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Tabar MS, Nilghaz M, Hekmatdoost A, Pashayee-Khamene F, Mokhtari Z, Karimi S, Ahmadzadeh S, Saberifiroozi M, Hatami B, Yari Z. Advanced glycation end products and risk of mortality in patients with cirrhosis: a prospective cohort study. Sci Rep 2025; 15:4798. [PMID: 39922975 PMCID: PMC11807124 DOI: 10.1038/s41598-025-89433-y] [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: 08/09/2024] [Accepted: 02/05/2025] [Indexed: 02/10/2025] Open
Abstract
The role of diet in reducing the burden of liver disease and mortality attributed to cirrhosis is very imperative. The present study scrutinized the relationship between dietary advanced glycation end products (AGEs) and mortality in patients with cirrhosis. This research was a prospective cohort study on 166 ambulatory cirrhotic patients who had been diagnosed with cirrhosis for a maximum of six months. Follow-up of patients continued for 5 years until May 2024. To determine the incidence of mortality in the quartiles of dietary AGEs, cox regression models were used with the adjustment of potential confounding variables. Although the first model of the analysis by adjusting the results for age and sex failed to show a significant increase in the risk of mortality in patients (HRQ4 vs. Q1 = 2.64; 95% CI = 0.9-7.5, P trend = 0.075), after adjusting the results for further confounders in the second (HRQ4 vs. Q1 = 3.56; 95% CI = 1.1-11.6, P trend = 0.040) and third (HRQ4 vs. Q1 = 3.3; 95% CI = 1.79-13.7, P trend = 0.048) models, the P trend for the risk of mortality during the quartiles of AGEs became significant. In addition, along with increasing trend of dietary AGEs, the number of deaths increased significantly (P = 0.024). Higher mortality risk was generally attributed to higher dietary AGEs in patients with cirrhosis.
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Affiliation(s)
- Mohsen Shaygan Tabar
- Student Research Committee, Department of Clinical Nutrition and dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Clinical Nutrition and dietetics Department, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Nilghaz
- Clinical Nutrition and dietetics Department, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Clinical Nutrition and dietetics Department, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Zeinab Mokhtari
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sara Karimi
- Clinical Nutrition and dietetics Department, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saleheh Ahmadzadeh
- Clinical Nutrition and dietetics Department, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Saberifiroozi
- Liver and Pancreatobiliary Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Yari
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- , West Arghavan St. Farahzadi Blvd., Sharake Qods, Tehran, Iran.
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Miyazaki S, Takino JI, Nagamine K, Takeuchi M, Hori T. RasGRP2 Attenuates TAGE Modification of eNOS in Vascular Endothelial Cells. Biol Pharm Bull 2025; 48:262-266. [PMID: 40101981 DOI: 10.1248/bpb.b24-00730] [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] [Indexed: 03/20/2025]
Abstract
Toxic advanced glycation end-products (TAGEs) are glyceraldehyde (GA)-derived AGEs with strong cytotoxic effects. TAGEs are also involved in lifestyle-related diseases. Notably, modification of TAGEs by GA causes protein dysfunction. As endothelial nitric oxide synthase (eNOS) is constitutively expressed in vascular endothelial cells and is a source of nitric oxide (NO), we focused on it as a TAGE modification-targeting protein. Our laboratory has reported that Ras guanyl nucleotide-releasing protein 2 (RasGRP2) activates Rap1 and R-Ras, among other small GTPases, and suppresses apoptosis and TAGE-induced vascular hyperpermeability in vascular endothelial cells. Therefore, in this study, we investigated the effects of RasGRP2 on cell death, TAGE formation, and TAGE modification of eNOS in vascular endothelial cells following GA treatment using RasGRP2-overexpressing (R) cells and mock (M) immortalized human umbilical vein endothelial cells. GA treatment decreases the viability of both cell types in a concentration-dependent manner. In M cells, GA treatment increased the formation of TAGEs and TAGE modification of eNOS in a concentration-dependent manner, but this increase was suppressed in R cells. Additionally, co-treatment with aminoguanidine, an inhibitor of AGEs formation, suppressed cell death and TAGE modification of eNOS induced by GA. These results indicate that GA induces cell death, the formation of TAGEs, and TAGE modification of eNOS in vascular endothelial cells. Additionally, RasGRP2 is a protective factor that suppresses TAGE formation.
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Affiliation(s)
- Shouhei Miyazaki
- Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
| | - Jun-Ichi Takino
- Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
| | - Kentaro Nagamine
- Faculty of Health Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku, Ishikawa 920-0293, Japan
| | - Takamitsu Hori
- Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
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Shen CY, Lu CH, Cheng CF, Li KJ, Kuo YM, Wu CH, Liu CH, Hsieh SC, Tsai CY, Yu CL. Advanced Glycation End-Products Acting as Immunomodulators for Chronic Inflammation, Inflammaging and Carcinogenesis in Patients with Diabetes and Immune-Related Diseases. Biomedicines 2024; 12:1699. [PMID: 39200164 PMCID: PMC11352041 DOI: 10.3390/biomedicines12081699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/22/2024] [Accepted: 07/27/2024] [Indexed: 09/02/2024] Open
Abstract
Increased production of advanced glycation end products (AGEs) among reducing sugars (glucose, fructose, galactose, or ribose) and amino acids/proteins via non-enzymatic Maillard reaction can be found in lifestyle-related disease (LSRD), metabolic syndrome (MetS), and obesity and immune-related diseases. Increased serum levels of AGEs may induce aging, diabetic complications, cardiovascular diseases (CVD), neurodegenerative diseases (NDD), cancer, and inflamm-aging (inflammation with immunosenescence). The Maillard reaction can also occur among reducing sugars and lipoproteins or DNAs to alter their structure and induce immunogenicity/genotoxicity for carcinogenesis. AGEs, as danger-associated molecular pattern molecules (DAMPs), operate via binding to receptor for AGE (RAGE) or other scavenger receptors on cell surface to activate PI3K-Akt-, P38-MAPK-, ERK1/2-JNK-, and MyD88-induced NF-κB signaling pathways to mediate various pathological effects. Recently, the concept of "inflamm-aging" became more defined, and we have unveiled some interesting findings in relation to it. The purpose of the present review is to dissect the potential molecular basis of inflamm-aging in patients with diabetes and immune-mediated diseases caused by different AGEs.
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Affiliation(s)
- Chieh-Yu Shen
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
| | - Cheng-Hsun Lu
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
- Institute of Clinical Medicine, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan
| | - Chiao-Feng Cheng
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
- Institute of Clinical Medicine, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan
| | - Ko-Jen Li
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
| | - Yu-Min Kuo
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
| | - Cheng-Han Wu
- Department of Internal Medicine, National Taiwan University Hospital-Hsinchu Branch, # 2, Section 1, Shengyi Road, Hsinchu County 302058, Taiwan;
| | - Chin-Hsiu Liu
- Department of Internal Medicine, National Taiwan University Hospital-Yunlin Branch, # 579, Section 2, Yunlin Road, Yunlin County 640203, Taiwan;
| | - Song-Chou Hsieh
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
| | - Chang-Youh Tsai
- Department of Internal Medicine, Fu-Jen Catholic University Hospital, College of Medicine, Fu-Jen Catholic University, # 69 Guizi Road, New Taipei City 24352, Taiwan
| | - Chia-Li Yu
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, # 7 Chung-Shan South Road, Taipei 10002, Taiwan; (C.-Y.S.); (C.-H.L.); (C.-F.C.); (K.-J.L.)
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Yoshizaki H, Kawaharada R, Tsutsumi S, Okami H, Toriumi A, Miyata E, Nakamura A. Unveiling the Threat of Maternal Advanced Glycation End Products to Fetal Muscle: Palmitoleic Acid to the Rescue. Nutrients 2024; 16:1898. [PMID: 38931253 PMCID: PMC11207069 DOI: 10.3390/nu16121898] [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: 05/18/2024] [Revised: 06/07/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Advanced glycation end products (AGEs) accumulate in the plasma of pregnant women with hyperglycemia, potentially inducing oxidative stress and fetal developmental abnormalities. Although intrauterine hyperglycemia has been implicated in excessive fetal growth, the effects of maternal AGEs on fetal development remain unclear. We evaluated the differentiation regulators and cellular signaling in the skeletal muscles of infants born to control mothers (ICM), diabetic mothers (IDM), and diabetic mothers supplemented with either cis-palmitoleic acid (CPA) or trans-palmitoleic acid (TPA). Cell viability, reactive oxygen species levels, and myotube formation were assessed in AGE-exposed C2C12 cells to explore potential mitigation by CPA and TPA. Elevated receptors for AGE expression and decreased Akt and AMPK phosphorylation were evident in rat skeletal muscles in IDM. Maternal palmitoleic acid supplementation alleviated insulin resistance by downregulating RAGE expression and enhancing Akt phosphorylation. The exposure of the C2C12 cells to AGEs reduced cell viability and myotube formation and elevated reactive oxygen species levels, which were attenuated by CPA or TPA supplementation. This suggests that maternal hyperglycemia and plasma AGEs may contribute to skeletal muscle disorders in offspring, which are mitigated by palmitoleic acid supplementation. Hence, the maternal intake of palmitoleic acid during pregnancy may have implications for fetal health.
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Affiliation(s)
- Hitomi Yoshizaki
- Department of Bioregulatory Science (Physiology), Nippon Medical School, Tokyo 113-8602, Japan;
| | - Ritsuko Kawaharada
- Department of Health and Nutrition, Takasaki University of Health and Welfare, Takasaki 370-0033, Japan;
| | - Saki Tsutsumi
- Department of Neurophysiology & Neural Repair, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan;
| | - Haruka Okami
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan;
| | - Akiyo Toriumi
- Department of Public Health, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan;
| | - Eri Miyata
- Department of Molecular Nutrition, Faculty of Human Life Sciences, Jissen Women’s University, Hino 191-8510, Japan;
| | - Akio Nakamura
- Department of Molecular Nutrition, Faculty of Human Life Sciences, Jissen Women’s University, Hino 191-8510, Japan;
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Kuzan A, Kozak-Sykała A, Fiedorowicz A, Kałas W, Strządała L, Gamian A. Advanced Glycation End-Products in Blood Serum-Novel Ischemic Stroke Risk Factors? Implication for Diabetic Patients. J Clin Med 2024; 13:443. [PMID: 38256577 PMCID: PMC10816329 DOI: 10.3390/jcm13020443] [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: 11/03/2023] [Revised: 01/03/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
New predictors of ischemic incidents are constantly sought since they raise the awareness of patients and their doctors of stroke occurrence. The goal was to verify whether Advanced Glycation End Products (AGEs), in particular AGE10, could be one of them. The AGE10 measurement was conducted using a non-commercial ELISA assay in the blood serum of neurological patients without cerebrovascular event (n = 24), those with transient brain attack (TIA) (n = 17), and severe ischemic stroke (n = 35). Twice as many of the people with TIA or severe stroke presented high AGE10 serum concentrations compared to the patients with other neurological conditions (χ2 = 8.2, p = 0.004; χ2 = 8.0, p = 0.005, respectively). The risk of ischemic incident was significantly risen in people with higher levels of AGE10 (OR = 6.5, CI95%: 1.7-24.8; OR = 4.7, CI95%: 1.5-14.5 for TIA and stroke subjects, respectively). We observed a positive correlation (r = 0.40) between high AGE10 levels and diabetes. Moreover, all the diabetic patients that had a high AGE10 content experienced either a severe ischemic stroke or TIA. The patients with high levels of AGE10 exhibited higher grades of disability assessed by the NIHSS scale (r = 0.35). AGE10 can be considered a new biomarker of ischemic stroke risk. Patients with diabetes presenting high AGE10 levels are particularly prone to the occurrence of cerebrovascular incidents.
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Affiliation(s)
- Aleksandra Kuzan
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Anna Kozak-Sykała
- Neurology and Stroke Department, Independent Public Healthcare Centre, Jankowski Regional Hospital in Przeworsk, Szpitalna 16, 37-200 Przeworsk, Poland;
| | - Anna Fiedorowicz
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland (W.K.); (L.S.); (A.G.)
| | - Wojciech Kałas
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland (W.K.); (L.S.); (A.G.)
| | - Leon Strządała
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland (W.K.); (L.S.); (A.G.)
| | - Andrzej Gamian
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland (W.K.); (L.S.); (A.G.)
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Zheng X, Gao Y, Huang Y, Dong R, Yang M, Zhang X, Zeng M, Zhang R, Wu Y, Yu Z, Liu J, Zha B. Clinical value of noninvasive lens advanced glycation end product detection in early screening and severity evaluation of patients with diabetic kidney disease. BMC Nephrol 2023; 24:379. [PMID: 38115082 PMCID: PMC10731831 DOI: 10.1186/s12882-023-03428-3] [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: 05/22/2023] [Accepted: 12/06/2023] [Indexed: 12/21/2023] Open
Abstract
BACKGROUND Advanced glycation end products (AGEs) deposited in the lens are correlated with those in the kidneys, indicating a possible value in evaluating diabetic kidney disease (DKD). This study explored the value of noninvasively measuring lens AGEs to diagnose and evaluate the severity of diabetic nephropathy in patients with type 2 diabetes mellitus (T2DM). METHODOLOGY A total of 134 T2DM patients admitted to the Fifth People's Hospital of Shanghai from March 2020 to May 2021 were selected randomly. Patients were divided into low-, medium-and high-risk groups according to the risk assessment criteria for DKD progression and into DKD and non-DKD (non-DKD) groups according to the Guidelines for the Prevention and Treatment of Diabetic Nephropathy in China. The concentrations of noninvasive AGEs in the lens in all the groups were retrospectively analyzed. RESULTS The concentration of noninvasive lens AGEs in the high-risk patients, according to the 2012 guidelines of the Global Organization for Improving the Prognosis of Kidney Diseases, was significantly higher than that in the remaining groups. Regression analysis suggested the value of lens AGEs in diagnosing DKD and evaluating DKD severity. Cox regression analysis indicated that the noninvasive lens AGE concentration was positive correlated with the course of disease. CONCLUSION The receiver operating characteristic (ROC) curve suggested that using noninvasive lens AGE measurements has clinical value in the diagnosis of DKD (area under the curve 62.4%,95% confidence interval (CI) 52.4%-73.9%, p = 0.014) and in assessing the severity of DKD (area under the curve 83.2%, 95% CI 74.1%-92.3%, P < 0.001). Noninvasive lens AGE testing helps screen T2DM patients for DKD and evaluate the severity of DKD.
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Affiliation(s)
- Xiaodi Zheng
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
- Center of Community-Based Health Research, Fudan University, Shanghai, China
| | - Yuan Gao
- General Practice Clinic, Pujiang Community Health Service Center in Minhang District, Shanghai, China
| | - Yuhong Huang
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
- Center of Community-Based Health Research, Fudan University, Shanghai, China
| | - Ruihua Dong
- Key Lab of Public Health Safety of the Ministry of Education, School of Public Health, Institute of Nutrition, Fudan university, Shanghai, China
| | - Mengxue Yang
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
- Center of Community-Based Health Research, Fudan University, Shanghai, China.
| | - Xuemeng Zhang
- Center of Community-Based Health Research, Fudan University, Shanghai, China
- General Practice Clinic, Pujiang Community Health Service Center in Minhang District, Shanghai, China
| | - Miao Zeng
- Department of Infectious Diseases, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Rui Zhang
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
- Center of Community-Based Health Research, Fudan University, Shanghai, China
| | - Yueyue Wu
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
- Center of Community-Based Health Research, Fudan University, Shanghai, China
| | - Zhiyan Yu
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
- Center of Community-Based Health Research, Fudan University, Shanghai, China
| | - Jun Liu
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
- Center of Community-Based Health Research, Fudan University, Shanghai, China
| | - Bingbing Zha
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
- Center of Community-Based Health Research, Fudan University, Shanghai, China
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Alafaleq NO, Alruwaished GI, Khan MS, Al-Shouli ST, Mujamammi AH, Sabi EM, Sumaily KM, Almansour M, Alokail MS. Non-enzymatic glycation and aggregation of camel immunoglobulins induce breast cancer cell proliferation. J Mol Recognit 2023; 36:e3062. [PMID: 37849017 DOI: 10.1002/jmr.3062] [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: 05/08/2023] [Revised: 09/13/2023] [Accepted: 09/14/2023] [Indexed: 10/19/2023]
Abstract
Glycation of biomolecules results in the formation of advanced glycation end products (AGEs). Immunoglobulin G (IgG) has been implicated in the progression of various diseases, including diabetes and cancer. This study purified three IgG subclasses (IgG1, IgG2, and IgG3) from Camelus dromedarius colostrum using ammonium sulfate fractionation and chromatographic procedures. SDS-PAGE was performed to confirm the purity and molecular weight of the IgG subclasses. Several biochemical and biophysical techniques were employed to study the effect of glycation on camel IgG using methylglyoxal (MGO), a dicarbonyl sugar. Early glycation measurement showed an increase in the fructosamine content by ~four-fold in IgG2, ~two-fold in IgG3, and a slight rise in IgG1. AGEs were observed in all classes of IgGs with maximum hyperchromicity (96.6%) in IgG2. Furthermore, glycation-induced oxidation of IgGs led to an increase in carbonyl content and loss of -SH groups. Among subclass, IgG2 showed the highest (39.7%) increase in carbonyl content accompanied by 82.5% decrease in -SH groups. Far UV-CD analysis illustrated perturbation of β-sheet structure during glycation reaction with MGO. Moreover, glycation of IgG proceeds to various conformational states like aggregation and increased hydrophobicity. In addition, the cytotoxicity assay (MTT) illustrated the proliferation of breast cancer cells (MCF-7) with IgG2 treatment.
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Affiliation(s)
- Nouf O Alafaleq
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Ghaida I Alruwaished
- National Drug and Cosmetic Control Laboratory, Saudi Food and Drug Authority (SFDA), Riyadh, Saudi Arabia
| | - Mohd Shahnawaz Khan
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Samia T Al-Shouli
- Immunology Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed H Mujamammi
- Clinical Biochemistry Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Essa M Sabi
- Clinical Biochemistry Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Khalid M Sumaily
- Clinical Biochemistry Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Almansour
- Medical Education Department, College of Medicine & KSUMC, King Saud University, Riyadh, Saudi Arabia
| | - Majed S Alokail
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
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Mao Z, Baker JR, Takeuchi M, Hyogo H, Tjønneland A, Eriksen AK, Severi G, Rothwell J, Laouali N, Katzke V, Kaaks R, Schulze MB, Palli D, Sieri S, de Magistris MS, Tumino R, Sacerdote C, Derksen JWG, Gram IT, Skeie G, Sandanger TM, Quirós JR, Crous-Bou M, Sánchez MJ, Amiano P, Colorado-Yohar SM, Guevara M, Harlid S, Johansson I, Perez-Cornago A, Freisling H, Gunter M, Weiderpass E, Heath AK, Aglago E, Jenab M, Fedirko V. Prediagnostic serum glyceraldehyde-derived advanced glycation end products and mortality among colorectal cancer patients. Int J Cancer 2023; 152:2257-2268. [PMID: 36715363 DOI: 10.1002/ijc.34449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 12/05/2022] [Accepted: 12/12/2022] [Indexed: 01/31/2023]
Abstract
Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) could contribute to colorectal cancer development and progression due to their pro-oxidative and pro-inflammatory properties. However, the association of glycer-AGEs with mortality after colorectal cancer diagnosis has not been previously investigated. Circulating glycer-AGEs were measured by competitive ELISA. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for associations of circulating glycer-AGEs concentrations with CRC-specific and all-cause mortality among 1034 colorectal cancer (CRC) cases identified within the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1993 and 2013. During a mean of 48 months of follow-up, 529 participants died (409 from CRC). Glycer-AGEs were statistically significantly positively associated with CRC-specific (HRQ5 vs Q1 = 1.53, 95% CI: 1.04-2.25, Ptrend = .002) and all-cause (HRQ5 vs Q1 = 1.62, 95% CI: 1.16-2.26, Ptrend < .001) mortality among individuals with CRC. There was suggestion of a stronger association between glycer-AGEs and CRC-specific mortality among patients with distal colon cancer (per SD increment: HRproximal colon = 1.02, 95% CI: 0.74-1.42; HRdistal colon = 1.51, 95% CI: 1.20-1.91; Peffect modification = .02). The highest HR was observed among CRC cases in the highest body mass index (BMI) and glycer-AGEs category relative to lowest BMI and glycer-AGEs category for both CRC-specific (HR = 1.78, 95% CI: 1.02-3.01) and all-cause mortality (HR = 2.15, 95% CI: 1.33-3.47), although no statistically significant effect modification was observed. Our study found that prediagnostic circulating glycer-AGEs are positively associated with CRC-specific and all-cause mortality among individuals with CRC. Further investigations in other populations and stratifying by tumor location and BMI are warranted.
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Affiliation(s)
- Ziling Mao
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jacqueline Roshelli Baker
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
- Lifecare Clinic Hiroshima, Hiroshima, Japan
| | - Anne Tjønneland
- Danish Cancer Society Research Center, Diet, Cancer and Health, Copenhagen, Denmark
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | | | - Gianluca Severi
- UVSQ, Inserm, Centre for Epidemiology and Population Health (U1018), Exposome and Heredity Team, Université Paris-Saclay, Villejuif, France
- Department of Statistics, Computer Science Applications, "G. Parenti" University of Florence, Florence, Italy
| | - Joseph Rothwell
- UVSQ, Inserm, Centre for Epidemiology and Population Health (U1018), Exposome and Heredity Team, Université Paris-Saclay, Villejuif, France
| | - Nasser Laouali
- UVSQ, Inserm, Centre for Epidemiology and Population Health (U1018), Exposome and Heredity Team, Université Paris-Saclay, Villejuif, France
| | - 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 of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Domenico Palli
- Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy
| | - Sabina Sieri
- Epidemiology and Prevention Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori di Milano Via Venezian, Milan, Italy
| | | | - Rosario Tumino
- Hyblean Association for Epidemiological Research, AIRE ONLUS, Ragusa, Italy
| | - Carlotta Sacerdote
- Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital, Turin, Italy
| | - Jeroen W G Derksen
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Inger T Gram
- Department of Community Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Guri Skeie
- Department of Community Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Torkjel M Sandanger
- Department of Community Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | | | - Marta Crous-Bou
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO) - Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Maria-Jose Sánchez
- Escuela Andaluza de Salud Pública (EASP), Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
- Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain
| | - Pilar Amiano
- Spanish Consortium for Research on 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
- Epidemiology of Chronic and Communicable Diseases Group, Biodonostia Health Research Institute, San Sebastián, Spain
| | - Sandra M Colorado-Yohar
- Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
- Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia
| | - Marcela Guevara
- Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Navarra Public Health Institute, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Sophia Harlid
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | | | - Aurora Perez-Cornago
- Cancer Epidemiology Unit (CEU), Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, UK
| | - Heinz Freisling
- Section of Nutrition and Metabolism, Nutritional Epidemiology Group, International Agency for Research on Cancer, World Health Organization (IARC-WHO), Lyon, France
| | - Marc Gunter
- Section of Nutrition and Metabolism, Nutritional Epidemiology Group, International Agency for Research on Cancer, World Health Organization (IARC-WHO), Lyon, France
| | - Elisabete Weiderpass
- Office of the Director, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Alicia K Heath
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Elom Aglago
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Mazda Jenab
- Section of Nutrition and Metabolism, Nutritional Epidemiology Group, International Agency for Research on Cancer, World Health Organization (IARC-WHO), Lyon, France
| | - Veronika Fedirko
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
- MD Anderson Cancer Center, Houston, Texas, USA
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9
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Sakasai-Sakai A, Takeda K, Takeuchi M. Involvement of Intracellular TAGE and the TAGE-RAGE-ROS Axis in the Onset and Progression of NAFLD/NASH. Antioxidants (Basel) 2023; 12:antiox12030748. [PMID: 36978995 PMCID: PMC10045097 DOI: 10.3390/antiox12030748] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/15/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
The repeated excessive intake of sugar, a factor that contributes to the onset of nonalcoholic fatty liver disease (NAFLD) and its progression to the chronic form of nonalcoholic steatohepatitis (NASH), markedly increases the hepatocyte content of glyceraldehyde (GA), a glucose/fructose metabolic intermediate. Toxic advanced glycation end-products (toxic AGEs, TAGE) are synthesized by cross-linking reactions between the aldehyde group of GA and the amino group of proteins, and their accumulation has been implicated in the development of NAFLD/NASH and hepatocellular carcinoma (HCC). Our previous findings not only showed that hepatocyte disorders were induced by the intracellular accumulation of TAGE, but they also indicated that extracellular leakage resulted in elevated TAGE concentrations in circulating fluids. Interactions between extracellular TAGE and receptor for AGEs (RAGE) affect intracellular signaling and reactive oxygen species (ROS) production, which may, in turn, contribute to the pathological changes observed in NAFLD/NASH. RAGE plays a role in the effects of the extracellular leakage of TAGE on the surrounding cells, which ultimately promote the onset and progression of NAFLD/NASH. This review describes the relationships between intracellular TAGE levels and hepatocyte and hepatic stellate cell (HSC) damage as well as the TAGE-RAGE-ROS axis in hepatocytes, HSC, and HCC cells. The "TAGE theory" will provide novel insights for future research on NAFLD/NASH.
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Affiliation(s)
- Akiko Sakasai-Sakai
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Kenji Takeda
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan
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10
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Comparison of Oleocanthal-Low EVOO and Oleocanthal against Amyloid-β and Related Pathology in a Mouse Model of Alzheimer's Disease. Molecules 2023; 28:molecules28031249. [PMID: 36770920 PMCID: PMC9921117 DOI: 10.3390/molecules28031249] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/06/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Alzheimer's disease (AD) is characterized by several pathological hallmarks, including the deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, blood-brain barrier (BBB) dysfunction, and neuroinflammation. Growing evidence support the neuroprotective effects of extra-virgin olive oil (EVOO) and oleocanthal (OC). In this work, we aimed to evaluate and compare the beneficial effects of equivalent doses of OC-low EVOO (0.5 mg total phenolic content/kg) and OC (0.5 mg OC/kg) on Aβ and related pathology and to assess their effect on neuroinflammation in a 5xFAD mouse model with advanced pathology. Homozygous 5xFAD mice were fed with refined olive oil (ROO), OC-low EVOO, or OC for 3 months starting at the age of 3 months. Our findings demonstrated that a low dose of 0.5 mg/kg EVOO-phenols and OC reduced brain Aβ levels and neuroinflammation by suppressing the nuclear factor-κB (NF-κB) pathway and reducing the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. On the other hand, only OC suppressed the receptor for advanced glycation endproducts/high-mobility group box 1 (RAGE/HMGB1) pathway. In conclusion, our results indicated that while OC-low EVOO demonstrated a beneficial effect against Aβ-related pathology in 5xFAD mice, EVOO rich with OC could provide a higher anti-inflammatory effect by targeting multiple mechanisms. Collectively, diet supplementation with EVOO or OC could prevent, halt progression, and treat AD.
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11
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Rao NL, Kotian GB, Shetty JK, Shelley BP, Dmello MK, Lobo EC, Shankar SP, Almeida SD, Shah SR. Receptor for Advanced Glycation End Product, Organ Crosstalk, and Pathomechanism Targets for Comprehensive Molecular Therapeutics in Diabetic Ischemic Stroke. Biomolecules 2022; 12:1712. [PMID: 36421725 PMCID: PMC9687999 DOI: 10.3390/biom12111712] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/03/2022] [Accepted: 11/05/2022] [Indexed: 08/10/2023] Open
Abstract
Diabetes mellitus, a well-established risk factor for stroke, is related to higher mortality and poorer outcomes following the stroke event. Advanced glycation end products(AGEs), their receptors RAGEs, other ligands, and several other processes contribute to the cerebrovascular pathomechanism interaction in the diabetes-ischemic stroke combination. Critical reappraisal of molecular targets and therapeutic agents to mitigate them is required to identify key elements for therapeutic interventions that may improve patient outcomes. This scoping review maps evidence on the key roles of AGEs, RAGEs, other ligands such as Leukotriene B4 (LTB4), High-mobility group box 1 (HMGB1) nuclear protein, brain-kidney-muscle crosstalk, alternate pathomechanisms in neurodegeneration, and cognitive decline related to diabetic ischemic stroke. RAGE, HMGB1, nitric oxide, and polyamine mechanisms are important therapeutic targets, inflicting common consequences of neuroinflammation and oxidative stress. Experimental findings on a number of existing-emerging therapeutic agents and natural compounds against key targets are promising. The lack of large clinical trials with adequate follow-up periods is a gap that requires addressing to validate the emerging therapeutic agents. Five therapeutic components, which include agents to mitigate the AGE-RAGE axis, improved biomarkers for risk stratification, better renal dysfunction management, adjunctive anti-inflammatory-antioxidant therapies, and innovative neuromuscular stimulation for rehabilitation, are identified. A comprehensive therapeutic strategy that features all the identified components is needed for outcome improvement in diabetic stroke patients.
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Affiliation(s)
- Nivedita L Rao
- Department of Biochemistry, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
| | - Greeshma B Kotian
- Department of Biochemistry, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
| | - Jeevan K Shetty
- Department of Biochemistry, School of Medicine, Royal College of Surgeons in Ireland Medical University of Bahrain, Muharraq 228, Bahrain
| | - Bhaskara P Shelley
- Department of Neurology, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
| | - Mackwin Kenwood Dmello
- Department of Public Health, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore 575018, Karnataka, India
| | - Eric C Lobo
- Department of Biochemistry, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
| | - Suchetha Padar Shankar
- College of Physiotherapy, Dayananda Sagar University, Bangalore 560111, Karnataka, India
| | - Shellette D Almeida
- School of Physiotherapy, D. Y. Patil (Deemed to be University), Navi Mumbai 400706, Maharashtra, India
| | - Saiqa R Shah
- Department of Biochemistry, Yenepoya Medical College, Yenepoya (deemed to be University), Mangalore 575018, Karnataka, India
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12
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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.
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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;
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13
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Takeuchi M, Sakasai-Sakai A, Takata T, Takino JI, Koriyama Y. Effects of Toxic AGEs (TAGE) on Human Health. Cells 2022; 11:2178. [PMID: 35883620 PMCID: PMC9317028 DOI: 10.3390/cells11142178] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/06/2022] [Accepted: 07/10/2022] [Indexed: 02/05/2023] Open
Abstract
The habitual and excessive consumption of sugar (i.e., sucrose and high-fructose corn syrup, HFCS) is associated with the onset and progression of lifestyle-related diseases (LSRD). Advanced glycation end-products (AGEs) have recently been the focus of research on the factors contributing to LSRD. Approaches that inhibit the effects of AGEs may be used to prevent and/or treat LSRD; however, since the structures of AGEs vary depending on the type of reducing sugars or carbonyl compounds to which they respond, difficulties are associated with verifying that AGEs are an etiological factor. Cytotoxic AGEs derived from glyceraldehyde, a triose intermediate in the metabolism of glucose and fructose, have been implicated in LSRD and are called toxic AGEs (TAGE). A dietary imbalance (the habitual and excessive intake of sucrose, HFCS, or dietary AGEs) promotes the generation/accumulation of TAGE in vivo. Elevated circulating levels of TAGE have been detected in non-diabetics and diabetics, indicating a strong relationship between the generation/accumulation of TAGE in vivo and the onset and progression of LSRD. We herein outline current findings on "TAGE as a new target" for human health.
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Affiliation(s)
- Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku 920-0293, Ishikawa, Japan;
| | - Akiko Sakasai-Sakai
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku 920-0293, Ishikawa, Japan;
| | - Takanobu Takata
- Department of Life Science, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku 920-0293, Ishikawa, Japan;
| | - Jun-ichi Takino
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure 737-0112, Hiroshima, Japan;
| | - Yoshiki Koriyama
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Mie, Japan;
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14
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De Masi R, Orlando S. GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review. Int J Mol Sci 2022; 23:7373. [PMID: 35806376 PMCID: PMC9266668 DOI: 10.3390/ijms23137373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022] Open
Abstract
Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc3Man9GlcNAc2 highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.
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Affiliation(s)
- Roberto De Masi
- Complex Operative Unit of Neurology, “F. Ferrari” Hospital, Casarano, 73042 Lecce, Italy;
- Laboratory of Neuroproteomics, Multiple Sclerosis Centre, “F. Ferrari” Hospital, Casarano, 73042 Lecce, Italy
| | - Stefania Orlando
- Laboratory of Neuroproteomics, Multiple Sclerosis Centre, “F. Ferrari” Hospital, Casarano, 73042 Lecce, Italy
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15
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Zhao L, Jin X, Li Y, Yu Y, He L, Liu R. Effects of A-type oligomer procyanidins on protein glycation using two glycation models coupled with spectroscopy, chromatography, and molecular docking. Food Res Int 2022; 155:111068. [DOI: 10.1016/j.foodres.2022.111068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 02/07/2022] [Accepted: 02/23/2022] [Indexed: 11/04/2022]
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16
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Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs. Cells 2022; 11:cells11081312. [PMID: 35455991 PMCID: PMC9029922 DOI: 10.3390/cells11081312] [Citation(s) in RCA: 287] [Impact Index Per Article: 95.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 01/27/2023] Open
Abstract
Advanced glycation end-products (AGEs) constitute a non-homogenous, chemically diverse group of compounds formed either exogeneously or endogeneously on the course of various pathways in the human body. In general, they are formed non-enzymatically by condensation between carbonyl groups of reducing sugars and free amine groups of nucleic acids, proteins, or lipids, followed by further rearrangements yielding stable, irreversible end-products. In the last decades, AGEs have aroused the interest of the scientific community due to the increasing evidence of their involvement in many pathophysiological processes and diseases, such as diabetes, cancer, cardiovascular, neurodegenerative diseases, and even infection with the SARS-CoV-2 virus. They are recognized by several cellular receptors and trigger many signaling pathways related to inflammation and oxidative stress. Despite many experimental research outcomes published recently, the complexity of their engagement in human physiology and pathophysiological states requires further elucidation. This review focuses on the receptors of AGEs, especially on the structural aspects of receptor-ligand interaction, and the diseases in which AGEs are involved. It also aims to present AGE classification in subgroups and to describe the basic processes leading to both exogeneous and endogeneous AGE formation.
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17
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Garlic Extract: Inhibition of Biochemical and Biophysical Changes in Glycated HSA. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app112211028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Glycation of various biomolecules contributes to structural changes and formation of several high molecular weight fluorescent and non-fluorescent, advanced glycation end products (AGEs). AGEs and glycation are involved in various health complications. Synthetic medicines, including metformin, have several adverse effects. Natural products and their derivatives are used in the treatment of various diseases due to their significant therapeutic qualities. Allium sativum (garlic) is used in traditional medicines because of its antioxidant, anti-inflammatory, and anti-diabetic properties. This study aimed to determine the anti-glycating and AGEs inhibitory activities of garlic. Biochemical and biophysical analyses were performed for in vitro incubated human serum albumin (HSA) with 0.05 M of glucose for 1, 5, and 10 weeks. Anti-glycating and AGEs inhibitory effect of garlic was investigated in glycated samples. Increased biochemical and biophysical changes were observed in glycated HSA incubated for 10 weeks (G-HSA-10W) as compared to native HSA (N-HSA) as well as glycated HSA incubated for 1 (G-HSA-1W) and 5 weeks (G-HSA-5W). Garlic extract with a concentration of ≥6.25 µg/mL exhibited significant inhibition in biophysical and biochemical changes of G-HSA-10W. Our findings demonstrated that garlic extract has the ability to inhibit biochemical and biophysical changes in HSA that occurred due to glycation. Thus, garlic extract can be used against glycation and AGE-related health complications linked with chronic diseases in diabetic patients due to its broad therapeutic potential.
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18
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Martin-Morales A, Arakawa T, Sato M, Matsumura Y, Mano-Usui F, Ikeda K, Inagaki N, Sato K. Development of a Method for Quantitation of Glyceraldehyde in Various Body Compartments of Rodents and Humans. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:13246-13254. [PMID: 34702032 DOI: 10.1021/acs.jafc.1c03177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
There is limited information available about the physiological content of glyceraldehyde, a precursor of toxic advanced glycation end products. The conventional derivatization method for aldoses using 1-phenyl-3-methyl-5-pyrazolone did not allow reproducible quantification of glyceraldehyde due to the instability of glyceraldehyde compared to other aldoses. We optimized the derivatization condition to achieve high and reproducible recovery of derivatives for liquid chromatography tandem mass spectrometry quantification. Based on the stability of glyceraldehyde during sample preparation and high recovery of spiked standard, the present method provides reproducible quantification of glyceraldehyde in the body. The glyceraldehyde contents in fasting conditions in the rodent liver (mice: 50.0 ± 3.9 nmol/g; rats: 35.5 ± 4.9 nmol/g) were higher than those in plasma (9.4 ± 1.7 and 7.2 ± 1.2 nmol/mL). The liver glyceraldehyde levels significantly increased after food consumption (p < 0.05) but remained constant in the plasma. High fat diet feeding significantly increased plasma glyceraldehyde levels in mice (p < 0.005). In healthy human volunteers, the plasma glyceraldehyde levels remained unchanged after the consumption of steamed rice. In patients with type 2 diabetes, the plasma glyceraldehyde level was positively correlated with the plasma glucose level (r = 0.84; p < 0.0001).
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Affiliation(s)
- Agustin Martin-Morales
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Kyoto 606 8054, Japan
| | - Takanori Arakawa
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Kyoto 606 8054, Japan
| | - Mona Sato
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Kyoto 606 8054, Japan
| | - Yasuki Matsumura
- Division of Agronomy and Horticultural Science, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611 0011, Japan
| | - Fumika Mano-Usui
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Kyoto 606 8507, Japan
| | - Kaori Ikeda
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Kyoto 606 8507, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Kyoto 606 8507, Japan
| | - Kenji Sato
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Kyoto 606 8054, Japan
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19
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Shi L, Lu PP, Dai GC, Li YJ, Rui YF. Advanced glycation end productions and tendon stem/progenitor cells in pathogenesis of diabetic tendinopathy. World J Stem Cells 2021; 13:1338-1348. [PMID: 34630866 PMCID: PMC8474716 DOI: 10.4252/wjsc.v13.i9.1338] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/26/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
Tendinopathy is a challenging complication observed in patients with diabetes mellitus. Tendinopathy usually leads to chronic pain, limited joint motion, and even ruptured tendons. Imaging and histological analyses have revealed pathological changes in various tendons of patients with diabetes, including disorganized arrangement of collagen fibers, microtears, calcium nodules, and advanced glycation end product (AGE) deposition. Tendon-derived stem/ progenitor cells (TSPCs) were found to maintain hemostasis and to participate in the reversal of tendinopathy. We also discovered the aberrant osteochondrogenesis of TSPCs in vitro. However, the relationship between AGEs and TSPCs in diabetic tendinopathy and the underlying mechanism remain unclear. In this review, we summarize the current findings in this field and hypothesize that AGEs could alter the properties of tendons in patients with diabetes by regulating the proliferation and differentiation of TSPCs in vivo.
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Affiliation(s)
- Liu Shi
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Pan-Pan Lu
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Guang-Chun Dai
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ying-Juan Li
- Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Yun-Feng Rui
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China.
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20
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Takino JI, Sato T, Nagamine K, Sakasai-Sakai A, Takeuchi M, Hori T. Suppression of Hepatic Stellate Cell Death by Toxic Advanced Glycation End-Products. Biol Pharm Bull 2021; 44:112-117. [PMID: 33390537 DOI: 10.1248/bpb.b20-00708] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Advanced glycation end-products (AGEs) are produced by the non-enzymatic reaction of sugars with proteins. It has been revealed that glyceraldehyde-derived toxic AGEs (TAGE) are elevated in the serum of non-alcoholic steatohepatitis (NASH) patients. NASH causes liver fibrosis and progresses to cirrhosis and hepatocellular carcinoma. However, the impact of TAGE in liver fibrosis caused by extracellular matrix accumulation remains poorly understood. In this study, we examined the effect of TAGE on the activation of hepatic stellate cells that are involved in liver fibrosis. LX-2 cells treated with transforming growth factor-β1 (TGF-β1) significantly reduced cell viability by apoptosis. However, the decrease in cell viability with TGF-β1 treatment was significantly suppressed by TAGE co-treatment. The levels of α-smooth muscle actin (α-SMA) and platelet-derived growth factor (PDGF)-Rβ and its ligand PDGF-B were increased in LX-2 cells following TGF-β1 treatment, suggesting that these cells were activated; however, these increases were unaffected by TAGE co-treatment. Moreover, collagen I level was increased with TGF-β1 treatment, and this increase was further increased by TAGE co-treatment. These results suggested that the suppression of apoptosis in activated LX-2 cells by TGF-β1 and TAGE co-treatment is related to an increase in the production of the extracellular matrix such as collagen I. Therefore, it was suggested that TAGE might aggravate the liver fibrosis of chronic hepatitis, such as NASH.
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Affiliation(s)
- Jun-Ichi Takino
- Faculty of Pharmaceutical Sciences, Hiroshima International University
| | - Takuma Sato
- Faculty of Pharmaceutical Sciences, Hiroshima International University
| | | | | | | | - Takamitsu Hori
- Faculty of Pharmaceutical Sciences, Hiroshima International University
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21
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Senavirathna L, Ma C, Chen R, Pan S. Proteomic Investigation of Glyceraldehyde-Derived Intracellular AGEs and Their Potential Influence on Pancreatic Ductal Cells. Cells 2021; 10:cells10051005. [PMID: 33923186 PMCID: PMC8145644 DOI: 10.3390/cells10051005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/14/2021] [Accepted: 04/23/2021] [Indexed: 02/07/2023] Open
Abstract
Glyceraldehyde-derived advanced glycation end products (AGEs) play an important role in the pathogenesis of many diseases including cancer. Accumulation of intracellular AGEs could stimulate cancer induction and facilitate cancer progression. We evaluated the toxic effect of glyceraldehyde-derived intracellular AGEs on normal and malignant pancreatic ductal cells by assessing the cell viability, toxicity, and oxidative stress, followed by proteomic analysis. Our functional studies showed that pancreatic cancer cells (PANC-1 and MIA PaCa-2) were more resistant to glyceraldehyde treatment compared to normal pancreatic ductal epithelial cells (HPDE), while cytotoxicity effects were observed in all cell types. Furthermore, using 13C isotopic labeled glyceraldehyde, the proteomic data revealed a dose-dependent increment of the number of glycation adducts in both these cell types. HPDE cells showed a higher number of intracellular AGEs compared to cancer cells. At a molecular level, the glycations in the lysine residues of proteins showed a concurrent increase with the concentration of the glyceraldehyde treatment, while the arginine glycations appeared to be less affected by the glyceraldehyde doses. Further pathway analysis of these glycated proteins suggested that the glycated proteins participate in important biological processes that are major hallmarks of cancer initiation and progression, including metabolic processes, immune response, oxidative stress, apoptosis, and S100 protein binding.
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Affiliation(s)
- Lakmini Senavirathna
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.S.); (C.M.)
| | - Cheng Ma
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.S.); (C.M.)
| | - Ru Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Sheng Pan
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.S.); (C.M.)
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Correspondence:
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22
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Glyceraldehyde-derived advanced glycation end-products having pyrrolopyridinium-based crosslinks. Biochem Biophys Rep 2021; 26:100963. [PMID: 33748437 PMCID: PMC7960790 DOI: 10.1016/j.bbrep.2021.100963] [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: 09/16/2020] [Revised: 01/10/2021] [Accepted: 02/22/2021] [Indexed: 11/21/2022] Open
Abstract
Reducing sugars and reactive aldehydes, such as glyceraldehyde, non-enzymatically react with amino or guanidino groups of proteins to form advanced glycation end-products (AGEs) by the Maillard reaction that involves Schiff base formation followed by Amadori rearrangement. AGEs are found relatively in abundance in the human eye and to accumulate at a higher rate in diseases that impair vision such as cataract, diabetic retinopathy or age-related macular degeneration. We identified two novel AGEs of pyrrolopyridinium lysine dimer derived from glyceraldehyde, PPG1 and PPG2, in the Maillard reaction of N α-acetyl-l-lysine with glyceraldehyde under physiological conditions. Having fluorophores similar to that of vesperlysine A, which was isolated from the human lens, PPGs were found to act as photosensitizers producing singlet oxygen in response to blue light irradiation. Moreover, PPG2 interacts with receptor for AGE (RAGE) in vitro with a higher binding affinity than GLAP, a well-known ligand of the receptor. We also proposed a pathway to form PPGs and discussed how they would be formed in vitro. As glyceraldehyde-derived AGEs have been studied extensively in connection with various hyperglycemia-related diseases, further studies will be required to find PPGs in vivo such as in the lens or other tissues.
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23
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Kuzan A. Toxicity of advanced glycation end products (Review). Biomed Rep 2021; 14:46. [PMID: 33786175 PMCID: PMC7995243 DOI: 10.3892/br.2021.1422] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/26/2021] [Indexed: 12/13/2022] Open
Abstract
Advanced glycation end-products (AGEs) are proteins or lipids glycated nonenzymatically by glucose, or other reducing sugars and their derivatives, such as glyceraldehyde, glycolaldehyde, methyloglyoxal and acetaldehyde. There are three different means of AGE formation: i) Maillard reactions, the polyol pathway and lipid peroxidation. AGEs participate in the pathological mechanisms underlying the development of several diseases, such as diabetes and its complications, retinopathy or neuropathy, neurological disorders (for example, Parkinson's disease and Alzheimer's disease), atherosclerosis, hypertension and several types of cancer. AGE levels are increased in patients with hyperglycaemia, and is likely the result of the high concentration of glycation substrates circulating in the blood. The present review summarises the formation and nomenclature of advanced glycation end-products, with an emphasis on the role of AGEs in the development of diabetes, neurological disorders, as well as in cancer and other pathologies. A particular focus is placed on the functions of toxic AGEs. Additionally, studies which have shown the cytotoxicity of glycated albumin and other AGEs are also discussed. Finally, the diagnostic relevance of AGEs as well as for targeting in therapeutic strategies are highlighted.
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Affiliation(s)
- Aleksandra Kuzan
- Department of Medical Biochemistry, Faculty of Medicine, Wrocław Medical University, Wrocław 50-368, Poland
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24
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Takeuchi M, Sakasai-Sakai A, Takata T, Takino JI, Koriyama Y, Kikuchi C, Furukawa A, Nagamine K, Hori T, Matsunaga T. Intracellular Toxic AGEs (TAGE) Triggers Numerous Types of Cell Damage. Biomolecules 2021; 11:biom11030387. [PMID: 33808036 PMCID: PMC8001776 DOI: 10.3390/biom11030387] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/24/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
The habitual intake of large amounts of sugar, which has been implicated in the onset/progression of lifestyle-related diseases (LSRD), induces the excessive production of glyceraldehyde (GA), an intermediate of sugar metabolism, in neuronal cells, hepatocytes, and cardiomyocytes. Reactions between GA and intracellular proteins produce toxic advanced glycation end-products (toxic AGEs, TAGE), the accumulation of which contributes to various diseases, such as Alzheimer’s disease, non-alcoholic steatohepatitis, and cardiovascular disease. The cellular leakage of TAGE affects the surrounding cells via the receptor for AGEs (RAGE), thereby promoting the onset/progression of LSRD. We demonstrated that the intracellular accumulation of TAGE triggered numerous cellular disorders, and also that TAGE leaked into the extracellular space, thereby increasing extracellular TAGE levels in circulating fluids. Intracellular signaling and the production of reactive oxygen species are affected by extracellular TAGE and RAGE interactions, which, in turn, facilitate the intracellular generation of TAGE, all of which may contribute to the pathological changes observed in LSRD. In this review, we discuss the relationships between intracellular TAGE levels and numerous types of cell damage. The novel concept of the “TAGE theory” is expected to open new perspectives for research into LSRD.
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Affiliation(s)
- Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan; (A.S.-S.); (T.T.)
- Correspondence: ; Tel.: +81-76-218-8456
| | - Akiko Sakasai-Sakai
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan; (A.S.-S.); (T.T.)
| | - Takanobu Takata
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan; (A.S.-S.); (T.T.)
| | - Jun-ichi Takino
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan; (J.-i.T.); (T.H.)
| | - Yoshiki Koriyama
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka, Mie 513-8670, Japan; (Y.K.); (A.F.)
| | - Chigusa Kikuchi
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan; (C.K.); (T.M.)
| | - Ayako Furukawa
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka, Mie 513-8670, Japan; (Y.K.); (A.F.)
| | - Kentaro Nagamine
- Department of Clinical Nutrition, Faculty of Health Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan;
| | - Takamitsu Hori
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan; (J.-i.T.); (T.H.)
| | - Tamihide Matsunaga
- Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan; (C.K.); (T.M.)
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25
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RasGRP2 inhibits glyceraldehyde-derived toxic advanced glycation end-products from inducing permeability in vascular endothelial cells. Sci Rep 2021; 11:2959. [PMID: 33536515 PMCID: PMC7859393 DOI: 10.1038/s41598-021-82619-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 01/22/2021] [Indexed: 01/17/2023] Open
Abstract
Advanced glycation end-products (AGEs) are formed by the non-enzymatic reaction of sugars and proteins. Among the AGEs, glyceraldehyde-derived toxic AGEs (TAGE) are associated with various diseases, including diabetic complications such as diabetic retinopathy (DR). The risk of developing DR is strongly associated with poor glycemic control, which causes AGE accumulation and increases AGE-induced vascular permeability. We previously reported that Ras guanyl nucleotide releasing protein 2 (RasGRP2), which activates small G proteins, may play an essential role in the cell response to toxicity when exposed to various factors. However, it is not known whether RasGRP2 prevents the adverse effects of TAGE in vascular endothelial cells. This study observed that TAGE enhanced vascular permeability by disrupting adherens junctions and tight junctions via complex signaling, such as ROS and non-ROS pathways. In particular, RasGRP2 protected adherens junction disruption, thereby suppressing vascular hyper-permeability. These results indicate that RasGRP2 is an essential protective factor of vascular permeability and may help develop novel therapeutic strategies for AGE-induced DR.
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26
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Inoue S, Takata T, Nakazawa Y, Nakamura Y, Guo X, Yamada S, Ishigaki Y, Takeuchi M, Miyazawa K. Potential of an Interorgan Network Mediated by Toxic Advanced Glycation End-Products in a Rat Model. Nutrients 2020; 13:80. [PMID: 33383715 PMCID: PMC7823945 DOI: 10.3390/nu13010080] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/25/2020] [Accepted: 12/25/2020] [Indexed: 12/22/2022] Open
Abstract
Excessive intake of glucose and fructose in beverages and foods containing high-fructose corn syrup (HFCS) plays a significant role in the progression of lifestyle-related diseases (LSRD). Glyceraldehyde-derived advanced glycation end-products (AGEs), which have been designated as toxic AGEs (TAGE), are involved in LSRD progression. Understanding of the mechanisms underlying the effects of TAGE on gene expression in the kidneys remains limited. In this study, DNA microarray analysis and quantitative real-time polymerase chain reaction (PCR) were used to investigate whether HFCS-consuming Wister rats generated increased intracellular serum TAGE levels, as well as the potential role of TAGE in liver and kidney dysfunction. HFCS consumption resulted in significant accumulation of TAGE in the serum and liver of rats, and induced changes in gene expression in the kidneys without TAGE accumulation or upregulation of receptor for AGEs (RAGE) upregulation. Changes in specific gene expression profiles in the kidney were more correlated with TAGE levels in the liver tissue than in the serum. These findings suggest a direct or indirect interaction may be present between the liver and kidneys that does not involve serum TAGE or RAGE. The involvement of internal signal transduction factors such as exosomes or cytokines without IL-1β and TNF-α is suggested to contribute to the observed changes in kidney gene expression.
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Affiliation(s)
- Shinya Inoue
- Department of Urology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; (Y.N.); (K.M.)
| | - Takanobu Takata
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; (T.T.); (M.T.)
| | - Yusuke Nakazawa
- Department of Urology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; (Y.N.); (K.M.)
| | - Yuka Nakamura
- Division of Molecular and Cell Biology, Department of Life Sciences, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; (Y.N.); (Y.I.)
| | - Xin Guo
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; (X.G.); (S.Y.)
| | - Sohsuke Yamada
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; (X.G.); (S.Y.)
| | - Yasuhito Ishigaki
- Division of Molecular and Cell Biology, Department of Life Sciences, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; (Y.N.); (Y.I.)
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; (T.T.); (M.T.)
| | - Katsuhito Miyazawa
- Department of Urology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; (Y.N.); (K.M.)
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27
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Takeuchi M. Toxic AGEs (TAGE) theory: a new concept for preventing the development of diseases related to lifestyle. Diabetol Metab Syndr 2020; 12:105. [PMID: 33292465 PMCID: PMC7708159 DOI: 10.1186/s13098-020-00614-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The habitual excessive intake of sugar (i.e., sucrose and high-fructose corn syrup), which has been implicated in the onset of diabetes mellitus, induces excessive production of glyceraldehyde, a metabolite produced during glucose and fructose metabolism, in hepatocytes, neuronal cells, and cardiomyocytes. MAIN TEXT Toxic advanced glycation end-products (toxic AGEs, TAGE) are formed from reactions between glyceraldehyde and intracellular proteins, and their accumulation contributes to various cellular disorders. TAGE leakage from cells affects the surrounding cells and increases serum TAGE levels, promoting the onset and/or development of lifestyle-related diseases (LSRD). Therefore, serum TAGE levels have potential as a novel biomarker for predicting the onset and/or progression of LSRD, and minimizing the effects of TAGE might help to prevent the onset and/or progression of LSRD. Serum TAGE levels are closely related to LSRD associated with the excessive ingestion of sugar and/or dietary AGEs. CONCLUSIONS The TAGE theory is also expected to open new perspectives for research into numerous other diseases.
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Affiliation(s)
- Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa, 920-0293, Japan.
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28
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Shigeta T, Sasamoto K, Yamamoto T. A novel crosslinked type of advanced glycation end-product derived from lactaldehyde. Heliyon 2020; 6:e05337. [PMID: 33204871 PMCID: PMC7653286 DOI: 10.1016/j.heliyon.2020.e05337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/05/2020] [Accepted: 10/21/2020] [Indexed: 11/16/2022] Open
Abstract
Glycation of amino or guanidino groups of proteins with glucose and glucose-derived reactive aldehydes, such as α-hydroxyaldehydes, leads to accumulation of advanced glycation end-products (AGEs) in the body, resulting in diabetic complications and age-related pathology. Although molecular structures of glycolaldehyde- and glyceraldehyde-derived AGEs have been described in previous studies, little is known about lactaldehyde-derived AGEs of α-hydroxyaldehydes. Here, we report a novel crosslinked type of AGE, named as lactaldehyde-derived lysine dimer (LAK2), which is produced due to non-enzymatic glycation of Nα-acetyl-L-lysine with lactaldehyde under physiological conditions. We have identified the molecular structure of LAK2 by extensive mass spectrometry and nuclear magnetic resonance analyses. Furthermore, we propose a reaction pathway to produce LAK2, in which it is formed through an intermediate common with the recently reported lactaldehyde-derived pyridinium-type lysine adduct (LAPL). Since lactaldehyde is known to be produced from L-threonine in a myeloperoxidase (MPO)-mediated reaction at sites of inflammation, LAK2 has the potential to be an oxidative stress marker of MPO-mediated reactions induced in inflammation.
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Affiliation(s)
- Tomoaki Shigeta
- Bloom Technology Corporation, 3-14-3 Minamikumamoto, Kumamoto 860-0812, Japan
| | - Kazumi Sasamoto
- Bloom Technology Corporation, 3-14-3 Minamikumamoto, Kumamoto 860-0812, Japan
| | - Tetsuro Yamamoto
- Bloom Technology Corporation, 3-14-3 Minamikumamoto, Kumamoto 860-0812, Japan
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29
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Nasu R, Furukawa A, Suzuki K, Takeuchi M, Koriyama Y. The Effect of Glyceraldehyde-Derived Advanced Glycation End Products on β-Tubulin-Inhibited Neurite Outgrowth in SH-SY5Y Human Neuroblastoma Cells. Nutrients 2020; 12:nu12102958. [PMID: 32992566 PMCID: PMC7601248 DOI: 10.3390/nu12102958] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/14/2020] [Accepted: 09/24/2020] [Indexed: 02/06/2023] Open
Abstract
Nutritional factors can affect the risk of developing neurological disorders and their rate of progression. In particular, abnormalities of carbohydrate metabolism in diabetes mellitus patients lead to an increased risk of neurological disorders such as Alzheimer’s disease (AD). In this study, we investigated the relationship between nervous system disorder and the pathogenesis of AD by exposing SH-SY5Y neuroblastoma cells to glyceraldehyde (GA). We previously reported that GA-derived toxic advanced glycation end products (toxic AGEs, TAGE) induce AD-like alterations including intracellular tau phosphorylation. However, the role of TAGE and their target molecules in the pathogenesis of AD remains unclear. In this study, we investigated the target protein for TAGE by performing two-dimensional immunoblot analysis with anti-TAGE antibody and mass spectrometry and identified β-tubulin as one of the targets. GA treatment induced TAGE-β-tubulin formation and abnormal aggregation of β-tubulin, and inhibited neurite outgrowth in SH-SY5Y cells. On the other hand, glucose-derived AGEs were also involved in developing AD. However, glucose did not make abnormal aggregation of β-tubulin and did not inhibit neurite outgrowth. Understanding the underlying mechanism of TAGE-β-tubulin formation by GA and its role in neurodegeneration may aid in the development of novel therapeutics and neuroprotection strategies.
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Affiliation(s)
- Ryuto Nasu
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan; (R.N.); (A.F.); (K.S.)
| | - Ayako Furukawa
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan; (R.N.); (A.F.); (K.S.)
| | - Keita Suzuki
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan; (R.N.); (A.F.); (K.S.)
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan;
| | - Yoshiki Koriyama
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki, Suzuka 513-8670, Japan; (R.N.); (A.F.); (K.S.)
- Correspondence:
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30
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Yassa NW, Khalil S, Saleh SR, Ghareeb DA, El Demellawy MA, El-Sayed MM. Ipriflavone and Ipriflavone loaded albumin nanoparticles reverse lipopolysaccharide induced neuroinflammation in rats. PLoS One 2020; 15:e0237929. [PMID: 32822403 PMCID: PMC7446929 DOI: 10.1371/journal.pone.0237929] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 08/06/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Neuroinflammation causes neurodegenerative conditions like Alzheimer's disease (AD). Ipriflavone (IP), therapeutic compound to postmenopausal osteoporosis, has limited estrogenic activity and is accounted as AChE inhibitor. The developing of drug delivery systems to enable drug targeting to specific sites increases the drug therapeutic effect. OBJECTIVE The aim of the present study was to formulate and evaluate ipriflavone loaded albumin nanoparticles (IP-Np) along with free ipriflavone against lipopolysaccharide (LPS) induced neuroinflammation in rats. METHODS Neuroinflammation was induced by intra-peritoneal (i.p) injection of LPS (250 μg/kg rat body weight) then treatments were conducted with (1) ipriflavone at two doses 50 mg/kg and 5 mg/kg, (2) IP-Np (5 mg ipriflavone/kg) or (3) IP-Np coated with polysorbate 80 (IP-Np-T80) (5 mg ipriflavone/kg). The alteration of the inflammatory response in male adult Wistar rats' brain hippocampus was investigated by examining associated indices using biochemical and molecular analyses. RESULTS A significant upsurge in inflammatory mediators and decline in antioxidant status were observed in LPS-induced rats. In one hand, ipriflavone (50 mg/kg), IP-Np and IP-Np-T80 ameliorated LPS induced brain hippocampal inflammation where they depreciated the level of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and enhanced antioxidant status. In another hand, ipriflavone at dose (5 mg/kg) didn't show the same therapeutic effect. CONCLUSION The current study provides evidence for the potential neuroprotective effect of ipriflavone (50 mg/kg) against LPS-induced neuroinflammation in rats through its anti-inflammatory and antioxidant activities. Moreover, nanoparticles significantly attenuated neuroinflammation in concentration lower than the effective therapeutic dose of free drug ten times.
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Affiliation(s)
- Nashwa W. Yassa
- Bioscreening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
- Biochemistry Department, Faulty of Science, Alexandria University, Alexandria, Egypt
| | - Sofia Khalil
- Biochemistry Department, Faulty of Science, Alexandria University, Alexandria, Egypt
| | - Samar R. Saleh
- Bioscreening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
- Biochemistry Department, Faulty of Science, Alexandria University, Alexandria, Egypt
- Pharmaceutical and Fermentation Industries Development Centre, The City of Scientific Research and Technological Applications, Alexandria, Egypt
| | - Doaa A. Ghareeb
- Bioscreening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
- Biochemistry Department, Faulty of Science, Alexandria University, Alexandria, Egypt
- Pharmaceutical and Fermentation Industries Development Centre, The City of Scientific Research and Technological Applications, Alexandria, Egypt
| | - Maha A. El Demellawy
- Pharmaceutical and Fermentation Industries Development Centre, The City of Scientific Research and Technological Applications, Alexandria, Egypt
- Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, Alexandria, Egypt
| | - Mohamed M. El-Sayed
- Bioscreening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
- Biochemistry Department, Faulty of Science, Alexandria University, Alexandria, Egypt
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31
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Fujimoto S, Murakami Y, Miyake H, Hayase F, Watanabe H. Identification of a novel advanced glycation end product derived from lactaldehyde. Biosci Biotechnol Biochem 2019; 83:1136-1145. [PMID: 30822216 DOI: 10.1080/09168451.2019.1585745] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Advanced glycation end products (AGEs) are implicated in the development of diabetic complications via the receptor for AGEs (RAGE). We have reported that the 3-hydroxypyridinium (3HP)-containing AGEs derived from α-hydroxyaldehydes physically interact with RAGE and show cytotoxicity. Lactaldehyde (LA) is formed from a reaction between threonine and myeloperoxidase, but no LA-derived AGEs have been characterized. Here, we identify the structure and physiological effects of an AGE derived from LA. We isolated a novel 3HP derivative, 2-acetamido-6-(3-hydroxy-5-methyl-pyridin-1-ium-1-yl)hexanoate, named as N-acetyl-LAPL (lactaldehyde-derived pyridinium-type lysine adduct), from a mixture of LA with Nα-acetyl-L-lysine. LAPL was also detected in the LA-modified protein. LAPL elicited toxicity in PC12 neuronal cells, but the effect was suppressed by the soluble form of RAGE as a decoy receptor. Moreover, surface plasmon resonance-based analysis revealed that LAPL specifically binds to recombinant RAGE. These results indicate that LA generates an AGE containing the 3HP moiety and contributes to RAGE-dependent cytotoxicity. Abbreviations: AGEs: advanced glycation end products; RAGE: receptor for advanced glycation end products; 3HP: 3-hydroxypyridinium; LA: lactaldehyde; LAPL: lactaldehyde-derived pyridinium-type lysine adduct; BSA: bovine serum albumin; GLAP: glyceraldehyde-derived pyridinium; MPO: myeloperoxidase; HFBA: heptafluorobutyric acid; TFA: trifluoroacetic acid; HPLC: high performance liquid chromatography; LC-ESI-QTOF-MS: liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry; NMR: nuclear magnetic resonance; LA-BSA: lactaldehyde-modified bovine serum albumin; PBS: phosphate buffered saline, GST, glutathione S-transferase; SPR: surface plasmon resonance; OP-lysine: 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate; GLO1: glyoxalase 1; MG, methylglyoxal.
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Affiliation(s)
- Shiori Fujimoto
- a Department of Agriculture , Meiji University , Kawasaki , Japan
| | - Yoto Murakami
- a Department of Agriculture , Meiji University , Kawasaki , Japan
| | - Haruna Miyake
- a Department of Agriculture , Meiji University , Kawasaki , Japan
| | - Fumitaka Hayase
- a Department of Agriculture , Meiji University , Kawasaki , Japan
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Takata T, Sakasai-Sakai A, Ueda T, Takeuchi M. Intracellular toxic advanced glycation end-products in cardiomyocytes may cause cardiovascular disease. Sci Rep 2019; 9:2121. [PMID: 30765817 PMCID: PMC6375929 DOI: 10.1038/s41598-019-39202-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 01/16/2019] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) and one of the largest public health issues. Risk factors for CVD correlate with an excessive intake of glucose and/or fructose, which has been shown to induce the production of advanced glycation end-products (AGEs). We previously identified AGEs derived from glyceraldehyde and named them toxic AGEs (TAGE) due to their cytotoxicities and relationship with LSRD. We also reported that extracellular TAGE in the vascular system may promote CVD and that serum TAGE levels are associated with risk factors for CVD. The mechanisms responsible for the onset and/or progression of CVD by extracellular TAGE or the above risk factors involve vascular disorders. In the present study, we revealed that rat primary cultured cardiomyocytes generated intracellular TAGE, which decreased beating rates and induced cell death. LC3-II/LC3-I, a factor of autophagy, also decreased. Although intracellular TAGE may be targets of degradation as cytotoxic proteins via autophagy, they may inhibit autophagy. Furthermore, the mechanisms by which intracellular TAGE decrease beating rates and induce cell death may involve the suppression of autophagy. The present results suggest that intracellular TAGE are generated in cardiomyocytes and directly damage them, resulting in CVD.
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Affiliation(s)
- Takanobu Takata
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa, 920-0293, Japan.
| | - Akiko Sakasai-Sakai
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa, 920-0293, Japan
| | - Tadashi Ueda
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa, 920-0293, Japan
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa, 920-0293, Japan
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Tarasuntisuk S, Palaga T, Kageyama H, Waditee-Sirisattha R. Mycosporine-2-glycine exerts anti-inflammatory and antioxidant effects in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Arch Biochem Biophys 2018; 662:33-39. [PMID: 30502329 DOI: 10.1016/j.abb.2018.11.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/31/2018] [Accepted: 11/27/2018] [Indexed: 10/27/2022]
Abstract
Mycosporine-like amino acids (MAAs) are a group of water-soluble low-molecular-weight secondary metabolites, which are well-documented UV-screening molecules and antioxidants. We have recently demonstrated that a rare MAA, mycosporine-2-glycine (M2G), efficiently inhibited the formation of advanced glycation end-products (AGEs). Because AGEs contribute significantly to the aging process, including the pathogenesis and progression of age-related diseases, the present study further evaluated anti-inflammatory effects of M2G using an in vitro model of RAW 264.7 macrophages. We measured the inflammatory signaling molecule nitric oxide (NO) under inflammatory stimulation by lipopolysaccharide (LPS), revealing that M2G diminished LPS-induced NO production. M2G inhibited NO production approximately 2-3-fold more potently than other MAAs, including shinorine, porphyra-334, and palythine. Transcriptional analyses revealed that M2G significantly suppressed iNOS and COX-2 expression. Therefore, M2G inhibits the production of inflammatory mediators by suppressing the NF-κB pathway. Furthermore, under H2O2-induced oxidative stress, M2G down-regulated Sod1, Cat, and Nrf2 expression. Our findings clearly demonstrate anti-inflammatory and antioxidant effects of M2G in LPS-stimulated RAW 264.7 macrophages. Structure-activity relationships of biologically active MAAs are also discussed.
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Affiliation(s)
- Supamate Tarasuntisuk
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand; The Chemical Approaches for Food Applications Research Group, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand
| | - Tanapat Palaga
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand
| | - Hakuto Kageyama
- Department of Chemistry, Faculty of Science and Technology, Meijo University, Nagoya, Aichi, 468-8502, Japan; Graduate School of Environmental and Human Sciences, Meijo University, Nagoya, Aichi, 468-8502, Japan.
| | - Rungaroon Waditee-Sirisattha
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand; The Chemical Approaches for Food Applications Research Group, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand.
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Takeuchi M, Takino JI, Sakasai-Sakai A, Takata T, Tsutsumi M. Toxic AGE (TAGE) Theory for the Pathophysiology of the Onset/Progression of NAFLD and ALD. Nutrients 2017; 9:E634. [PMID: 28632197 PMCID: PMC5490613 DOI: 10.3390/nu9060634] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 06/06/2017] [Accepted: 06/16/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are among the most common causes of chronic liver diseases in the westernized world. NAFLD and ALD are frequently accompanied by extrahepatic complications, including hepatocellular carcinoma and cardiovascular diseases, which have a negative impact on patient survival. The chronic ingestion of an excessive daily diet containing sugar/high-fructose corn syrup increases the level of the fructose/glucose metabolite, glyceraldehyde (GA), while the chronic consumption of an excessive number of alcoholic beverages increases the level of the alcohol metabolite, acetaldehyde (AA) in the liver. GA and AA are known to react non-enzymatically with the ε- or α-amino groups of proteins, thereby generating advanced glycation end-products (AGEs, GA-AGEs, and AA-AGEs, respectively) in vivo. The interaction between GA-AGEs and the receptor for AGEs (RAGE) alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the production of reactive oxygen species by human hepatocytes and hepatic stellate cells, all of which may contribute to the pathological changes associated with chronic liver diseases. We herein discuss the pathophysiological roles of GA-AGEs and AA-AGEs (toxic AGEs, TAGE) and a related novel theory for preventing the onset/progression of NAFLD and ALD.
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Affiliation(s)
- Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
| | - Jun-Ichi Takino
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
| | - Akiko Sakasai-Sakai
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
| | - Takanobu Takata
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
| | - Mikihiro Tsutsumi
- Department of Hepatology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
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Watanabe M, Toyomura T, Wake H, Liu K, Teshigawara K, Takahashi H, Nishibori M, Mori S. Advanced glycation end products attenuate the function of tumor necrosis factor-like weak inducer of apoptosis to regulate the inflammatory response. Mol Cell Biochem 2017; 434:153-162. [DOI: 10.1007/s11010-017-3045-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 04/25/2017] [Indexed: 12/31/2022]
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Byun K, Yoo Y, Son M, Lee J, Jeong GB, Park YM, Salekdeh GH, Lee B. Advanced glycation end-products produced systemically and by macrophages: A common contributor to inflammation and degenerative diseases. Pharmacol Ther 2017; 177:44-55. [PMID: 28223234 DOI: 10.1016/j.pharmthera.2017.02.030] [Citation(s) in RCA: 246] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Advanced glycation end products (AGEs) and their receptor have been implicated in the progressions of many intractable diseases, such as diabetes and atherosclerosis, and are also critical for pathologic changes in chronic degenerative diseases, such as Alzheimer's disease, Parkinson's disease, and alcoholic brain damage. Recently activated macrophages were found to be a source of AGEs, and the most abundant form of AGEs, AGE-albumin excreted by macrophages has been implicated in these diseases and to act through common pathways. AGEs inhibition has been shown to prevent the pathogenesis of AGEs-related diseases in human, and therapeutic advances have resulted in several agents that prevent their adverse effects. Recently, anti-inflammatory molecules that inhibit AGEs have been shown to be good candidates for ameliorating diabetic complications as well as degenerative diseases. This review was undertaken to present, discuss, and clarify current understanding regarding AGEs formation in association with macrophages, different diseases, therapeutic and diagnostic strategy and links with RAGE inhibition.
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Affiliation(s)
- Kyunghee Byun
- Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Republic of Korea; Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon 406-799, Republic of Korea
| | - YongCheol Yoo
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 305-811, Republic of Korea
| | - Myeongjoo Son
- Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon 406-799, Republic of Korea
| | - Jaesuk Lee
- Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Republic of Korea
| | - Goo-Bo Jeong
- Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon 406-799, Republic of Korea
| | - Young Mok Park
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 305-811, Republic of Korea.
| | - Ghasem Hosseini Salekdeh
- Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Bonghee Lee
- Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Republic of Korea; Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon 406-799, Republic of Korea.
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Ashe S, Nayak D, Kumari M, Nayak B. Ameliorating Effects of Green Synthesized Silver Nanoparticles on Glycated End Product Induced Reactive Oxygen Species Production and Cellular Toxicity in Osteogenic Saos-2 Cells. ACS APPLIED MATERIALS & INTERFACES 2016; 8:30005-30016. [PMID: 27749032 DOI: 10.1021/acsami.6b10639] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Advanced glycation end-products (AGEs) that result from nonenzymatic glycation are one of the major factors involved in diabetes and its secondary complications and diseases. This necessitates our urge to discover new compounds that may be used as potential AGEs inhibitors without affecting the normal structure and function of biomolecules. In the present study, we investigated the inhibitory effects of AgNP (silver nanoparticles) on AGEs formation as well as their inhibitory effects on glycation mediated cell toxicity via reactive oxygen species (ROS) production and DNA damage. The excitation-emission fluorescence spectroscopy was employed to investigate the interaction of AgNP during glycation. The values of conditional stability constant (log Ka = 4.44) derived from the Stern-Volmer equation indicate that AgNP have strong binding capacity for glycated protein. UV-vis, fluorescence, and Fourier transform infrared spectral data reveal complexation of AgNP with glycated bovine serum albumin, which significantly inhibits AGEs formation in a concentration-dependent manner. Cytotoxic evaluations suggest that simultaneous administration of AgNP and glycated product reduces cell death (42.82% ± 3.54) as compared to the glycated product alone. Similarly, ROS production in AgNP treated cells is significantly less compared to only glycated product treated cells. Although DNA damage studies show DNA damage in both GP and GP-AgNP treated cells, fluorescence activated cell sorting analysis demonstrates that glycated products induce cell death by necrosis, while AgNP cause cell death via apoptotic pathways. AgNP have a positive effect on restoring native protein structure deduced from spectral studies, and hence, inferences can be drawn that AgNP have ameliorating effects on glycated induced cytotoxicity observed in osteogenic Saos-2 cells.
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Affiliation(s)
- Sarbani Ashe
- Immunology and Molecular Medicine Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Debasis Nayak
- Immunology and Molecular Medicine Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Manisha Kumari
- Immunology and Molecular Medicine Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Bismita Nayak
- Immunology and Molecular Medicine Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
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Tomosugi N, Yamamoto S, Takeuchi M, Yonekura H, Ishigaki Y, Numata N, Katsuda S, Sakai Y. Effect of Collagen Tripeptide on Atherosclerosis in Healthy Humans. J Atheroscler Thromb 2016; 24:530-538. [PMID: 27725401 PMCID: PMC5429168 DOI: 10.5551/jat.36293] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
AIM Collagen tripeptide (CTP) is a functional food with a high content of Gly-X-Y tripeptides derived from collagen. The objective of this study was to evaluate the effect of CTP administration on the development of atherosclerosis in healthy individuals. METHODS The present study was conducted in the form of an open-label, single-dose trial for 6 months. All subjects ingested CTP twice daily: at breakfast and supper (total intake per day: 16 g). The effect of CTP on atherosclerosis was verified by measuring several indices, including serum lipid levels, toxic advanced glycation end-products (TAGE), and the cardio-ankle vascular index (CAVI), at baseline and 6 months. RESULTS The low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (LDL-C/HDL-C ratio) was significantly reduced in patients with an initial ratio of ≥2.5 (p=0.025). A significant reduction in TAGE was observed in all the subjects (p=0.031) and in the high-risk group (p=0.024). A significant reduction in CAVI was observed in all the subjects (right side: p=0.048, left side: p=0.047). As a result of multiple regression analysis, a significant relationship between the change in CAVI and that in each factor was not observed. No adverse events were observed during the study period. CONCLUSIONS The results of the present study indicate that CTP contributes to the prevention and treatment of atherosclerosis in healthy humans (UMIN000018525).
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Affiliation(s)
- Naohisa Tomosugi
- Division of Aging Research, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University
| | | | - Masayoshi Takeuchi
- Division of AGEs Research, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University
| | | | - Yasuhito Ishigaki
- Division of Molecular Oncology and Virology, Department of Life Science, Medical Research Institute, Kanazawa Medical University
| | | | - Shogo Katsuda
- Department of Pathology II, President of Kanazawa Medical University
| | - Yasuo Sakai
- Central Research Institute, Jellice Co., Ltd
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Takeuchi M. Serum Levels of Toxic AGEs (TAGE) May Be a Promising Novel Biomarker for the Onset/Progression of Lifestyle-Related Diseases. Diagnostics (Basel) 2016; 6:E23. [PMID: 27338481 PMCID: PMC4931418 DOI: 10.3390/diagnostics6020023] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 05/30/2016] [Accepted: 06/01/2016] [Indexed: 12/11/2022] Open
Abstract
Advanced glycation end-products (AGEs) generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde (Glycer-AGEs; termed toxic AGEs (TAGE)), were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE). TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer's disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD) and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or Nε-(carboxymethyl)lysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD.
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Affiliation(s)
- Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Kahoku, Ishikawa 920-0293, Japan.
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Nε-(carboxymethyl)-lysine, White Matter, and Cognitive Function in Diabetes Patients. Can J Neurol Sci 2016; 43:518-22. [PMID: 26889714 DOI: 10.1017/cjn.2015.398] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To study the relationship of Nε-(carboxymethyl)-lysine level (CML) with microstructure changes of white matter (WM), and cognitive impairment in patients with type 2 diabetes mellitus (T2DM) and to discuss the potential mechanism underlying T2DM-associated cognitive impairment. METHODS The study was performed in T2DM patients (n=22) with disease course ≥5 years and age ranging from 65 to 75 years old. A control group consisted of 25 sex- and age-matched healthy volunteers. Fractional anisotropy (FA) of several WM regions was analyzed by diffusion tensor imaging scan. Plasma CML levels were measured by enzyme-linked immunosorbent assay, and cognitive function was assessed by Mini-Mental State Examination and Montreal cognitive assessment (MoCA). RESULTS The total Mini-Mental State Examination score in the patient group (25.72±3.13) was significantly lower than the control group (28.16±2.45) (p<0.05). In addition, the total MoCA score in the patient group (22.15±3.56) was significantly lower than the control group 25.63±4.12) (p<0.01). In the patient group, FA values were significantly decreased in the corpus callosum, cingulate fasciculus, inferior fronto-occipital fasciculus, parietal WM, hippocampus, and temporal lobes relative to corresponding regions of healthy controls (p<0.05). Plasma CML level was negatively correlated with average FA values in the global brain (r=-0.58, p<0.01) and MoCA scores (r=-0.47, p<0.05). CONCLUSIONS In T2DM, WM microstructure changes occur in older patients, and elevations in CML may play a role in the development of cognitive impairment.
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Shimomura M, Oyama JI, Takeuchi M, Shibata Y, Yamamoto Y, Kawasaki T, Komoda H, Kodama K, Sakuma M, Toyoda S, Inoue Y, Mine D, Natsuaki M, Komatsu A, Hikichi Y, Yamagishi SI, Inoue T, Node K. Acute effects of statin on reduction of angiopoietin-like 2 and glyceraldehyde-derived advanced glycation end-products levels in patients with acute myocardial infarction: a message from SAMIT (Statin for Acute Myocardial Infarction Trial). Heart Vessels 2015; 31:1583-9. [PMID: 26699899 DOI: 10.1007/s00380-015-0773-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 11/20/2015] [Indexed: 11/29/2022]
Abstract
Experimental ischemia-reperfusion models have shown that 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, have cardioprotective effects. SAMIT (Statin Acute Myocardial Infarction Trial) is a multicenter prospective open randomized trial, designed to evaluate the effects of statin treatment from the earliest stage on cardioprotection in patients with acute myocardial infarction (AMI). Patients were randomly assigned to receive atorvastatin (initial dose of 40 mg at admission followed by the maintenance dose of 10 mg/day for 30 days) or not (control), and then immediately underwent percutaneous coronary intervention (PCI) for the culprit lesion. The primary endpoints were infarct size and left ventricular function. The secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) and various biomarkers. There were no significant differences in baseline characteristics between 2 groups of the statin treatment group and the control group. The left ventricular ejection fraction increased at 6 months after the onset of AMI, compared with the baseline level in the atorvastatin group (P < 0.05), while it did not change in the control group. Although there were no significant differences in the MACCE, the changes in the levels of angiopoietin-like protein 2 (ANGPTL2) (P < 0.05), and glyceraldehyde-derived advanced glycation end-products, (TAGE) (P < 0.01) were suppressed at 2 weeks in the atorvastatin group, compared with the control group. Statin therapy started early after the onset reduced the levels of ANGPTL2 and TAGE, and thus, might have cardioprotective effects in patients with AMI.
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Affiliation(s)
- Mitsuhiro Shimomura
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Jun-Ichi Oyama
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan
| | - Yoshisato Shibata
- Department of Cardiology, Miyazaki Medical Association Hospital, Miyazaki, Japan
| | - Yusuke Yamamoto
- Division of Cardiology, Cardiovascular and Aortic Center, Saiseikai Fukuoka General Hospital, Fukuoka, Japan
| | | | - Hiroshi Komoda
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Kazuhisa Kodama
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Masashi Sakuma
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Shigeru Toyoda
- Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Yohei Inoue
- Department of Cardiology, Miyazaki Medical Association Hospital, Miyazaki, Japan
| | - Daigo Mine
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Masahiro Natsuaki
- Division of Cardiology, Cardiovascular and Aortic Center, Saiseikai Fukuoka General Hospital, Fukuoka, Japan
| | - Aiko Komatsu
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Yutaka Hikichi
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Fukuoka, Japan
| | - Teruo Inoue
- Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
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Kong SY, Takeuchi M, Hyogo H, McKeown-Eyssen G, Yamagishi SI, Chayama K, O'Brien PJ, Ferrari P, Overvad K, Olsen A, Tjønneland A, Boutron-Ruault MC, Bastide N, Carbonnel F, Kühn T, Kaaks R, Boeing H, Aleksandrova K, Trichopoulou A, Lagiou P, Vasilopoulou E, Masala G, Pala V, Santucci De Magistris M, Tumino R, Naccarati A, Bueno-de-Mesquita HB, Peeters PH, Weiderpass E, Quirós JR, Jakszyn P, Sánchez MJ, Dorronsoro M, Gavrila D, Ardanaz E, Rutegård M, Nyström H, Wareham NJ, Khaw KT, Bradbury KE, Romieu I, Freisling H, Stavropoulou F, Gunter MJ, Cross AJ, Riboli E, Jenab M, Bruce WR. The Association between Glyceraldehyde-Derived Advanced Glycation End-Products and Colorectal Cancer Risk. Cancer Epidemiol Biomarkers Prev 2015; 24:1855-63. [PMID: 26404963 PMCID: PMC6284787 DOI: 10.1158/1055-9965.epi-15-0422] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 07/28/2015] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND A large proportion of colorectal cancers are thought to be associated with unhealthy dietary and lifestyle exposures, particularly energy excess, obesity, hyperinsulinemia, and hyperglycemia. It has been suggested that these processes stimulate the production of toxic reactive carbonyls from sugars such as glyceraldehyde. Glyceraldehyde contributes to the production of a group of compounds known as glyceraldehyde-derived advanced glycation end-products (glycer-AGEs), which may promote colorectal cancer through their proinflammatory and pro-oxidative properties. The objective of this study nested within a prospective cohort was to explore the association of circulating glycer-AGEs with risk of colorectal cancer. METHODS A total of 1,055 colorectal cancer cases (colon n = 659; rectal n = 396) were matchced (1:1) to control subjects. Circulating glycer-AGEs were measured by a competitive ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (95% CI), adjusting for potential confounding factors, including smoking, alcohol, physical activity, body mass index, and diabetes status. RESULTS Elevated glycer-AGEs levels were not associated with colorectal cancer risk (highest vs. lowest quartile, 1.10; 95% CI, 0.82-1.49). Subgroup analyses showed possible divergence by anatomical subsites (OR for colon cancer, 0.83; 95% CI, 0.57-1.22; OR for rectal cancer, 1.90; 95% CI, 1.14-3.19; Pheterogeneity = 0.14). CONCLUSIONS In this prospective study, circulating glycer-AGEs were not associated with risk of colon cancer, but showed a positive association with the risk of rectal cancer. IMPACT Further research is needed to clarify the role of toxic products of carbohydrate metabolism and energy excess in colorectal cancer development.
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Affiliation(s)
- So Yeon Kong
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Kanazawa, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | | | - Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - Peter J O'Brien
- Department of Pharmacology, University of Toronto, Toronto, Canada
| | - Pietro Ferrari
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Kim Overvad
- Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Anja Olsen
- Diet, Genes, and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Anne Tjønneland
- Diet, Genes, and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Marie-Christine Boutron-Ruault
- Lifestyle, Genes, and Health: Trans-generational Integrated Epidemiology, EMT, Institute Gustave Roussy, Villejuif, France
| | - Nadia Bastide
- Lifestyle, Genes, and Health: Trans-generational Integrated Epidemiology, EMT, Institute Gustave Roussy, Villejuif, France
| | - Franck Carbonnel
- Lifestyle, Genes, and Health: Trans-generational Integrated Epidemiology, EMT, Institute Gustave Roussy, Villejuif, France. Service d'hépato-gastroentérologie, Hôpital Bicetre, Le Kremlin-Bicêtre Cedex, France
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Heiner Boeing
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Krasimira Aleksandrova
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece. Department of Hygiene, Epidemiology, and Medical Statistics, University of Athens Medical School, Athens, Greece. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece
| | - Pagona Lagiou
- Department of Hygiene, Epidemiology, and Medical Statistics, University of Athens Medical School, Athens, Greece. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - Effie Vasilopoulou
- Department of Hygiene, Epidemiology, and Medical Statistics, University of Athens Medical School, Athens, Greece
| | - Giovanna Masala
- Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy
| | - Valeria Pala
- Epidemiology and Prevention Unit, IRCCS Foundation, National Cancer Institute, Milan, Italy
| | | | - Rosario Tumino
- Cancer Registry and Histopathology Unit, "Civic - MP Arezzo" Hospital, Ragusa, Italy
| | - Alessio Naccarati
- Human Genetics Foundation, Torino Molecular and Genetic Epidemiology Unit, Torino, Italy
| | - H B Bueno-de-Mesquita
- Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and Environment (RIVM), Bilthoven, the Netherlands. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands. Department of Epidemiology and Biostatistics, The School of Public Health, Imperil College London, London, United Kingdom. Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Petra H Peeters
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatics, School of Public Health, Imperial College, London, United Kingdom
| | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway. Cancer Registry of Norway, Oslo, Norway. Department of Medical Epidemiology and Biostatistics, Karolinska Instituet, Stockholm, Sweden. Department of Genetic Epidemiology, Folkhälsan Research Center, Helsinki, Finland
| | | | - Paula Jakszyn
- Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain
| | - María-José Sánchez
- CIBER Epidemiology and Public Health (CIBERESP), Spain. Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs. GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
| | - Miren Dorronsoro
- Public Health Direction and CIBERESP-Biodonostia Research Institute, Basque Regional Health Department, San Sebastian, Spain
| | - Diana Gavrila
- CIBER Epidemiology and Public Health (CIBERESP), Spain. Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
| | - Eva Ardanaz
- CIBER Epidemiology and Public Health (CIBERESP), Spain. Navarre Public Health Institute, Pamplona, Spain
| | - Martin Rutegård
- Department of Surgery, Department of Surgical and Perioperative Sciences, Umeå University, Sweden
| | - Hanna Nyström
- Department of Surgery, Department of Surgical and Perioperative Sciences, Umeå University, Sweden
| | - Nicholas J Wareham
- MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Kay-Tee Khaw
- Clinical Gerontology Unit, Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, United Kingdom
| | - Kathryn E Bradbury
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Isabelle Romieu
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Heinz Freisling
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Faidra Stavropoulou
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Marc J Gunter
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Mazda Jenab
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
| | - W Robert Bruce
- Department of Nutritional Sciences, University of Toronto, Toronto, Canada.
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Takino JI, Nagamine K, Hori T, Sakasai-Sakai A, Takeuchi M. Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma. World J Hepatol 2015; 7:2459-2469. [PMID: 26483867 PMCID: PMC4606201 DOI: 10.4254/wjh.v7.i23.2459] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 05/07/2015] [Accepted: 09/07/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The main etiologies of HCC are hepatitis B virus and hepatitis C virus (HCV), and non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) has also been identified as an etiological factor. Although the incidence of HCV-related HCC in Japan has decreased slightly in recent years, that of NBNC-HCC has increased. The onset mechanism of NBNC-HCC, which has various etiologies, remains unclear; however, nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is known to be an important risk factor for NBNC-HCC. Among the different advanced glycation end-products (AGEs) formed by the Maillard reaction, glyceraldehyde-derived AGEs, the predominant components of toxic AGEs (TAGE), have been associated with NASH and NBNC-HCC, including NASH-related HCC. Furthermore, the expression of the receptor for AGEs (RAGE) has been correlated with the malignant progression of HCC. Therefore, TAGE induce oxidative stress by binding with RAGE may, in turn, lead to adverse effects, such as fibrosis and malignant transformation, in hepatic stellate cells and tumor cells during NASH or NASH-related HCC progression. The aim of this review was to examine the contribution of the TAGE-RAGE axis in NASH-related HCC.
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Müller HD, Cvikl B, Janjić K, Nürnberger S, Moritz A, Gruber R, Agis H. Effects of Prolyl Hydroxylase Inhibitor L-mimosine on Dental Pulp in the Presence of Advanced Glycation End Products. J Endod 2015; 41:1852-61. [PMID: 26395911 DOI: 10.1016/j.joen.2015.08.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 07/30/2015] [Accepted: 08/04/2015] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Proangiogenic prolyl hydroxylase (PHD) inhibitors represent a novel approach to stimulate tissue regeneration. Diabetes mellitus involves the accumulation of advanced glycation end products (AGEs). Here we evaluated the impact of AGEs on the response of human pulp tissue to the PHD inhibitor L-mimosine (L-MIM) in monolayer cultures of dental pulp-derived cells (DPCs) and tooth slice organ cultures. METHODS In monolayer cultures, DPCs were incubated with L-MIM and AGEs. Viability was assessed based on formazan formation, live-dead staining, annexin V/propidium iodide, and trypan blue exclusion assay. Vascular endothelial growth factor (VEGF), interleukin (IL)-6, and IL-8 production was evaluated by quantitative polymerase chain reaction and immunoassays. Furthermore, expression levels of odontoblast markers were assessed, and alizarin red staining was performed. Tooth slice organ cultures were performed, and VEGF, IL-6, and IL8 levels in their supernatants were measured by immunoassays. Pulp tissue vitality and morphology were assessed by MTT assay and histology. RESULTS In monolayer cultures of DPCs, L-MIM at nontoxic concentrations increased the production of VEGF and IL-8 in the presence of AGEs. Stimulation with L-MIM decreased alkaline phosphatase levels and matrix mineralization also in the presence of AGEs, whereas no significant changes in dentin matrix protein 1 and dentin sialophosphoprotein expression were observed. In tooth slice organ cultures, L-MIM increased VEGF but not IL-6 and IL-8 production in the presence of AGEs. The pulp tissue was vital, and no signs of apoptosis or necrosis were observed. CONCLUSIONS Overall, in the presence of AGEs, L-MIM increases the proangiogenic capacity, but decreases alkaline phosphatase expression and matrix mineralization.
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Affiliation(s)
- Heinz-Dieter Müller
- Department of Prosthodontics, Medical University of Vienna, Vienna, Austria; Department of Preventive, Restorative and Pediatric Dentistry, University of Bern, Bern, Switzerland; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Barbara Cvikl
- Department of Preventive, Restorative and Pediatric Dentistry, University of Bern, Bern, Switzerland; Austrian Cluster for Tissue Regeneration, Vienna, Austria; Department of Conservative Dentistry and Periodontology, Medical University of Vienna, Vienna, Austria
| | - Klara Janjić
- Austrian Cluster for Tissue Regeneration, Vienna, Austria; Department of Conservative Dentistry and Periodontology, Medical University of Vienna, Vienna, Austria
| | - Sylvia Nürnberger
- Austrian Cluster for Tissue Regeneration, Vienna, Austria; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria; Department of Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Andreas Moritz
- Austrian Cluster for Tissue Regeneration, Vienna, Austria; Department of Conservative Dentistry and Periodontology, Medical University of Vienna, Vienna, Austria
| | - Reinhard Gruber
- Austrian Cluster for Tissue Regeneration, Vienna, Austria; Department of Oral Biology, Medical University of Vienna, Vienna, Austria; Laboratory for Oral Cell Biology, University of Bern, Bern, Switzerland
| | - Hermann Agis
- Austrian Cluster for Tissue Regeneration, Vienna, Austria; Department of Conservative Dentistry and Periodontology, Medical University of Vienna, Vienna, Austria.
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Kumagai Y, Nakatani S, Onodera H, Nagatomo A, Nishida N, Matsuura Y, Kobata K, Wada M. Anti-Glycation Effects of Pomegranate (Punica granatum L.) Fruit Extract and Its Components in Vivo and in Vitro. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:7760-7764. [PMID: 26242637 DOI: 10.1021/acs.jafc.5b02766] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Accumulation of advanced glycation end products (AGEs) leads to various diseases such as diabetic complications and arteriosclerosis. In this study, we examined the effect of pomegranate fruit extract (PFE) and its constituent polyphenols on AGE formation in vivo and in vitro. PFE, fed with a high-fat and high-sucrose (HFS) diet to KK-A(y) mice, significantly reduced glycation products such as glycoalbumin (22.0 ± 2.4%), hemoglobin A1c (5.84 ± 0.23%), and serum AGEs (8.22 ± 0.17 μg/mL), as compared to a control HFS group (30.6 ± 2.6%, 7.45 ± 0.12%, and 9.55 ± 0.17 μg/mL, respectively, P < 0.05). In antiglycation assays, PFE, punicalin, punicalagin, ellagic acid, and gallic acid suppressed the formation of AGEs from bovine serum albumin and sugars. In this study, we discuss the mechanism of the antiglycation effects of PFE and its components in vivo and in vitro.
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Affiliation(s)
- Yuya Kumagai
- Department of Pharmaceutial and Health Sciences, Faculty of Pharmaceutical Sciences, Josai University , Saitama, Japan
| | - Sachie Nakatani
- Department of Pharmaceutial and Health Sciences, Faculty of Pharmaceutical Sciences, Josai University , Saitama, Japan
| | - Hideaki Onodera
- Department of Pharmaceutial and Health Sciences, Faculty of Pharmaceutical Sciences, Josai University , Saitama, Japan
| | | | | | | | - Kenji Kobata
- Department of Pharmaceutial and Health Sciences, Faculty of Pharmaceutical Sciences, Josai University , Saitama, Japan
| | - Masahiro Wada
- Department of Pharmaceutial and Health Sciences, Faculty of Pharmaceutical Sciences, Josai University , Saitama, Japan
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Koriyama Y, Furukawa A, Muramatsu M, Takino JI, Takeuchi M. Glyceraldehyde caused Alzheimer's disease-like alterations in diagnostic marker levels in SH-SY5Y human neuroblastoma cells. Sci Rep 2015; 5:13313. [PMID: 26304819 PMCID: PMC4548441 DOI: 10.1038/srep13313] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 07/21/2015] [Indexed: 01/12/2023] Open
Abstract
Clinical evidence has implicated diabetes mellitus as one of the risk factors for the development and progression of Alzheimer’s disease (AD). However, the neurotoxic pathway activated due to abnormalities in glucose metabolism has not yet been identified in AD. In order to investigate the relationship between impaired cerebral glucose metabolism and the pathophysiology of AD, SH-SY5Y human neuroblastoma cells were exposed to glyceraldehyde (GA), an inhibitor of glycolysis. GA induced the production of GA-derived advanced glycation end-products (GA-AGEs) and cell apoptosis, glycolytic inhibition, decreases in the medium concentrations of diagnostic markers of AD, such as amyloid β 1-42 (Aβ42), and increases in tau phosphorylation. These results suggest that the production of GA-AGEs and/or inhibition of glycolysis induce AD-like alterations, and this model may be useful for examining the pathophysiology of AD.
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Affiliation(s)
- Yoshiki Koriyama
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, 513-8670, Japan
| | - Ayako Furukawa
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, 513-8670, Japan
| | - Michiru Muramatsu
- Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Ishikawa, 920-1181, Japan
| | - Jun-ichi Takino
- Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa, 920-0293, Japan
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Ferreira MES, de Vasconcelos AS, da Costa Vilhena T, da Silva TL, da Silva Barbosa A, Gomes ARQ, Dolabela MF, Percário S. Oxidative Stress in Alzheimer's Disease: Should We Keep Trying Antioxidant Therapies? Cell Mol Neurobiol 2015; 35:595-614. [PMID: 25616523 PMCID: PMC11486210 DOI: 10.1007/s10571-015-0157-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 01/13/2015] [Indexed: 11/28/2022]
Abstract
The risk of chronic diseases such as Alzheimer's disease is growing as a result of the continuous increasing average life span of the world population, a syndrome characterized by the presence of intraneural neurofibrillary tangles and senile plaques composed mainly by beta-amyloid protein, changes that may cause a number of progressive disorders in the elderly, causing, in its most advanced stage, difficulty in performing normal daily activities, among other manifestations. Therefore, it is important to understand the underlying pathogenic mechanisms of this syndrome. Nevertheless, despite intensive effort to access the physiopathological pathways of the disease, it remains poorly understood. In that context, some hypotheses have arisen, including the recent oxidative stress hypothesis, theory supported by the involvement of oxidative stress in aging, and the vulnerability of neurons to oxidative attack. In the present revision, oxidative changes and redox mechanisms in Alzheimer's disease will be further stressed, as well as the grounds for antioxidant supplementation as adjuvant therapy for the disease will be addressed.
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Affiliation(s)
- Michelli Erica Souza Ferreira
- Oxidative Stress Research Lab, Institute of Biological Sciences (LAPEO – ICB), Federal University of Pará, Av. Augusto Correa, 01, Belém, PA 66075-110 Brazil
| | - Amanda Soares de Vasconcelos
- Oxidative Stress Research Lab, Institute of Biological Sciences (LAPEO – ICB), Federal University of Pará, Av. Augusto Correa, 01, Belém, PA 66075-110 Brazil
| | - Thyago da Costa Vilhena
- Pharmacy Department, Institute of Health Sciences, Federal University of Pará, Av. Augusto Correa, 01, Belém, PA 66075-110 Brazil
| | - Thiago Leite da Silva
- Pharmacy Department, Institute of Health Sciences, Federal University of Pará, Av. Augusto Correa, 01, Belém, PA 66075-110 Brazil
| | - Aline da Silva Barbosa
- Oxidative Stress Research Lab, Institute of Biological Sciences (LAPEO – ICB), Federal University of Pará, Av. Augusto Correa, 01, Belém, PA 66075-110 Brazil
| | - Antonio Rafael Quadros Gomes
- Oxidative Stress Research Lab, Institute of Biological Sciences (LAPEO – ICB), Federal University of Pará, Av. Augusto Correa, 01, Belém, PA 66075-110 Brazil
| | - Maria Fani Dolabela
- Pharmacy Department, Institute of Health Sciences, Federal University of Pará, Av. Augusto Correa, 01, Belém, PA 66075-110 Brazil
| | - Sandro Percário
- Oxidative Stress Research Lab, Institute of Biological Sciences (LAPEO – ICB), Federal University of Pará, Av. Augusto Correa, 01, Belém, PA 66075-110 Brazil
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Takeda M, Ohnuma T, Takeuchi M, Katsuta N, Maeshima H, Takebayashi Y, Higa M, Nakamura T, Nishimon S, Sannohe T, Hotta Y, Hanzawa R, Higashiyama R, Shibata N, Gohda T, Suzuki Y, Yamagishi SI, Tomino Y, Arai H. Altered serum glyceraldehyde-derived advanced glycation end product (AGE) and soluble AGE receptor levels indicate carbonyl stress in patients with schizophrenia. Neurosci Lett 2015; 593:51-5. [PMID: 25766756 DOI: 10.1016/j.neulet.2015.03.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 02/26/2015] [Accepted: 03/02/2015] [Indexed: 12/20/2022]
Abstract
Recent cross-sectional and longitudinal studies indicate that measurements of peripheral blood carbonyl stress markers such as the advanced glycation end product (AGE) pentosidine and the reactive carbonyl-detoxifying B6 vitamin pyridoxal could be used as therapeutic biological markers in subpopulations of schizophrenia patients. Glyceraldehyde-derived AGEs (Glycer-AGE) have strong neurotoxicity, and soluble receptors for AGEs (sRAGE) may ameliorate the effects of AGEs. In the present study, we measured Glycer-AGEs and sRAGE levels to determine their potential as diagnostic, therapeutic, or clinical biological markers in patients with schizophrenia. After enrollment of 61 admitted Japanese patients with acute schizophrenia and 39 healthy volunteers, 54 patients were followed up from the acute stage to remission. Serum biomarkers were measured in blood samples taken before breakfast using competitive enzyme-linked immunosorbent assays, and Glycer-AGEs were significantly higher and sRAGE levels were significantly lower in patients with acute schizophrenia than in healthy controls. Glycer-AGEs/sRAGE ratios were also higher in schizophrenia patients and were stable during the clinical course. Furthermore, discriminant analyses confirmed that Glycer-AGEs and Glycer-AGEs/sRAGE ratios are significant diagnostic markers for schizophrenia, and distinguished between patients and healthy controls in 70.0% of cases. However, these markers of carbonyl stress were not correlated with clinical features, including disease severity, or with daily chlorpromazine doses. These data indicate the potential of Glycer-AGEs, RAGEs, and their relative ratios as diagnostic markers for patients with schizophrenia.
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Affiliation(s)
- Mayu Takeda
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Tohru Ohnuma
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan.
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan
| | - Narimasa Katsuta
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Hitoshi Maeshima
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Yuto Takebayashi
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Motoyuki Higa
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Toru Nakamura
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Shohei Nishimon
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Takahiro Sannohe
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Yuri Hotta
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Ryo Hanzawa
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Ryoko Higashiyama
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Nobuto Shibata
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Tomohito Gohda
- Division of Nephrology, Department of Internal Medicine, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Sho-ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Juntendo University, Faculty of Medicine, Tokyo, Japan
| | - Heii Arai
- Juntendo University Schizophrenia Projects (JUSP), Department of Psychiatry, Juntendo University, Faculty of Medicine, Tokyo, Japan
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Takeuchi M, Takino JI, Furuno S, Shirai H, Kawakami M, Muramatsu M, Kobayashi Y, Yamagishi SI. Assessment of the concentrations of various advanced glycation end-products in beverages and foods that are commonly consumed in Japan. PLoS One 2015; 10:e0118652. [PMID: 25730321 PMCID: PMC4346397 DOI: 10.1371/journal.pone.0118652] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 01/09/2015] [Indexed: 01/24/2023] Open
Abstract
Dietary consumption has recently been identified as a major environmental source of pro-inflammatory advanced glycation end-products (AGEs) in humans. It is disputed whether dietary AGEs represent a risk to human health. Nε-(carboxymethyl)lysine (CML), a representative AGE compound found in food, has been suggested to make a significant contribution to circulating CML levels. However, recent studies have found that the dietary intake of AGEs is not associated with plasma CML concentrations. We have shown that the serum levels of glyceraldehyde-derived AGEs (Glycer-AGEs), but not hemoglobin A1c, glucose-derived AGEs (Glu-AGEs), or CML, could be used as biomarkers for predicting the progression of atherosclerosis and future cardiovascular events. We also detected the production/accumulation of Glycer-AGEs in normal rats administered Glu-AGE-rich beverages. Therefore, we assessed the concentrations of various AGEs in a total of 1,650 beverages and foods that are commonly consumed in Japan. The concentrations of four kinds of AGEs (Glu-AGEs, fructose-derived AGEs (Fru-AGEs), CML, and Glycer-AGEs) were measured with competitive enzyme-linked immunosorbent assays involving immunoaffinity-purified specific antibodies. The results of the latter assays indicated that Glu-AGEs and Fru-AGEs (especially Glu-AGEs), but not CML or Glycer-AGEs, are present at appreciable levels in beverages and foods that are commonly consumed by Japanese. Glu-AGEs, Fru-AGEs, CML, and Glycer-AGEs exhibited concentrations of ≥85%, 2–12%, <3%, and trace amounts in the examined beverages and ≥82%, 5–15%, <3%, and trace amounts in the tested foods, respectively. The results of the present study indicate that some lactic acid bacteria beverages, carbonated drinks, sugar-sweetened fruit drinks, sports drinks, mixed fruit juices, confectionery (snacks), dried fruits, cakes, cereals, and prepared foods contain markedly higher Glu-AGE levels than other classes of beverages and foods. We provide useful data on the concentrations of various AGEs, especially Glu-AGEs, in commonly consumed beverages and foods.
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Affiliation(s)
- Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa, Japan
- * E-mail:
| | - Jun-ichi Takino
- Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, Japan
| | - Satomi Furuno
- Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Ishikawa, Japan
| | - Hikari Shirai
- Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Ishikawa, Japan
| | - Mihoko Kawakami
- Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Ishikawa, Japan
| | - Michiru Muramatsu
- Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Ishikawa, Japan
| | - Yuka Kobayashi
- Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Ishikawa, Japan
| | - Sho-ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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Takeuchi M, Takino JI, Sakasai-Sakai A, Takata T, Ueda T, Tsutsumi M, Hyogo H, Yamagishi SI. Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies. World J Hepatol 2014; 6:880-893. [PMID: 25544875 PMCID: PMC4269907 DOI: 10.4254/wjh.v6.i12.880] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 09/12/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM-induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH.
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