts and crosslinks, collectively named advanced glycoxidation end products (AGEs), arises. They are accumulated in an age-dependent manner in different tissues and organs and can contribute to inflammatory processes. In particular, detrimental effects of the end products are realized via activation of the specific receptor for AGEs (RAGE) and RAGE-dependent inflammatory signaling cascade. Although it is unclear, whether carbonyl stress is causal for age-associated impairments or it results from age- and disease-related cell damages, increased levels of RCS and AGEs are tightly related to inflammaging, and therefore, attenuation of the RAGE signaling is suggested as an effective approach for the treatment of inflammation and age-related disorders. The question raised in this review is whether specific metabolism in the aging brain related to carbonyl/RCS/AGE/RAGE stress.
Collapse
Affiliation(s)
- Halyna Semchyshyn
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str, Ivano-Frankivsk, 76018, Ukraine.
| |
Collapse
|
|
39
|
Chambers A, Bury JJ, Minett T, Richardson CD, Brayne C, Ince PG, Shaw PJ, Garwood CJ, Heath PR, Simpson JE, Matthews FE, Wharton SB. Advanced Glycation End Product Formation in Human Cerebral Cortex Increases With Alzheimer-Type Neuropathologic Changes but Is Not Independently Associated With Dementia in a Population-Derived Aging Brain Cohort. J Neuropathol Exp Neurol 2021; 79:950-958. [PMID: 32766675 DOI: 10.1093/jnen/nlaa064] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/12/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus is a risk factor for dementia, and nonenzymatic glycosylation of macromolecules results in formation of advanced glycation end-products (AGEs). We determined the variation in AGE formation in brains from the Cognitive Function and Ageing Study population-representative neuropathology cohort. AGEs were measured on temporal neocortex by enzyme-linked immunosorbent assay (ELISA) and cell-type specific expression on neurons, astrocytes and endothelium was detected by immunohistochemistry and assessed semiquantitatively. Fifteen percent of the cohort had self-reported diabetes, which was not significantly associated with dementia status at death or neuropathology measures. AGEs were expressed on neurons, astrocytes and endothelium and overall expression showed a positively skewed distribution in the population. AGE measures were not significantly associated with dementia. AGE measured by ELISA increased with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurofibrillary tangle score (p = 0.03) and Thal Aβ phase (p = 0.04), while AGE expression on neurons (and astrocytes), detected immunohistochemically, increased with increasing Braak tangle stage (p < 0.001), CERAD tangle score (p = 0.002), and neuritic plaques (p = 0.01). Measures of AGE did not show significant associations with cerebral amyloid angiopathy, microinfarcts or neuroinflammation. In conclusion, AGE expression increases with Alzheimer's neuropathology, particular later stages but is not independently associated with dementia. AGE formation is likely to be important for impaired brain cell function in aging and Alzheimer's.
Collapse
Affiliation(s)
- Annabelle Chambers
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Joanna J Bury
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Thais Minett
- Institute of Public Health, University of Cambridge, Cambridge, UK
| | - Connor D Richardson
- Population Health Sciences Institute, University of Newcastle, Newcastle, UK
| | - Carol Brayne
- Institute of Public Health, University of Cambridge, Cambridge, UK
| | - Paul G Ince
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Pamela J Shaw
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Claire J Garwood
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Paul R Heath
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Julie E Simpson
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Fiona E Matthews
- Population Health Sciences Institute, University of Newcastle, Newcastle, UK
| | - Stephen B Wharton
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| |
Collapse
|
|
40
|
Abstract
Coronary artery atherosclerosis and atherosclerotic plaque rupture cause coronary artery disease (CAD). Advanced glycation end products (AGE) and its cell receptor RAGE, and soluble receptor (sRAGE) and endogenous secretory RAGE (esRAGE) may be involved in the development of atherosclerosis. AGE and its interaction with RAGE are atherogenic, while sRAGE and esRAGE have antiatherogenic effects. AGE-RAGE stress is a ratio of AGE/sRAGE. A high AGE-RAGE stress results in development and progression of CAD and vice-versa. AGE levels in serum and skin, AGE/sRAGE in patients with CAD, and expression of RAGE in animal model of atherosclerosis were higher, while serum levels of esRAGE were lower in patients with CAD compared with controls. Serum levels of sRAGE in CAD patients were contradictory, increased or decreased. This contradictory data may be due to type of patients used, because the sRAGE levels are elevated in diabetics and end-stage renal disease. AGE/sRAGE ratio is elevated in patients with reduced or elevated levels of serum sRAGE. It is to stress that AGE, RAGE, sRAGE, or esRAGE individually cannot serve as universal biomarker. AGE and sRAGE should be measured simultaneously to assess the AGE-RAGE stress. The treatment of CAD should be targeted at reduction in AGE levels, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of RAGE, elevation of sRAGE, and use of antioxidants. In conclusion, AGE-RAGE stress would initiate the development and progression of atherosclerosis. Treatment modalities would prevent, regress, and slow the progression of CAD.
Collapse
Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Canada
| |
Collapse
|
|
41
|
Ene CD, Penescu MN, Georgescu SR, Tampa M, Nicolae I. Posttranslational Modifications Pattern in Clear Cell Renal Cell Carcinoma. Metabolites 2020; 11:10. [PMID: 33375435 PMCID: PMC7824589 DOI: 10.3390/metabo11010010] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/18/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023] Open
Abstract
Posttranslational modifications are dynamic enzymatic-mediated processes, regulated in time and space, associated with cancer development. We aimed to evaluate the significance of posttranslational modifications in the pathogenesis of clear cell renal cell carcinoma. The authors developed a prospective, observational study during a period of three years and included 55 patients with localized renal cell carcinoma and 30 heathy subjects. Glycosylation, nitration and carbonylation, thiol-disulfide homeostasis, methylation, phosphorylation and proteolytic cleavage were evaluated in the serum of the evaluated subjects in the present study. Our results showed some characteristics for early ccRCC: high production of cytokines, substrate hypersialylation, induced nitrosative and carbonylic stress, arginine hypermethylation, thiol/disulfide homeostasis (TDH) alteration, the regulatory role of soluble receptors (sRAGE, sIL-6R) in RAGE and IL-6 signaling, the modulatory effect of TK-1and TuM2-PK in controlling the level of phosphometabolites in neoplastic cells. These data could be the initial point for development of a panel of biomarkers such as total sialic acid, orosomucoids, nitrotyrosine, carbonylic metabolites, ADMA, SDMA, and thiol-disulfide equilibrium for early diagnosis of ccRCC. Moreover, they could be considered a specific disease PTM signature which underlines the transition from early to advanced stages in this neoplasia, and of a therapeutic target in kidney oncogenesis.
Collapse
Affiliation(s)
- Corina Daniela Ene
- Faculty of General Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (M.N.P.); (S.R.G.); (M.T.)
- Carol Davila Clinical Hospital of Nephrology, 010731 Bucharest, Romania
| | - Mircea Nicolae Penescu
- Faculty of General Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (M.N.P.); (S.R.G.); (M.T.)
- Carol Davila Clinical Hospital of Nephrology, 010731 Bucharest, Romania
| | - Simona Roxana Georgescu
- Faculty of General Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (M.N.P.); (S.R.G.); (M.T.)
- Victor Babes Clinical Hospital of Tropical and Infectious Diseases, 030303 Bucharest, Romania;
| | - Mircea Tampa
- Faculty of General Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (M.N.P.); (S.R.G.); (M.T.)
- Victor Babes Clinical Hospital of Tropical and Infectious Diseases, 030303 Bucharest, Romania;
| | - Ilinca Nicolae
- Victor Babes Clinical Hospital of Tropical and Infectious Diseases, 030303 Bucharest, Romania;
| |
Collapse
|
|
42
|
Sierra-Colomina M, García-Salido A, Leoz-Gordillo I, Martínez de Azagra-Garde A, Melen G, García-Teresa MÁ, Iglesias-Bouzas M, Nieto-Moro M, Ramírez-Orellana M, Serrano-González A. sRAGE as severe acute bronchiolitis biomarker, prospective observational study. Pediatr Pulmonol 2020; 55:3429-3436. [PMID: 32852101 DOI: 10.1002/ppul.25048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/02/2020] [Accepted: 08/12/2020] [Indexed: 11/11/2022]
Abstract
INTRODUCTION AND OBJECTIVES Acute bronchiolitis (AB) is the leading cause of hospitalization in infants and around 5% require intensive care treatment. Early identification of children diagnosed with AB at a high risk of severe progression is of great interest. The receptor for advanced glycation end products (RAGE), highly expressed in lung tissue, regulates immune responses and inflammation, and its soluble form, sRAGE, is believed to have an anti-inflammatory role. We hypothesized serum sRAGE might be a major determinant of AB severity and prognosis. This study was conducted to measure serum sRAGE in infants with severe AB and to assess its correlation with clinical severity, immediate complications, and outcome. METHODS Single-center, prospective, observational study of hospitalized children with severe bronchiolitis admitted to the Pediatric Intensive Care Unit (PICU), from September 2015 to September 2016. RESULTS A total of 52 children and 27 controls were included. The cases age ranged from 11 days to 21 months, resulting in a significant age difference with controls (11.85 vs 4.84 months, P < .01). Serum levels of sRAGE were lower but not significant in severe AB patients than in controls (1350.93 vs 1450.42 pg/mL; P = .399). No correlation was found between serum sRAGE and causative viruses, clinical symptoms, Wood-Downes score (a clinical severity score) on admission, respiratory support, or length of hospital stay. Serum sRAGE was also lower in the cases having had a previous respiratory disease (1463.84 vs 1072.43 pg/mL; P = .049). However, it was higher in patients with any lung consolidation on the chest X-ray (1584.79 vs 1131.62 pg/mL; P = .044) and weakly positively correlated with classical biomarkers (maximum C-reactive protein, +0.295, P = .034; maximum procalcitonin, +0.309; P = .029). CONCLUSION This single-center study reveals that sRAGE couldn't predict AB severity or outcome in children hospitalized at PICU. Nevertheless, it significantly increased in the presence of any lung consolidation and had a positive correlation with classical biomarkers. The utility of sRAGE in this population could be probably elucidated with a better understanding of AGE-RAGE axis.
Collapse
Affiliation(s)
| | - Alberto García-Salido
- Department of Pediatric Critical Care, Niño Jesús Children's University Hospital, Madrid, Spain
| | - Inés Leoz-Gordillo
- Department of Pediatric Critical Care, Niño Jesús Children's University Hospital, Madrid, Spain
| | | | - Gustavo Melen
- Department of PediatricHematology and Oncology, Niño Jesús Children's University Hospital, Autonomous University of Madrid, Madrid, Spain
| | | | - Mabel Iglesias-Bouzas
- Department of Pediatric Critical Care, Niño Jesús Children's University Hospital, Madrid, Spain
| | - Montserrat Nieto-Moro
- Department of Pediatric Critical Care, Niño Jesús Children's University Hospital, Madrid, Spain
| | - Manuel Ramírez-Orellana
- Department of PediatricHematology and Oncology, Niño Jesús Children's University Hospital, Autonomous University of Madrid, Madrid, Spain
| | - Ana Serrano-González
- Department of Pediatric Critical Care, Niño Jesús Children's University Hospital, Madrid, Spain
| |
Collapse
|
|
43
|
Effects of the age/rage axis in the platelet activation. Int J Biol Macromol 2020; 166:1149-1161. [PMID: 33161078 DOI: 10.1016/j.ijbiomac.2020.10.270] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/28/2020] [Accepted: 10/31/2020] [Indexed: 02/07/2023]
Abstract
Platelet activity is essential in cardiovascular diseases. Therefore our objective was to evaluate the main effects of activating RAGE in platelets which are still unknown. A search for RAGE expression in different databases showed poor or a nonexistent presence in platelets. We confirmed the expression in platelets and secreted variable of RAGE (sRAGE). Platelets from elderly adults expressed in resting showed 3.2 fold more RAGE from young individuals (p < 0.01) and 3.3 fold with TRAP-6 (p < 0.001). These results could indicate that the expression of RAGE is more inducible in older adults. Then we found that activating RAGE with AGE-BSA-derived from methylglyoxal and subthreshold TRAP-6, showed a considerable increase with respect to the control in platelet aggregation and expression of P-selectin (respectively, p < 0.01). This effect was almost completely blocked by using a specific RAGE inhibitor (FSP-ZM1), confirming that RAGE is important for the function and activation platelet. Finally, we predict the region stimulated by AGE-BSA is located in region V of RAGE and 13 amino acids are critical for its binding. In conclusion, the activation of RAGE affects platelet activation and 13 amino acids are critical for its stimulation, this information is crucial for future possible treatments for CVD.
Collapse
|
|
44
|
Brinkley TE, Semba RD, Kritchevsky SB, Houston DK. Dietary protein intake and circulating advanced glycation end product/receptor for advanced glycation end product concentrations in the Health, Aging, and Body Composition Study. Am J Clin Nutr 2020; 112:1558-1565. [PMID: 33301008 PMCID: PMC7727487 DOI: 10.1093/ajcn/nqaa241] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 08/04/2020] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Advanced glycation end products (AGEs) promote adverse health effects and may contribute to the multi-system functional decline observed in aging. Diet is a major source of AGEs, and foods high in protein may increase circulating AGE concentrations. However, epidemiological evidence that high-protein diets increase AGEs is lacking. OBJECTIVES We examined whether dietary protein intake was associated with serum concentrations of the major AGE carboxymethyl-lysine (CML) and the soluble receptor for AGEs (sRAGE) in 2439 participants from the Health, Aging, and Body Composition study (mean age, 73.6 ± 2.9 y; 52% female; 37% black). METHODS CML and sRAGE were measured by ELISA, and the CML/sRAGE ratio was calculated. Protein intake was estimated using an interviewer-administered FFQ and categorized based on current recommendations for older adults: <0.8 g/kg/d (n = 1077), 0.8 to <1.2 g/kg/d (n = 922), and ≥1.2 g/kg/d (n = 440). Associations between protein intake and AGE-RAGE biomarkers were examined using linear regression models adjusted for demographics, height, lifestyle behaviors, prevalent disease, cognitive function, inflammation, and other dietary factors. RESULTS CML concentrations were higher in individuals with higher total protein intake (adjusted least squares mean ± SE: <0.8 g/kg/d, 829 ± 17 ng/ml; 0.8 to <1.2 g/kg/d, 860 ± 15 ng/ml; ≥1.2 g/kg/d, 919 ± 23 ng/ml; P for trend = 0.001), as were sRAGE concentrations (<0.8 g/kg/d, 1412 ± 34 pg/ml; 0.8 to <1.2 g/kg/d, 1479 ± 31 pg/ml; ≥1.2 g/kg/d, 1574 ± 47 pg/ml; P for trend < 0.0001). Every 0.1 g/kg/d increment in total protein intake was associated with a 13.3 ± 3.0 ng/ml increment in CML and a 22.1 ± 6.0 pg/ml increment in sRAGE (P < 0.0001 for both). Higher CML and sRAGE concentrations were also associated with higher intakes of both animal and vegetable protein (all P values ≤ 0.01). There were no significant associations with the CML/sRAGE ratio. CONCLUSIONS Higher dietary protein intake was associated with higher CML and sRAGE concentrations in older adults; however, the CML/sRAGE ratio remained similar across groups.
Collapse
Affiliation(s)
| | - Richard D Semba
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Stephen B Kritchevsky
- Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Denise K Houston
- Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | | |
Collapse
|
|
45
|
Steenbeke M, De Bruyne S, De Buyzere M, Lapauw B, Speeckaert R, Petrovic M, Delanghe JR, Speeckaert MM. The role of soluble receptor for advanced glycation end-products (sRAGE) in the general population and patients with diabetes mellitus with a focus on renal function and overall outcome. Crit Rev Clin Lab Sci 2020; 58:113-130. [PMID: 32669010 DOI: 10.1080/10408363.2020.1791045] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Isoforms of the receptor for advanced glycation end-product (RAGE) protein, which lack the transmembrane and the signaling (soluble RAGE or sRAGE) domains are hypothesized to counteract the detrimental action of the full-length receptor by acting as a decoy, and they provide a potential tool to treat RAGE-associated diseases. Multiple studies have explored the relationship between sRAGE and endogenous secretory RAGE and its polymorphism and obesity, metabolic syndrome, atherosclerosis, kidney function, and increased mortality in the general population. In addition, sRAGE may be a key player in the pathogenesis of diabetes mellitus and its microvascular (e.g. kidney disease) as well as macrovascular (e.g. cardiovascular disease) complications. In this review, we focus on the role of sRAGE as a biomarker in these specific areas. As there is a lack of an underlying unifying hypothesis about how sRAGE changes according to the disease condition or risk factor, there is a call to incorporate all three players of the AGE-RAGE axis into a new universal biomarker/risk marker: (AGE + RAGE)/sRAGE. However, the measurement of RAGE in humans is not practical as it is a cell-bound receptor for which tissue is required for analysis. A high AGE/sRAGE ratio may be a valuable alternative and practical universal biomarker/risk marker for diseases associated with the AGE-RAGE axis, irrespective of low or high serum sRAGE concentrations.
Collapse
Affiliation(s)
- Mieke Steenbeke
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium
| | - Sander De Bruyne
- Department of Clinical Chemistry, Ghent University Hospital, Ghent, Belgium
| | - Marc De Buyzere
- Department of Internal Medicine, Ghent University, Ghent, Belgium
| | - Bruno Lapauw
- Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | | | - Mirko Petrovic
- Department of Geriatrics, Ghent University Hospital, Ghent, Belgium
| | - Joris R Delanghe
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Marijn M Speeckaert
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium.,Research Foundation Flanders, Brussels, Belgium
| |
Collapse
|
|
46
|
Kotani K, Gugliucci A. Advanced glycation end-products and their receptors: Exercise effects. Obes Rev 2020; 21:e13018. [PMID: 32181566 DOI: 10.1111/obr.13018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 02/28/2020] [Indexed: 01/17/2023]
Affiliation(s)
- Kazuhiko Kotani
- Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan.,Glycation, Oxidation and Disease Lab, Research Department, Touro California College of Osteopathic Medicine, Vallejo, California
| | - Alejandro Gugliucci
- Glycation, Oxidation and Disease Lab, Research Department, Touro California College of Osteopathic Medicine, Vallejo, California
| |
Collapse
|
|
47
|
Santanasto AJ, Marron MM, Boudreau RM, Feitosa MF, Wojczynski MK, Arbeev KG, Thyagarajan B, Schupf N, Stallard E, Sebastiani P, Cosentino S, Christensen K, Newman AB. Prevalence, Incidence, and Risk Factors for Overall, Physical, and Cognitive Independence Among Those From Exceptionally Long-Lived Families: The Long Life Family Study. J Gerontol A Biol Sci Med Sci 2020; 75:899-905. [PMID: 31086986 PMCID: PMC7164521 DOI: 10.1093/gerona/glz124] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The Long Life Family Study (LLFS) enrolled families exhibiting exceptional longevity. The goal of this article was to determine the prevalence and predictors of remaining independent after 7 years in the oldest generation. METHODS We examined 7-year change in physical (free of activities of daily living difficulty), cognitive (Mini-Mental State Examination score ≥ 24), and overall independence (physically/cognitively independent) in adults aged 90.3 ± 6.3 from LLFS's oldest generation. Potential predictors (n = 28) of remaining independent included demographics, diseases, biomarkers, anthropometrics, and physical and cognitive performance tasks and were determined using generalized estimating equations (α: p < .05). This was a discovery/exploratory analysis, so no multiple testing correction was employed and the results require independent replication. RESULTS At baseline (n = 1442), 67.3%, 83.8%, and 79.7% were overall, physically, and cognitively independent, respectively. After 7 years, 66% died, 7.5% were lost to follow-up, and the prevalence of overall independence decreased to 59.1% in survivors (-8.2%, 95% confidence interval: -14.1%, 2.2%). Of those with baseline independence, 156/226 (69.0%) remained independent. Predictors of remaining physically independent included younger age, better Short Physical Performance Battery score and lung function, smaller waist circumference, and lower soluble receptor for advanced glycation end-product levels (p < .05). Predictors of remaining cognitively independent included no cancer history, better Digit Symbol Substitution Test performance, and higher body weight (p < .05). CONCLUSIONS The prevalence of independence decreased by only 8.2% after 7 years, demonstrating the close correspondence between disability and mortality. Further, despite a mean baseline age of 90 years, a large proportion of survivors remained independent, suggesting this exceptional subgroup may harbor protective mechanisms.
Collapse
Affiliation(s)
- Adam J Santanasto
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania
| | - Megan M Marron
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania
| | - Robert M Boudreau
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania
| | - Mary F Feitosa
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine in St. Louis, Missouri
| | - Mary K Wojczynski
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine in St. Louis, Missouri
| | - Konstantin G Arbeev
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Nicole Schupf
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York
| | - Eric Stallard
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina
| | - Paola Sebastiani
- Department of Biostatistics, School of Public Health, Boston University, Massachusetts
| | - Stephanie Cosentino
- Department of Neurology, College of Physicians and Surgeons, Columbia University, New York
| | - Kaare Christensen
- Epidemiology Unit, Institute of Public Health, The Danish Aging Research Center, University of Southern Denmark, Sønderborg, Denmark
| | - Anne B Newman
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania
| |
Collapse
|
|
48
|
Cho CH, Cha J. Analysis of neutrophil gelatinase-associated lipocalin, vascular endothelial growth factor, and soluble receptor for advanced glycation end-products in bone marrow supernatant in hematologic malignancies. Clin Biochem 2020; 80:19-24. [PMID: 32304694 DOI: 10.1016/j.clinbiochem.2020.04.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 01/20/2023]
Abstract
BACKGROUND Inflammation is a known risk factor of cancer development, including inflammation-driven leukemogenesis. Evaluation of inflammation-related cytokines in early diagnosis stages is crucial to understand the development of hematologic malignancy. Our aim was to measure three cytokines- neutrophil gelatinase-associated lipocalin (NGAL), vascular endothelial growth factor (VEGF), and soluble receptor for advanced glycation end-products (sRAGE) in bone marrow (BM) samples from patients diagnosed with hematologic malignancy and compare these measurements with the control. Additionally, we evaluated whether NGAL was significantly associated with sRAGE, VEGF, and several hematological parameters. METHODS BM samples were collected from 73 patients, who were classified into myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), plasma cell neoplasm (PCN) and control groups according to the BM smear and pathology review. An immunoassay, a Luminex assay, and an enzyme-linked immunosorbent assay were used to quantitate NGAL, VEGF, and sRAGE, respectively, while all measurements of NGAL, VEGF and sRAGE were performed on BM supernatants. Data on hematological parameters were collected from medical records. Intergroup comparisons were performed using the Kruskal-Wallis H-test and Pearson Chi-Square test. Single and multiple regression analyses were performed to analyze the relationships among the parameters. RESULTS The independent factors associated with NGAL were neutrophil counts and VEGF. As for both NGAL and VEGF, the MPN (n = 23) group showed the highest level, while the MDS (n = 12) group showed low levels. NGAL levels in the AML (n = 13) and MDS groups were lower than in the control group (n = 14). The MPN group demonstrated higher VEGF levels than the AML and MDS groups. The MDS group showed lower VEGF levels than the PCN (n = 11) group. No statistical difference between the hematologic malignancy and control groups or among the hematologic malignancy groups was observed for sRAGE levels. CONCLUSION NGAL was related to neutrophil count and VEGF. NGAL and VEGF showed similar intergroup patterns, reflecting that NGAL was associated with VEGF.
Collapse
Affiliation(s)
- Chi-Hyun Cho
- Department of Laboratory Medicine, College of Medicine, Korea University Ansan Hospital, 123, Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do 425-707, Republic of Korea.
| | - Jaehyung Cha
- Medical Science Research Center, Korea University Ansan Hospital, Ansan-si, Gyeonggi-do, Republic of Korea
| |
Collapse
|
|
49
|
The role of advanced glycation end products in vascular aging: which parameter is the most suitable as a biomarker? J Hum Hypertens 2020; 35:240-249. [PMID: 32203073 DOI: 10.1038/s41371-020-0327-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/28/2020] [Accepted: 02/28/2020] [Indexed: 02/08/2023]
Abstract
Advanced glycation end products (AGEs) are involved in several pathophysiologic processes in vascular diseases, including progressive loss of elasticity of the vessel wall (arterial stiffness). Circulating soluble receptors for AGEs (sRAGE) act as a decoy and counterbalanced the harmful properties of AGEs as the natural protective factor. We compared the role of circulating or skin-deposed AGEs and sRAGE regarding the natural course of arterial stiffening. In a prospective cohort study, we longitudinally followed 536 general population-based subjects (subsample of Czech post-MONICA study). Aortic pulse-wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE and carboxymethyl lysine (circulating AGEs) were assessed at the follow-up visit by ELISA, while skin AGEs were measured using the autofluorescence-based device AGE Reader. Using multiple regressions, we found significant association between ∆PWV/year as a dependent variable, and both, sRAGE and skin AGEs as independent ones (each on its own model). However, the closest associations to ∆PWV/year were found for the ratio of these two factors (skin AGEs/sRAGE) [β coeff = 0.0747 (SE 0.0189), p < 0.0001]. In a categorized manner, subjects with skin AGEs/sRAGE ratio ≥ 3.3 showed about twofold higher risk having ΔPWV/year ≥ 0.2 m/s [adjusted odds ratio was 2.09 (95% CI: 1.35-3.22), p = 0.001]. In contrast, neither circulating AGEs nor circulating AGEs/sRAGE showed any significant relation to ΔPWV/year. In conclusion, skin AGEs/sRAGE ratio seems to be a more sensitive biomarker of vascular aging than these single factors themselves or circulation status of AGEs.
Collapse
|
|
50
|
Le Bagge S, Fotheringham AK, Leung SS, Forbes JM. Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes. Med Res Rev 2020; 40:1200-1219. [PMID: 32112452 DOI: 10.1002/med.21654] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases manifesting in early life, with the prevalence increasing worldwide at a rate of approximately 3% per annum. The prolonged hyperglycaemia characteristic of T1D upregulates the receptor for advanced glycation end products (RAGE) and accelerates the formation of RAGE ligands, including advanced glycation end products, high-mobility group protein B1, S100 calcium-binding proteins, and amyloid-beta. Interestingly, changes in the expression of RAGE and these ligands are evident in patients before the onset of T1D. RAGE signals via various proinflammatory cascades, resulting in the production of reactive oxygen species and cytokines. A large number of proinflammatory ligands that can signal via RAGE have been implicated in several chronic diseases, including T1D. Therefore, it is unsurprising that RAGE has become a potential therapeutic target for the treatment and prevention of disease. In this review, we will explore how RAGE might be targeted to prevent the development of T1D.
Collapse
Affiliation(s)
- Selena Le Bagge
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Amelia K Fotheringham
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Sherman S Leung
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Josephine M Forbes
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Mater Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| |
Collapse
|