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Zhu J, Wang Z, Lv C, Li M, Wang K, Chen Z. Advanced Glycation End Products and Health: A Systematic Review. Ann Biomed Eng 2024; 52:3145-3156. [PMID: 38705931 DOI: 10.1007/s10439-024-03499-9] [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: 01/11/2024] [Accepted: 03/19/2024] [Indexed: 05/07/2024]
Abstract
Advanced glycation end products (AGEs) have garnered significant attention due to their association with chronic diseases and the aging process. The prevalence of geriatric diseases among young individuals has witnessed a notable surge in recent years, potentially attributed to the accelerated pace of modern life. The accumulation of AGEs is primarily attributed to their inherent difficulty in metabolism, which makes them promising biomarkers for chronic disease detection. This review aims to provide a comprehensive overview of the recent advancements and findings in AGE research. The discussion is divided into two main sections: endogenous AGEs (formed within the body) and exogenous AGEs (derived from external sources). Various aspects of AGEs are subsequently summarized, including their production pathways, pathogenic mechanisms, and detection methods. Moreover, this review delves into the future research prospects concerning AGEs. Overall, this comprehensive review underscores the importance of AGEs in the detection of chronic diseases and provides a thorough understanding of their significance. It emphasizes the necessity for further research endeavors to deepen our comprehension of AGEs and their implications for human health.
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Affiliation(s)
- Jianming Zhu
- School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, 541004, China
- Guangxi Key Laboratory of Automatic Detecting Technology and Instruments, Guilin University of Electronic Technology, Guilin, China
| | - Ziming Wang
- School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, 541004, China
| | - Chunyan Lv
- School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, 541004, China
| | - Mengtian Li
- School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, 541004, China
| | - Kaiyi Wang
- School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, 541004, China
| | - Zhencheng Chen
- School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, 541004, China.
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Takeuchi M. Toxic AGEs (TAGE) Cause Lifestyle-Related Diseases. Antioxidants (Basel) 2024; 13:1372. [PMID: 39594514 PMCID: PMC11591050 DOI: 10.3390/antiox13111372] [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: 10/10/2024] [Revised: 11/01/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Advanced glycation end-products (AGEs) play a role in the onset/progression of lifestyle-related diseases (LSRD), suggesting that the suppression of AGE-induced effects can be exploited to prevent and treat LSRD. However, AGEs have a variety of structures with different biological effects. Glyceraldehyde (GA) is an intermediate of glucose, and fructose metabolism and GA-derived AGEs (GA-AGEs) have been associated with LSRD, leading to the concept of toxic AGEs (TAGE). Elevated blood TAGE levels have been implicated in the onset/progression of LSRD; therefore, the measurement of TAGE levels may enable disease prediction at an early stage. Moreover, recent studies have revealed the structures and degradation pathways of TAGE. Herein, we provide an overview of the research on TAGE. The TAGE theory provides novel insights into LSRD and is expected to elucidate new targets for many diseases.
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Affiliation(s)
- Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, 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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Yamaguchi M, Fukuyama R, Fujita M. Effect of nattokinase on the pathological conditions in streptozotocin induced diabetic rats. Heliyon 2024; 10:e28835. [PMID: 38586318 PMCID: PMC10998082 DOI: 10.1016/j.heliyon.2024.e28835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 04/09/2024] Open
Abstract
Nattokinase (NK), also known as subtilisin NAT (EC 3.4.21.62), is a serine protease produced by Bacillus subtilis natto that has anti-inflammatory and fibrinolytic properties. To study whether NK prevents the progression of pathological changes in diabetes as an inflammatory disease, we examined the effect of NK on pathological conditions in streptozotocin (STZ)-induced diabetic rats using the following parameters: fasting blood glucose (glucose), total plasma protein (TP), creatinine, histopathology of renal corpuscles and tubules, advanced glycation end products (AGEs), and C-reactive protein (CRP). STZ-administered rats were maintained on a basic diet (CE-2) as control, low-NK diet (containing 0.2 mg NK/g diet), and high-NK diet (0.6 mg NK/g diet) for 14 days. High-dose NK significantly inhibited both glycogen deposition in the renal tubules and increase in the circulating AGE levels without downregulating glucose levels. Compared with the control group, the group treated with the high-NK diet presented a significant inhibition of the increase in the circulating CRP level on day 7 after the beginning of the treatment. However, the CRP level in the NK-H group reached the same level as that in the control group on Day 14. AGEs are known to induce CRP expression in hepatocytes, but the increase in CRP levels in our animal model was independent on the circulating AGE levels. In contrast, low-dose NK did not suppress changes in these parameters. Our present study suggests that NK suppresses glycogen deposition in renal tubules in a dose-dependent manner by the downregulation of AGE formation under hyperglycaemia in the rats with STZ-induced short-term diabetes. However, it is unclear whether this downregulation is caused by intact NK or peptides derived from NK during its digestion in the digestive tract.
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Affiliation(s)
- Moe Yamaguchi
- Laboratory of Pharmacology, Graduate School of Pharmaceutical Science, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima, 737-0112, Japan
| | - Ryo Fukuyama
- Laboratory of Pharmacology, Graduate School of Pharmaceutical Science, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima, 737-0112, Japan
| | - Mitsugu Fujita
- Laboratory of Pharmacology, Graduate School of Pharmaceutical Science, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima, 737-0112, Japan
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Demirer B, Fisunoğlu M. Evaluation of the effects of dietary advanced glycation end products on inflammation. NUTR BULL 2024; 49:6-18. [PMID: 38114851 DOI: 10.1111/nbu.12653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 11/16/2023] [Accepted: 11/20/2023] [Indexed: 12/21/2023]
Abstract
Advanced glycation end products (AGEs) are a large number of heterogeneous compounds formed by the glycation of proteins, fats or nucleic acids. Endogenous AGEs have been associated with various health problems such as obesity, type 2 diabetes mellitus and cardiovascular disease. Inflammation is thought to be one of the main mechanisms in the development of these disorders. Although AGEs are produced endogenously in the body, exogenous sources such as smoking and diet also contribute to the body pool. Therefore, when the AGE pool in the body rises above physiological levels, different pathological conditions may occur through various mechanisms, especially inflammation. While the effects of endogenous AGEs on the development of inflammation have been studied relatively extensively, and current evidence indicates that dietary AGEs (dAGEs) contribute to the body's AGE pool, it is not yet known whether dAGEs have the same effect on the development of inflammation as endogenous AGEs. Therefore, this review aimed to evaluate the results of cross-sectional and intervention studies to understand whether dAGEs are associated with inflammation and, if there is an effect on inflammation, through which mechanisms this effect might occur.
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Affiliation(s)
- Büşra Demirer
- Nutrition and Dietetics, Karabuk University, Karabuk, Turkey
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Sakai-Sakasai A, Takeda K, Suzuki H, Takeuchi M. Structures of Toxic Advanced Glycation End-Products Derived from Glyceraldehyde, A Sugar Metabolite. Biomolecules 2024; 14:202. [PMID: 38397439 PMCID: PMC10887030 DOI: 10.3390/biom14020202] [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: 01/12/2024] [Revised: 02/01/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Advanced glycation end-products (AGEs) have recently been implicated in the onset/progression of lifestyle-related diseases (LSRDs); therefore, the suppression of AGE-induced effects may be used in both the prevention and treatment of these diseases. Various AGEs are produced by different biological pathways in the body. Glyceraldehyde (GA) is an intermediate of glucose and fructose metabolism, and GA-derived AGEs (GA-AGEs), cytotoxic compounds that accumulate and induce damage in mammalian cells, contribute to the onset/progression of LSRDs. The following GA-AGE structures have been detected to date: triosidines, GA-derived pyridinium compounds, GA-derived pyrrolopyridinium lysine dimers, methylglyoxal-derived hydroimidazolone 1, and argpyrimidine. GA-AGEs are a key contributor to the formation of toxic AGEs (TAGE) in many cells. The extracellular leakage of TAGE affects the surrounding cells via interactions with the receptor for AGEs. Elevated serum levels of TAGE, which trigger different types of cell damage, may be used as a novel biomarker for the prevention and early diagnosis of LSRDs as well as in evaluations of treatment efficacy. This review provides an overview of the structures of GA-AGEs.
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Affiliation(s)
- Akiko Sakai-Sakasai
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan; (A.S.-S.); (K.T.)
- General Medicine Center, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan
| | - Kenji Takeda
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan; (A.S.-S.); (K.T.)
- Department of Cardiology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan
| | - Hirokazu Suzuki
- Department of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Ishikawa, Japan;
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku 920-0293, Ishikawa, Japan; (A.S.-S.); (K.T.)
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Nishinaka T, Hatipoglu OF, Wake H, Watanabe M, Toyomura T, Mori S, Nishibori M, Takahashi H. Different modulation of STING/TBK1/IRF3 signaling by advanced glycation end products. Arch Biochem Biophys 2023; 750:109808. [PMID: 37918647 DOI: 10.1016/j.abb.2023.109808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/26/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
Advanced glycation end products (AGEs) are a heterogeneous group of compounds that are non-enzymatically produced by reactions between carbonyl compounds and proteins. Many types of AGEs are produced according to the type or concentration of the reacting carbonyl compound. We have previously demonstrated that a glycolaldehyde-derived AGE suppresses stimulator of interferon gene (STING)/TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3), which is a component of the innate immune system. In this report, we investigated the effects of AGEs prepared by several carbonyl compounds on STING/TBK1/IRF3 signaling. AGEs used in the present study were numbered based on the carbonyl compound type: AGE1, derived from glucose; AGE2, derived from glyceraldehyde; AGE3, derived from glycolaldehyde; AGE4, derived from methylglyoxal; and AGE5, derived from glyoxal. AGEs derived from aldehyde (AGE2 and AGE3) and dicarbonyl compounds (AGE4 and AGE5) suppressed cyclic GMP-AMP (cGAMP)-induced activation of STING/TBK1/IRF3 signaling, with different suppression efficiencies observed. Lysine modification by carbonyl compounds was related to the efficiency of the suppressive effect on STING/TBK1/IRF3 signaling. Among the AGEs used, only AGE1 enhanced cGAMP-induced activation of STING/TBK1/IRF3 signaling. Enhancing the modulation of STING/TBK1/IRF3 signaling by AGE1 was mediated by toll-like receptor 4. These results indicated that modulation of STING/TBK1/IRF3 signaling by prepared AGEs is dependent on the type and concentration of the carbonyl compound present. Modulating STING/TBK1/IRF3 signaling by AGEs may involve modification of lysine residues in proteins.
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Affiliation(s)
- Takashi Nishinaka
- Department of Pharmacology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Omer Faruk Hatipoglu
- Department of Pharmacology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Hidenori Wake
- Department of Pharmacology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
| | - Masahiro Watanabe
- Department of Pharmacology, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, Japan
| | - Takao Toyomura
- Department of Pharmacology, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, Japan
| | - Shuji Mori
- Department of Pharmacology, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, Japan
| | - Masahiro Nishibori
- Department of Translational Research & Drug Development, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, Japan
| | - Hideo Takahashi
- Department of Pharmacology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
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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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Yasuda Y, Aoki H, Fujita W, Fujibayashi K, Wakasa M, Kawai Y, Nakanishi H, Saito K, Takeuchi M, Kajinami K. Glyceraldehyde-derived advanced glycation end-products are associated with left ventricular ejection fraction and brain natriuretic peptide in patients with diabetic adverse cardiac remodeling. SCAND CARDIOVASC J 2022; 56:208-216. [PMID: 35792728 DOI: 10.1080/14017431.2022.2095013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Objectives: Glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs) have a strong binding affinity for their cognate receptor and elicit oxidative stress and inflammation. However, it remains unknown whether the levels of Glycer-AGEs correlate with the severity of cardiac function and heart failure in patients with diabetic adverse cardiac remodeling (DbCR). Fourteen heart failure patients with type 2 diabetes mellitus (DM) without other cardiac disorders (DbCR group) were enrolled. Another 14 patients with idiopathic dilated cardiomyopathy (DCM) without DM were served as a control (DCM group). All patients were assessed for serum Glycer-AGEs, nitrotyrosine (NT), and tumor necrosis factor alpha (TNFα) and for plasma brain natriuretic peptide (BNP). The left ventricular ejection fraction (LVEF) was evaluated by echocardiography. Results: The mean serum levels of Glycer-AGEs, NT, and TNFα in the DbCR group were significantly higher than those in the DCM group (for Glycer-AGEs, p = .0073; for NT, p = .005; for TNFα, p < .0001, respectively). In the patients with DbCR, the levels of serum Glycer-AGEs and TNFα were closely associated with LVEF and BNP values. Conclusions: Both Glycer-AGEs and TNFα showed close associations with LVEF and the levels of BNP in patients with DbCR. Glycer-AGEs and TNFα may play a pathological role in the development of DbCR.
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Affiliation(s)
- Yuushi Yasuda
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | - Hirofumi Aoki
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | - Wataru Fujita
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | | | - Minoru Wakasa
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | - Yasuyuki Kawai
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | - Hiroaki Nakanishi
- Department of Forensic Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Kazuyuki Saito
- Department of Forensic Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan
| | - Kouji Kajinami
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
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10
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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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11
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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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12
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Ooi H, Nasu R, Furukawa A, Takeuchi M, Koriyama Y. Pyridoxamine and Aminoguanidine Attenuate the Abnormal Aggregation of β-Tubulin and Suppression of Neurite Outgrowth by Glyceraldehyde-Derived Toxic Advanced Glycation End-Products. Front Pharmacol 2022; 13:921611. [PMID: 35721214 PMCID: PMC9204210 DOI: 10.3389/fphar.2022.921611] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/13/2022] [Indexed: 01/03/2023] Open
Abstract
Diabetes mellitus (DM) has been identified as a risk factor for the onset and progression of Alzheimer’s disease (AD). In our previous study, we demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (toxic AGEs, TAGE) induced similar alterations to those observed in AD. GA induced dysfunctional neurite outgrowth via TAGE-β-tubulin aggregation, which resulted in the TAGE-dependent abnormal aggregation of β-tubulin and tau phosphorylation in human neuroblastoma SH-SY5Y cells. However, the effects of inhibitors of AGE formation on dysfunctional neurite outgrowth caused by GA-induced abnormalities in the aggregation of β-tubulin and tau phosphorylation remain unknown. Aminoguanidine (AG), an AGE inhibitor, and pyridoxamine (PM), a natural form of vitamin B6 (VB6), are effective AGE inhibitors. Therefore, the present study investigated whether AG or PM ameliorate TAGE-β-tubulin aggregation and the suppression of neurite outgrowth by GA. The results obtained showed that AG and PM inhibited the formation of TAGE-β-tubulin, mitigated the GA-induced suppression of neurite outgrowth, and reduced GA-mediated increases in tau phosphorylation levels. Collectively, these results suggest the potential of AG and PM to prevent the DM-associated onset and progression of AD.
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Affiliation(s)
- Hayahide Ooi
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Ryuto Nasu
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Ayako Furukawa
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Japan
| | - Yoshiki Koriyama
- Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
- *Correspondence: Yoshiki Koriyama,
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13
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Kawao N, Kawaguchi M, Ohira T, Ehara H, Mizukami Y, Takafuji Y, Kaji H. Renal failure suppresses muscle irisin expression, and irisin blunts cortical bone loss in mice. J Cachexia Sarcopenia Muscle 2022; 13:758-771. [PMID: 34997830 PMCID: PMC8818650 DOI: 10.1002/jcsm.12892] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/25/2021] [Accepted: 11/22/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Chronic renal failure induces bone mineral disorders and sarcopenia. Skeletal muscle affects other tissues, including bone, by releasing myokines. However, the effects of chronic renal failure on the interactions between muscle and bone remain unclear. METHODS We investigated the effects of renal failure on bone, muscle, and myokines linking muscle to bone using a mouse 5/6 nephrectomy (Nx) model. Muscle mass and bone mineral density (BMD) were analysed by quantitative computed tomography 8 weeks after Nx. RESULTS Nephrectomy significantly reduced muscle mass in the whole body (12.1% reduction, P < 0.05), grip strength (10.1% reduction, P < 0.05), and cortical BMD at the femurs of mice (9.5% reduction, P < 0.01) 8 weeks after surgery, but did not affect trabecular BMD at the femurs. Among the myokines linking muscle to bone, Nx reduced the expression of irisin, a proteolytic product of fibronectin type III domain-containing 5 (Fndc5), in the gastrocnemius muscles of mice (38% reduction, P < 0.01). Nx increased myostatin mRNA levels in the gastrocnemius muscles of mice (54% increase, P < 0.01). In simple regression analyses, cortical BMD, but not trabecular BMD, at the femurs was positively related to Fndc5 mRNA levels in the gastrocnemius muscles of mice (r = 0.651, P < 0.05). The weekly administration of recombinant irisin to mice ameliorated the decrease in cortical BMD, but not muscle mass or grip strength, induced by Nx (6.2% reduction in mice with Nx vs. 3.3% reduction in mice with Nx and irisin treatment, P < 0.05). CONCLUSIONS The present results demonstrated that renal failure decreases the expression of irisin in the gastrocnemius muscles of mice. Irisin may contribute to cortical bone loss induced by renal failure in mice as a myokine linking muscle to bone.
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Affiliation(s)
- Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Miku Kawaguchi
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Takashi Ohira
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Hiroki Ehara
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Yuya Mizukami
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Yoshimasa Takafuji
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
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14
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Ahmad S, Pandey AR, Singh SP, Singh S, Sashidhara KV, Tamrakar AK. Antiglycation activity of β-glucogallin from Asparagus racemosus. Nat Prod Res 2022; 36:6329-6335. [PMID: 35021947 DOI: 10.1080/14786419.2022.2025799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The increased formation and accumulation of advanced glycation end products (AGEs) has been implicated in pathogenesis of various chronic ailments, including diabetes-associated secondary complications, atherosclerosis, aging, inflammatory and neurodegenerative diseases. Therefore, inhibition of AGEs formation is an imperative strategy for alleviating diverse pathologies. Here, we have demonstrated the AGEs inhibitory activity of β-glucogallin, isolated for the first time from the roots of Asparagus racemosus. β-glucogallin significantly mitigated fructose-, glucose- and methylglyoxal-induced glycation of bovine serum albumin (BSA). Also, the presence of β-glucogallin decreased fructosamine and protein carbonyls content, and increased thiol group content in the fructose-BSA system. These activities of β-glucogallin from Asparagus racemosus underscore its likely pharmacological potential for impeding AGEs-related metabolic disorders.
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Affiliation(s)
- Shadab Ahmad
- Division of Biochemistry & Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Alka Raj Pandey
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.,Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India
| | - Suriya Pratap Singh
- Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India
| | - Sushmita Singh
- Division of Biochemistry & Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Koneni V Sashidhara
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.,Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.,Sophisticated Analytical Instrument Facility & Research, CSIR-Central Drug Research Institute, Lucknow, India
| | - Akhilesh K Tamrakar
- Division of Biochemistry & Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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15
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Cao XJ, Wu R, Qian HY, Chen X, Zhu HY, Xu GY, Sun YZ, Zhang PA. Metformin attenuates diabetic neuropathic pain via AMPK/NF-κB signaling pathway in dorsal root ganglion of diabetic rats. Brain Res 2021; 1772:147663. [PMID: 34555415 DOI: 10.1016/j.brainres.2021.147663] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/26/2021] [Accepted: 09/15/2021] [Indexed: 10/20/2022]
Abstract
Neuropathic pain is a common complication of diabetes mellitus with poorly relieved by conventional analgesics. Metformin, a first-line drug for type 2 diabetes, reduces blood glucose by activating adenosine monophosphate protein kinase (AMPK) signalling system. However, the effect of Metformin on diabetic neuropathic pain is still unknown. In the present study, we showed that Metformin was capable of attenuating diabetes induced mechanical allodynia, and the analgesia effect could be blocked by Compound C (an AMPK inhibitor). Importantly, Metformin enhanced the phosphorylation level of AMPK in L4-6 DRGs of diabetic rats but not affect the expression of total AMPK. Intrathecal injection of AICAR (an AMPK agonist) could activate AMPK and alleviate the mechanical allodynia of diabetic rats. Additionally, phosphorylated AMPK and NF-κB was co-localized in small and medium neurons of L4-6 DRGs. Interestingly, the regulation of NF-κB in diabetic rats was obviously reduced when AMPK was activated by AICAR. Notably, Metformin could decrease NF-κB expression in L4-6 DRGs of diabetic rats, but the decrease was blocked by Compound C. In conclusion, Metformin alleviates diabetic mechanical allodynia via activation of AMPK signaling pathway in L4-6 DRGs of diabetic rats, which might be mediated by the downregulation of NF-κB, and this providing certain basis for Metformin to become a potential drug in the clinical treatment of diabetic neuropathic pain.
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Affiliation(s)
- Xiao-Jun Cao
- Department of Endocrine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China
| | - Rui Wu
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, PR China
| | - He-Ya Qian
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China
| | - Xiang Chen
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China
| | - Hong-Yan Zhu
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China
| | - Guang-Yin Xu
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, PR China
| | - Ye-Zi Sun
- Department of Endocrine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China.
| | - Ping-An Zhang
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, PR China.
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16
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Jo YH, Lee S, Yeon SW, Turk A, Lee JH, Hong SM, Han YK, Lee KY, Hwang BY, Kim SY, Lee MK. Anti-diabetic potential of Masclura tricuspidata leaves: Prenylated isoflavonoids with α-glucosidase inhibitory and anti-glycation activity. Bioorg Chem 2021; 114:105098. [PMID: 34153812 DOI: 10.1016/j.bioorg.2021.105098] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/10/2021] [Accepted: 06/12/2021] [Indexed: 01/20/2023]
Abstract
Investigation of chemical constituents of Masclura tricuspidata leaves resulted in the isolation of 47 isoflavonoids possessing prenyl groups with different numbers and structures. Among them, sixteen compounds named cudracusisoflavones A-P (1-16) were first isolated from nature. The isoflavonoids isolated from M. tricuspidata leaves showed anti-diabetic effects as measured by inhibition on α-glucosidase activity and advanced glycation end-products (AGEs) formations. Especially, cudracusisoflavone L (12), a new compound, together with gancaonin M (27), erysenegalensein E (41) and millewanin G (44) showed strong α-glucosidase inhibition with IC50 values <10.0 μM. In addition, cudracusisoflavones A (1), D (4), M (13) and N (14), together with known prenylated isoflavonoids efficiently inhibited methylglyoxal (MGO)- or glyoxal (GO)-induced AGE formations. Structure activity relationship together with molecular docking analysis suggested the importance of hydroxy group and linear type of prenyl moiety for α-glucosidase inhibition. Conclusively, diverse prenylated isoflavonoids in M. tricuspidata leaves might ameliorate glycotoxicity-induced metabolic diseases.
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Affiliation(s)
- Yang Hee Jo
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
| | - Solip Lee
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
| | - Sang Won Yeon
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
| | - Ayman Turk
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
| | - Jae Hyuk Lee
- College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Seong-Min Hong
- College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Yoo Kyong Han
- College of Pharmacy, Korea University, Sejong 47236, Republic of Korea
| | - Ki Yong Lee
- College of Pharmacy, Korea University, Sejong 47236, Republic of Korea
| | - Bang Yeon Hwang
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
| | - Sun Yeou Kim
- College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Mi Kyeong Lee
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea.
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17
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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: 29] [Impact Index Per Article: 7.3] [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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18
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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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19
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Kitaura A, Nishinaka T, Hamasaki S, Hatipoglu OF, Wake H, Nishibori M, Mori S, Nakao S, Takahashi H. Advanced glycation end-products reduce lipopolysaccharide uptake by macrophages. PLoS One 2021; 16:e0245957. [PMID: 33493233 PMCID: PMC7833212 DOI: 10.1371/journal.pone.0245957] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 01/11/2021] [Indexed: 01/19/2023] Open
Abstract
Hyperglycaemia provides a suitable environment for infections and the mechanisms of glucose toxicity include the formation of advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups. Among AGE-associated phenotypes, glycolaldehyde-derived toxic AGE (AGE-3) is involved in the pathogenesis of diabetic complications. Internalisation of endotoxin by various cell types contributes to innate immune responses against bacterial infection. An endotoxin derived from Gram-negative bacteria, lipopolysaccharide (LPS), was reported to enhance its own uptake by RAW264.7 mouse macrophage-like cells, and an LPS binding protein, CD14, was involved in the LPS uptake. The LPS uptake induced the activation of RAW264.7 leading to the production of chemokine CXC motif ligand (CXCL) 10, which promotes T helper cell type 1 responses. Previously, we reported that AGE-3 was internalised into RAW264.7 cells through scavenger receptor-1 Class A. We hypothesized that AGEs uptake interrupt LPS uptake and impair innate immune response to LPS in RAW264.7 cells. In the present study, we found that AGE-3 attenuated CD14 expression, LPS uptake, and CXCL10 production, which was concentration-dependent, whereas LPS did not affect AGE uptake. AGEs were reported to stimulate the receptor for AGEs and Toll-like receptor 4, which cause inflammatory reactions. We found that inhibitors for RAGE, but not Toll-like receptor 4, restored the AGE-induced suppression of CD14 expression, LPS uptake, and CXCL10 production. These results indicate that the receptor for the AGE-initiated pathway partially impairs the immune response in diabetes patients.
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Affiliation(s)
- Atsuhiro Kitaura
- Department of Anesthesiology, Faculty of Medicine, Kindai University, Osaka-Sayama, Osaka, Japan
| | - Takashi Nishinaka
- Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka-Sayama, Osaka, Japan
| | - Shinichi Hamasaki
- Department of Anesthesiology, Faculty of Medicine, Kindai University, Osaka-Sayama, Osaka, Japan
| | - Omer Faruk Hatipoglu
- Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka-Sayama, Osaka, Japan
| | - Hidenori Wake
- Department of Pharmacology, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Masahiro Nishibori
- Department of Pharmacology, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Shuji Mori
- Department of Pharmacy, Shujitsu University, Okayama, Japan
| | - Shinichi Nakao
- Department of Anesthesiology, Faculty of Medicine, Kindai University, Osaka-Sayama, Osaka, Japan
| | - Hideo Takahashi
- Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka-Sayama, Osaka, Japan
- * E-mail:
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20
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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:nu13010080. [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] [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.)
- Correspondence: ; Tel.: +81-76-218-8145
| | - 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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21
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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: 29] [Impact Index Per Article: 5.8] [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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22
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Zucchini S, Fabi M, Maltoni G, Zioutas M, Trevisani V, Di Natale V, Cassio A, Pession A. Adolescents with severe obesity show a higher cardiovascular (CV) risk than those with type 1 diabetes: a study with skin advanced glycation end products and intima media thickness evaluation. Acta Diabetol 2020; 57:1297-1305. [PMID: 32504306 DOI: 10.1007/s00592-020-01537-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 04/11/2020] [Indexed: 12/25/2022]
Abstract
AIMS Type 1 diabetes (T1D) and obesity are strongly associated with cardiovascular (CV) risk and can start in the paediatric age. The CV risk profile of two groups of adolescents was compared through the evaluation of sAGE, IMT and known variables associated with CV risk. The first group was affected by T1D with duration of disease of at least 5 years or 3 years since puberty onset, and the second by severe obesity for more than 3 years. METHODS A total of 116 patients were prospectively enrolled in the study (71 T1D, 33 males and 38 females; 45 obese, 18 males and 27 females), and their sAGE, IMT, waist/height ratio, LDL cholesterol, triglycerides/cholesterol HDL ratio, BMI, HbA1c and blood pressure were measured. RESULTS An IMT value > 0.7 mm, cut-off value to define CV risk, was present in 28% of the obese patients and in no T1D patients. Age-adjusted sAGE and HbA1c levels were higher T1D patients, whereas a higher percentage of pathological values was present in most of the remaining studied variables. In T1D patients, there was a higher percentage of females with waist/height ratio > 0.5, LDL cholesterol > 100 mg/dL, triglycerides/HDL cholesterol ratio > 2 and BMI > 99° centile and a higher percentage of males with HbA1c > 7%. On the contrary, in obese patients there were no differences between males and females. Multiple analysis is identified BMI SDS as the only variable with a significant influence on IMT in both groups. Furthermore, it showed that HbA1c and gender affected sAGE in T1D patients, whereas only age and gender in the obese patients. CONCLUSIONS Our study demonstrates that our adolescents with severe obesity carry a much higher CV risk than adolescents with T1D unless in bad metabolic control. Apart from lower sAGE levels, most of the variables considered to define CV risk were higher in the obese group than in the T1D group. Gender seems to have a significant impact on sAGE levels but not on IMT.
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Affiliation(s)
- Stefano Zucchini
- Department of Woman, Child and Urologic Diseases, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy.
| | - Marianna Fabi
- Department of Woman, Child and Urologic Diseases, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy
| | - Giulio Maltoni
- Department of Woman, Child and Urologic Diseases, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy
| | - Maximiliano Zioutas
- Department of Woman, Child and Urologic Diseases, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy
| | | | - Valeria Di Natale
- Department of Woman, Child and Urologic Diseases, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy
| | - Alessandra Cassio
- Department of Woman, Child and Urologic Diseases, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy
| | - Andrea Pession
- Department of Woman, Child and Urologic Diseases, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy
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23
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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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24
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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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25
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Kim OY, Song J. The importance of BDNF and RAGE in diabetes-induced dementia. Pharmacol Res 2020; 160:105083. [PMID: 32679182 DOI: 10.1016/j.phrs.2020.105083] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/30/2020] [Accepted: 07/12/2020] [Indexed: 01/11/2023]
Abstract
Diabetes-induced dementia is an emerging neurodisorder all over the world. The prevalence rates of dementia and diabetes have been gradually increasing worldwide. Diabetes has been known to lead to oxidative stress, inflammation aggravation, and hyperglycemia conditions in the brain. Various diabetic implications cause the lower secretion of brain-derived neurotrophic factor (BDNF) and the increase of receptor for advanced glycation end products (RAGE), ultimately leading to both cerebrovascular dysfunction and cognitive decline. Here, we summarized the significant evidences highlighting the specific mechanisms between BDNF and RAGE and cerebrovascular dysfunction and memory function and how these relate to diabetes-induced dementia. Especially, we review that the association between BDFN and RAGE in neuroinflammation, the reduction of long-term potentiation, and the vascular implications in brain.
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Affiliation(s)
- Oh Yoen Kim
- The Department of Food Science and Nutrition, Dong-A University, Busan 49315, Republic of Korea; The Center for Silver-Targeted Biomaterials, Brain Busan 21 Plus Program, Graduate School, Dong-A University, Busan 49315, Republic of Korea.
| | - Juhyun Song
- The Department of Anatomy, Chonnam National University, Chonnam National University Medical School, Hwasun 58128, Jeollanam-do, Republic of Korea.
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26
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Hirahara I, Kusano E, Jin D, Takai S. Hypermetabolism of glutathione, glutamate and ornithine via redox imbalance in methylglyoxal-induced peritoneal injury rats. J Biochem 2020; 167:185-194. [PMID: 31593282 DOI: 10.1093/jb/mvz077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 09/17/2019] [Indexed: 11/13/2022] Open
Abstract
Peritoneal dialysis (PD) is a blood purification treatment for patients with reduced renal function. However, the peritoneum is exposed to oxidative stress during PD and long-term PD results in peritoneal damage, leading to the termination of PD. Methylglyoxal (MGO) contained in commercial PD fluids is a source of strong oxidative stress. The aim of this study was to clarify the mechanism of MGO-induced peritoneal injury using metabolome analysis in rats. We prepared peritoneal fibrosis rats by intraperitoneal administration of PD fluids containing MGO for 21 days. As a result, MGO-induced excessive proliferation of mesenchymal cells with an accumulation of advanced glycation end-products (AGEs) at the surface of the thickened peritoneum in rats. The effluent levels of methionine sulfoxide, an oxidative stress marker and glutathione peroxidase activity were increased in the MGO-treated rats. The levels of glutathione, glutamate, aspartate, ornithine and AGEs were also increased in these rats. MGO upregulated the gene expression of transporters and enzymes related to the metabolism of glutathione, glutamate and ornithine in the peritoneum. These results suggest that MGO may induce peritoneal injury with mesenchymal cell proliferation via increased redox metabolism, directly or through the formation of AGEs during PD.
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Affiliation(s)
- Ichiro Hirahara
- Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 568-8686
| | - Eiji Kusano
- JCHO Utsunomiya Hospital, 11-17 Minamitakasago-chou, Utsunomiya, Tochigi 321-0143, Japan
| | - Denan Jin
- Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 568-8686
| | - Shinji Takai
- Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 568-8686
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27
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Takata T, Sakasai-Sakai A, Takeuchi M. Impact of intracellular toxic advanced glycation end-products (TAGE) on murine myoblast cell death. Diabetol Metab Syndr 2020; 12:54. [PMID: 32684984 PMCID: PMC7362572 DOI: 10.1186/s13098-020-00561-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 06/17/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Sarcopenia is a progressive condition that is characterized by decreases in skeletal muscle mass and function. Although sarcopenia is associated with lifestyle-related diseases (LSRD), the mechanisms underlying cell death in myoblasts, which differentiate to myotubes, remain unclear. We previously designated glyceraldehyde (an intermediate of glucose/fructose metabolism)-derived advanced glycation end-products (AGEs) as toxic AGEs (TAGE) because of their cytotoxicity and involvement in LSRD, and hypothesized that TAGE contribute to cell death in myoblasts. METHODS C2C12 cells, which are murine myoblasts, were treated with 0, 0.5, 1, 1.5, and 2 mM glyceraldehyde for 24 h. Cell viability and intracellular TAGE were then assessed using 5-[2,4,-bis(sodioxysulfonyl)phenyl]-3-(2-methoxy-4-nitrophenyl)-2-(4-nitrophenyl)-2H-tetrazole-3-ium (WST-8) and slot blot assays. Cells were pretreated with 8 mM aminoguanidine, an inhibitor of AGE production, for 2 h, followed by 0, 1.5, and 2 mM glyceraldehyde for 24 h. Cell viability and intracellular TAGE levels were then assessed. Serum TAGE levels in STAM mice, in which there were four stages (no steatosis, simple steatosis, steatohepatitis, and fibrosis), were measured using a competitive enzyme-linked immunosorbent assay. Results were expressed as TAGE units (U) per milliliter of serum, with 1 U corresponding to 1.0 μg of glyceraldehyde-derived AGE-bovine serum albumin (BSA) (TAGE-BSA). The viability of cells treated with 20, 50, and 100 μg/mL non-glycated BSA and TAGE-BSA for 24 h was assessed using the WST-8 assay. RESULTS In C2C12 cells treated with 1.5 and 2 mM glyceraldehyde, cell viability decreased to 47.7% (p = 0.0021) and 5.0% (p = 0.0001) and intracellular TAGE levels increased to 6.0 and 15.9 μg/mg protein, respectively. Changes in cell viability and TAGE production were completely inhibited by 8 mM aminoguanidine. Serum TAGE levels at the steatohepatitis and fibrosis stages were 10.51 ± 1.16 and 10.44 ± 0.95 U/mL, respectively, and were higher than those at the no steatosis stage (7.27 ± 0.18 U/mL). Cell death was not induced by 20 or 50 μg/mL TAGE-BSA. The viabilities of C2C12 cells treated with 100 μg/mL non-glycated BSA and TAGE-BSA were 105.0% (p = 0.2890) and 85.3% (p = 0.0217), respectively. CONCLUSION Intracellular TAGE strongly induced cell death in C2C12 cells and may also induce myoblast cell death in LSRD model mice.
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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
| | - 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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Cavero-Redondo I, Soriano-Cano A, Álvarez-Bueno C, Cunha PG, Martínez-Hortelano JA, Garrido-Miguel M, Berlanga-Macías C, Martínez-Vizcaíno V. Skin Autofluorescence-Indicated Advanced Glycation End Products as Predictors of Cardiovascular and All-Cause Mortality in High-Risk Subjects: A Systematic Review and Meta-analysis. J Am Heart Assoc 2019; 7:e009833. [PMID: 30371199 PMCID: PMC6222966 DOI: 10.1161/jaha.118.009833] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Background Chronic deposits of advanced glycation end products produced by enzymatic glycation have been suggested as predictors of atherosclerotic‐related disorders. This study aimed to estimate the relationship between advanced glycation end products indicated by skin autofluorescence levels and the risk of cardiovascular and all‐cause mortality based on data from observational studies. Methods and Results We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and the Web of Science databases from their inceptions until November 2017 for observational studies addressing the association of advanced glycation end products by skin autofluorescence levels with cardiovascular and all‐cause mortality. The DerSimonian and Laird random‐effects method was used to compute pooled estimates of hazard ratios and their respective 95% confidence intervals for the risk of cardiovascular and all‐cause mortality associated with levels of advanced glycation end products by skin autofluorescence. Ten published studies were included in the systematic review and meta‐analysis. Higher skin autofluorescence levels were significantly associated with a higher pooled risk estimate for cardiovascular mortality (hazard ratio: 2.06; 95% confidence interval, 1.58–2.67), which might not be important to moderate heterogeneity (I2=34.7%; P=0.163), and for all‐cause mortality (hazard ratio: 1.91; 95% confidence interval, 1.42–2.56) with substantial heterogeneity (I2=60.8%; P=0.0.18). Conclusions Our data suggest that skin autofluorescence levels could be considered predictors of all‐cause mortality and cardiovascular mortality in patients at high and very high risk.
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Affiliation(s)
- Ivan Cavero-Redondo
- 1 Universidad de Castilla-La Mancha Health and Social Research Center Cuenca Spain
| | - Alba Soriano-Cano
- 1 Universidad de Castilla-La Mancha Health and Social Research Center Cuenca Spain
| | - Celia Álvarez-Bueno
- 1 Universidad de Castilla-La Mancha Health and Social Research Center Cuenca Spain
| | - Pedro G Cunha
- 2 Center for the Research and Treatment of Arterial Hypertension and Cardiovascular Risk Internal Medicine Department Guimarães Portugal.,3 School of Medicine Minho University Braga Portugal.,4 Life and Health Science Research Institute (ICVS)/3B's PT Government Associate Laboratory Braga/Guimarães Portugal
| | | | | | | | - Vicente Martínez-Vizcaíno
- 1 Universidad de Castilla-La Mancha Health and Social Research Center Cuenca Spain.,5 Universidad Autónoma de Chile Facultad de Ciencias de la Salud Talca Chile
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29
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Papaevgeniou N, Hoehn A, Tur JA, Klotz LO, Grune T, Chondrogianni N. Sugar-derived AGEs accelerate pharyngeal pumping rate and increase the lifespan of Caenorhabditis elegans. Free Radic Res 2019; 53:1056-1067. [DOI: 10.1080/10715762.2019.1661403] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- Nikoletta Papaevgeniou
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
- Nutrigenomics Section, Institute of Nutritional Sciences, Friedrich Schiller University of Jena, Jena, Germany
| | - Annika Hoehn
- Department of Molecular Toxicology, German Institute of Human Nutrition, Nuthetal, Germany
- German Center for Diabetes Research, München, Germany
| | - Josep A. Tur
- Research Group on Nutrition and Oxidative Stress, University of the Balearic Islands and CIBEROBN (Physiopathology of Obesity and Nutrition), Palma de Mallorca, Spain
| | - Lars-Oliver Klotz
- Nutrigenomics Section, Institute of Nutritional Sciences, Friedrich Schiller University of Jena, Jena, Germany
| | - Tilman Grune
- Department of Molecular Toxicology, German Institute of Human Nutrition, Nuthetal, Germany
- German Center for Diabetes Research, München, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Institute of Nutritional Sciences, University of Potsdam, Nuthetal, Germany
| | - Niki Chondrogianni
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
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30
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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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31
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Mol M, Degani G, Coppa C, Baron G, Popolo L, Carini M, Aldini G, Vistoli G, Altomare A. Advanced lipoxidation end products (ALEs) as RAGE binders: Mass spectrometric and computational studies to explain the reasons why. Redox Biol 2018; 23:101083. [PMID: 30598328 PMCID: PMC6859533 DOI: 10.1016/j.redox.2018.101083] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/06/2018] [Accepted: 12/15/2018] [Indexed: 12/27/2022] Open
Abstract
Advanced Lipoxidation End-products (ALEs) are modified proteins that can act as pathogenic factors in several chronic diseases. Several molecular mechanisms have so far been considered to explain the damaging action of ALEs and among these a pathway involving the receptor for advanced glycation end products (RAGE) should be considered. The aim of the present work is to understand if ALEs formed from lipid peroxidation derived reactive carbonyl species (RCS) are able to act as RAGE binders and also to gain a deeper insight into the molecular mechanisms involved in the protein-protein engagement. ALEs were produced in vitro, by incubating human serum albumin (HSA) with 4-hydroxy-trans− 2-nonenal (HNE), acrolein (ACR) and malondialdehyde (MDA). The identification of ALEs was performed by MS. ALEs were then subjected to the VC1 Pull-Down assay (VC1 is the ligand binding domain of RAGE) and the enrichment factor (the difference between the relative abundance in the enriched sample minus the amount in the untreated one) as an index of affinity, was determined. Computation studies were then carried out to explain the factors governing the affinity of the adducted moieties and the site of interaction on adducted HSA for VC1-binding. The in silico analyses revealed the key role played by those adducts which strongly reduce the basicity of the modified residues and thus occur at their neutral state at physiological conditions (e.g. the MDA adducts, dihydropyridine-Lysine (DHPK) and N-2-pyrimidyl-ornithine (NPO), and acrolein derivatives, N-(3-formyl-3,4-dehydro-piperidinyl) lysine, FDPK). These neutral adducts become unable to stabilize ion-pairs with the surrounding negative residues which thus can contact the RAGE positive residues. In conclusion, ALEs derived from lipid peroxidation-RCS are binders of RAGE and this affinity depends on the effect of the adduct moiety to reduce the basicity of the target amino acid and on the acid moieties surrounding the aminoacidic target.
A wide set of ALEs-HSA was obtained by in vitro incubation of HSA with different RCS. ALEs-HSA before and after VC1 enrichment were fully characterized by MS. Retention efficiency of the identified ALEs-HSA by VC1 was determined. Elucidation of structural requirements making an ALE a RAGE binder was obtained by computational studies. The mechanism here proposed for ALEs can be considered as a general mechanism of protein-protein interaction.
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Affiliation(s)
- Marco Mol
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Genny Degani
- Department of Biosciences, Via Celoria 26, Università degli Studi di Milano, 20133 Milano, Italy
| | - Crescenzo Coppa
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Giovanna Baron
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Laura Popolo
- Department of Biosciences, Via Celoria 26, Università degli Studi di Milano, 20133 Milano, Italy
| | - Marina Carini
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy.
| | - Giulio Vistoli
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Alessandra Altomare
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
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Kobayashi M, Zochodne DW. Diabetic neuropathy and the sensory neuron: New aspects of pathogenesis and their treatment implications. J Diabetes Investig 2018; 9:1239-1254. [PMID: 29533535 PMCID: PMC6215951 DOI: 10.1111/jdi.12833] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/20/2018] [Accepted: 03/03/2018] [Indexed: 12/17/2022] Open
Abstract
Diabetic polyneuropathy (DPN) continues to be generally considered as a "microvascular" complication of diabetes mellitus alongside nephropathy and retinopathy. The microvascular hypothesis, however, might be tempered by the concept that diabetes directly targets dorsal root ganglion sensory neurons. This neuron-specific concept, supported by accumulating evidence, might account for important features of DPN, such as its early sensory neuron degeneration. Diabetic sensory neurons develop neuronal atrophy alongside a series of messenger ribonucleic acid (RNA) changes related to declines in structural proteins, increases in heat shock protein, increases in the receptor for advanced glycation end-products, declines in growth factor signaling and other changes. Insulin is recognized as a potent neurotrophic factor, and insulin ligation enhances neurite outgrowth through activation of the phosphoinositide 3-kinase-protein kinase B pathway within sensory neurons and attenuates phenotypic features of experimental DPN. Several interventions, including glucagon-like peptide-1 agonism, and phosphatase and tensin homolog inhibition to activate growth signals in sensory neurons, or heat shock protein overexpression, prevent or reverse neuropathic abnormalities in experimental DPN. Diabetic sensory neurons show a unique pattern of microRNA alterations, a key element of messenger RNA silencing. For example, let-7i is widely expressed in sensory neurons, supports their growth and is depleted in experimental DPN; its replenishment improves features of DPN models. Finally, impairment of pre-messenger RNA splicing in diabetic sensory neurons including abnormal nuclear RNA metabolism and structure with loss of survival motor neuron protein, a neuron survival molecule, and overexpression of CWC22, a splicing factor, offer further novel insights. The present review addresses these new aspects of DPN sensory neurodegeneration.
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Affiliation(s)
- Masaki Kobayashi
- Department of Neurology and Neurological ScienceGraduate School of MedicineTokyo Medical and Dental UniversityTokyoJapan
- Department of NeurologyYokufukai Geriatric HospitalTokyoJapan
| | - Douglas W Zochodne
- Division of Neurology and Department of MedicineNeuroscience and Mental Health InstituteFaculty of Medicine and DentistryUniversity of AlbertaEdmontonAlbertaCanada
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Chen JH, Lin X, Bu C, Zhang X. Role of advanced glycation end products in mobility and considerations in possible dietary and nutritional intervention strategies. Nutr Metab (Lond) 2018; 15:72. [PMID: 30337945 PMCID: PMC6180645 DOI: 10.1186/s12986-018-0306-7] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 09/21/2018] [Indexed: 02/08/2023] Open
Abstract
Advanced glycation end products (AGEs), a group of compounds that are formed by non-enzymatic reactions between carbonyl groups of reducing sugars and free amino groups of proteins, lipids or nucleic acids, can be obtained exogenously from diet or formed endogenously within the body. AGEs accumulate intracellularly and extracellularly in all tissues and body fluids and can cross-link with other proteins and thus affect their normal functions. Furthermore, AGEs can interact with specific cell surface receptors and hence alter cell intracellular signaling, gene expression, the production of reactive oxygen species and the activation of several inflammatory pathways. High levels of AGEs in diet as well as in tissues and the circulation are pathogenic to a wide range of diseases. With respect to mobility, AGEs accumulate in bones, joints and skeletal muscles, playing important roles in the development of osteoporosis, osteoarthritis, and sarcopenia with aging. This report covered the related pathological mechanisms and the potential pharmaceutical and dietary intervention strategies in reducing systemic AGEs. More prospective studies are needed to determine whether elevated serum AGEs and/or skin autofluorescence predict a decline in measures of mobility. In addition, human intervention studies are required to investigate the beneficial effects of exogenous AGEs inhibitors on mobility outcomes.
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Affiliation(s)
- Jie-Hua Chen
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
| | - Xu Lin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Cuihong Bu
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
| | - Xuguang Zhang
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
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Fernandes R, Viana SD, Nunes S, Reis F. Diabetic gut microbiota dysbiosis as an inflammaging and immunosenescence condition that fosters progression of retinopathy and nephropathy. Biochim Biophys Acta Mol Basis Dis 2018; 1865:1876-1897. [PMID: 30287404 DOI: 10.1016/j.bbadis.2018.09.032] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 09/18/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
Abstract
The increased prevalence of type 2 diabetes mellitus (T2DM) and life expectancy of diabetic patients fosters the worldwide prevalence of retinopathy and nephropathy, two major microvascular complications that have been difficult to treat with contemporary glucose-lowering medications. The gut microbiota (GM) has become a lively field research in the last years; there is a growing recognition that altered intestinal microbiota composition and function can directly impact the phenomenon of ageing and age-related disorders. In fact, human GM, envisaged as a potential source of novel therapeutics, strongly modulates host immunity and metabolism. It is now clear that gut dysbiosis and their products (e.g. p-cresyl sulfate, trimethylamine‑N‑oxide) dictate a secretory associated senescence phenotype and chronic low-grade inflammation, features shared in the physiological process of ageing ("inflammaging") as well as in T2DM ("metaflammation") and in its microvascular complications. This review provides an in-depth look on the crosstalk between GM, host immunity and metabolism. Further, it characterizes human GM signatures of elderly and T2DM patients. Finally, a comprehensive scrutiny of recent molecular findings (e.g. epigenetic changes) underlying causal relationships between GM dysbiosis and diabetic retinopathy/nephropathy complications is pinpointed, with the ultimate goal to unravel potential pathophysiological mechanisms that may be explored, in a near future, as personalized disease-modifying therapeutic approaches.
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Affiliation(s)
- Rosa Fernandes
- Institute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, CNC.IBILI Consortium & CIBB Consortium, University of Coimbra, Coimbra, Portugal
| | - Sofia D Viana
- Institute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, CNC.IBILI Consortium & CIBB Consortium, University of Coimbra, Coimbra, Portugal; Polytechnic Institute of Coimbra, ESTESC-Coimbra Health School, Pharmacy, Coimbra, Portugal
| | - Sara Nunes
- Institute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, CNC.IBILI Consortium & CIBB Consortium, University of Coimbra, Coimbra, Portugal
| | - Flávio Reis
- Institute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, CNC.IBILI Consortium & CIBB Consortium, University of Coimbra, Coimbra, Portugal.
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Sugiura S, Taniguchi R, Nishioka Y, Iwase R, Tanaka R, Miyake H, Mori T, Ueda M, Shibata T. Evaluation of Anti-glycation Activities of Phlorotannins in Human and Bovine Serum Albumin-glyceraldehyde Models. Nat Prod Commun 2018. [DOI: 10.1177/1934578x1801300820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The anti-glycation activities of phlorotannins contained in the Japanese Lessoniaceae ( Ecklonia cava, Eck. kurome, Eck. stolonifera, Eisenia arborea, and Eis. bicyclis) were tested using serum albumin-glyceraldehyde (GA) models. In the human serum albumin (HSA)-GA model and the bovine serum albumin (BSA)-GA model, the concentrations of crude phlorotannins at 50% inhibition (IC50) of fluorescent advanced glycation end products (AGEs) formation was in the range of 0.48 to 0.70 mg/mL and 0.52 to 0.75 mg/mL, respectively. In tests using phloroglucinol and purified phlorotannins (eckol, fucofuroeckol A, phlorofucofuroeckol A, dieckol, and 8,8'-bieckol), dieckol had the highest inhibitory activity (IC50: 5.5 × 102 μM) against fluorescent AGEs formation in HSA-GA model and showed about 18 times inhibition compared with aminoguanidine hydrochloride of positive control. In the BSA albumin model, 8,8'-bieckol had about 27 times AGEs formation inhibitory activity (IC50: 6.2 × 102 μM) against aminoguanidine hydrochloride. In tests on GA scavenging activity, it was shown that compounds with phloroglucinol tetramer or higher had a scavenging rate of 70%, or more, with a reaction time of 120 minutes. These results suggest that among the phlorotannins, in particular the dimers of eckol (dieckol and 8,8'-bieckol), there are effective compounds for inhibiting the formation of AGEs derived from GA.
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Affiliation(s)
- Shingo Sugiura
- Graduate School of Bioresources, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
- Japan Science and Technology Agency, CREST, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
| | - Ryosuke Taniguchi
- Graduate School of Bioresources, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
- Japan Science and Technology Agency, CREST, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
| | - Yoshihiko Nishioka
- Graduate School of Bioresources, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
| | - Ryota Iwase
- Faculty of Bioresources, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
| | - Reiji Tanaka
- Graduate School of Bioresources, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
- Seaweed Biorefinery Research Center, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
- Japan Science and Technology Agency, CREST, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
| | - Hideo Miyake
- Graduate School of Bioresources, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
- Seaweed Biorefinery Research Center, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
- Japan Science and Technology Agency, CREST, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
| | - Tetsushi Mori
- Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
- Seaweed Biorefinery Research Center, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
- Japan Science and Technology Agency, CREST, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
| | - Mitsuyoshi Ueda
- Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake, Sakyo-ku, Kyoto 606-8502, Japan
- Japan Science and Technology Agency, CREST, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
| | - Toshiyuki Shibata
- Graduate School of Bioresources, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
- Seaweed Biorefinery Research Center, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
- Japan Science and Technology Agency, CREST, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
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Li P, Chen D, Cui Y, Zhang W, Weng J, Yu L, Chen L, Chen Z, Su H, Yu S, Wu J, Huang Q, Guo X. Src Plays an Important Role in AGE-Induced Endothelial Cell Proliferation, Migration, and Tubulogenesis. Front Physiol 2018; 9:765. [PMID: 29977209 PMCID: PMC6021521 DOI: 10.3389/fphys.2018.00765] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 05/31/2018] [Indexed: 01/10/2023] Open
Abstract
Advanced glycation end products (AGEs), produced by the non-enzymatic glycation of proteins and lipids under hyperglycemia or oxidative stress conditions, has been implicated to be pivotal in the development of diabetic vascular complications, including diabetic retinopathy. We previously demonstrated that Src kinase played a causative role in AGE-induced hyper-permeability and barrier dysfunction in human umbilical vein endothelial cells (HUVECs). While the increase of vascular permeability is the early event of angiogenesis, the effect of Src in AGE-induced angiogenesis and the mechanism has not been completely revealed. Here, we investigated the impact of Src on AGE-induced HUVECs proliferation, migration, and tubulogenesis. Inhibition of Src with inhibitor PP2 or siRNA decreased AGE-induced migration and tubulogenesis of HUVECs. The inactivation of Src with pcDNA3/flag-SrcK298M also restrained AGE-induced HUVECs proliferation, migration, and tube formation, while the activation of Src with pcDNA3/flag-SrcY530F enhanced HUVECs angiogenesis alone and exacerbated AGE-induced angiogenesis. AGE-enhanced HUVECs angiogenesis in vitro was accompanied with the phosphorylation of ERK in HUVECs. The inhibition of ERK with its inhibitor PD98059 decreased AGE-induced HUVECs angiogenesis. Furthermore, the inhibition and silencing of Src suppressed the AGE-induced ERK activation. And the silencing of AGEs receptor (RAGE) inhibited the AGE-induced ERK activation and angiogenesis as well. In conclusions, this study demonstrated that Src plays a pivotal role in AGE-promoted HUVECs angiogenesis by phosphorylating ERK, and very likely through RAGE-Src-ERK pathway.
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Affiliation(s)
- Peixin Li
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Deshu Chen
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Yun Cui
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Weijin Zhang
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Jie Weng
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Lei Yu
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Lixian Chen
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Zhenfeng Chen
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Haiying Su
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Shengxiang Yu
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Jie Wu
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Qiaobing Huang
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
| | - Xiaohua Guo
- Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, China
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Hamasaki S, Kobori T, Yamazaki Y, Kitaura A, Niwa A, Nishinaka T, Nishibori M, Mori S, Nakao S, Takahashi H. Effects of scavenger receptors-1 class A stimulation on macrophage morphology and highly modified advanced glycation end product-protein phagocytosis. Sci Rep 2018; 8:5901. [PMID: 29651042 PMCID: PMC5897562 DOI: 10.1038/s41598-018-24325-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 03/29/2018] [Indexed: 12/30/2022] Open
Abstract
Advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups, play an important role in several diseases and aging processes including angiopathy, renal failure, diabetic complications, and neurodegenerative diseases. Among AGE-associated phenotypes, toxic AGEs, glyceraldehyde-derived AGE-2, and glycolaldehyde-derived AGE-3 are involved in the pathogenesis of diabetic complications. In addition, macrophages are reported to remove extracellular AGEs from tissues via scavenger receptors, leading to the progression of atherosclerosis. In the present study, we found that AGE-2 and AGE-3 enhanced their own endocytic uptake by RAW264.7 mouse macrophage-like cells in a concentration-dependent manner. Furthermore, we demonstrated, for the first time, the morphology of phagocytic macrophages and the endocytosis of AGE particles. The toxic AGEs induced the expression of a scavenger receptor, CD204/scavenger receptors-1 class A (SR-A). Notably, an antibody against CD204 significantly prevented toxic AGE uptake. Moreover, an SR-A antagonistic ligand, fucoidan, also attenuated the AGE-2- and AGE-3-evoked uptake in a concentration-dependent manner. These results indicated that SR-A stimulation, at least in part, plays a role in AGE uptake.
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Affiliation(s)
- Shinichi Hamasaki
- Department of Anesthesiology, Kindai University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Takuro Kobori
- Department of Pharmacology, Kindai University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Yui Yamazaki
- Department of Pharmacology, Kindai University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Atsuhiro Kitaura
- Department of Anesthesiology, Kindai University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Atsuko Niwa
- Department of Pharmacology, Kindai University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Takashi Nishinaka
- Department of Pharmacology, Kindai University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Masahiro Nishibori
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, Japan
| | - Shuji Mori
- Department of Pharmacy, Shujitsu University, 1-6-1 Nishikawahara, Okayama, Japan
| | - Shinichi Nakao
- Department of Anesthesiology, Kindai University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Hideo Takahashi
- Department of Pharmacology, Kindai University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
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Investigation of the Effect of Diabetes on Radiculopathy Induced by Nucleus Pulposus Application to the DRG in a Spontaneously Diabetic Rat Model. Spine (Phila Pa 1976) 2017; 42:1749-1756. [PMID: 28658037 DOI: 10.1097/brs.0000000000002299] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A controlled, interventional animal study. OBJECTIVE The aim of this study was to evaluate the effect of diabetes mellitus (DM) on radiculopathy due to lumbar disc herniation (LDH), by investigating pain-related behavior and the expression of tumor necrosis factor-alpha (TNF-α) and growth-associated protein 43 (GAP43) in type 2 diabetic rats following application of nucleus pulposus (NP) to the dorsal root ganglion (DRG). SUMMARY OF BACKGROUND DATA Previous clinical studies suggested negative effects of DM on radiculopathy due to LDH, and that inflammation and nerve regeneration could interact with DM and radiculopathy. METHODS We applied autologous NP to the left L5 DRG of adult male Wistar rats and Goto-Kakizaki rats. Behavioral testing measured the mechanical withdrawal threshold of rats. We immunohistochemically evaluated the localization of ionized calcium-binding adapter molecule-1 (Iba-1), receptor of advanced glycation end products (RAGE), and TNF-α in DRGs. TNF-α and GAP43 expression levels in DRG were determined by quantitative real-time PCR and western blotting. RESULTS The mechanical withdrawal threshold significantly declined in the non-DM NP group compared with the non-DM sham group for 28 days, whereas the decline in threshold extended to 35 days in the DM NP group compared with the DM sham group. RAGE and TNF-α expression in DRGs was colocalized in Iba-1 positive cells. The non-DM NP rats had higher TNF-α protein expression levels versus the non-DM sham rats on day 7, and the DM NP group had higher levels versus the DM sham group on days 7 and 14. The non-DM NP group had higher GAP43 mRNA expression than the non-DM sham group for 28 days, while the DM NP group had a higher level than the DM sham group for 35 days. CONCLUSION DM prolongs the pain-related behavior caused by NP. The prolonged inflammation and nerve regeneration could elucidate the pathogenesis of continuous pain of radiculopathy initiated by LDH. LEVEL OF EVIDENCE N /A.
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Activation of NLRP3 Inflammasome by Advanced Glycation End Products Promotes Pancreatic Islet Damage. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:9692546. [PMID: 29230270 PMCID: PMC5694574 DOI: 10.1155/2017/9692546] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 08/05/2017] [Accepted: 08/29/2017] [Indexed: 12/18/2022]
Abstract
Accumulation of advanced glycation end products (AGEs) contributes to ageing and age-related diseases, especially type 2 diabetes. The NLRP3 inflammasome, as a vital component of the innate immune system, is implicated in the pathogenesis of type 2 diabetes. However, the role of the NLRP3 inflammasome in AGE-induced pancreatic islet damage remains largely unclear. Results showed that administration of AGEs (120 mg/kg for 6 weeks) in C57BL/6J mice induced an abnormal response to glucose (as measured by glucose tolerance and insulin release), pancreatic β-cell ultrastructural lesion, and cell death. These effects were associated with an excessive superoxide anion level, significant increased protein expression levels for NADPH oxidase 2 (NOX2), thioredoxin-interacting protein (TXNIP), NLRP3, and cleaved IL-1β, enhanced caspase-1 activity, and a significant increase in the levels of TXNIP–NLRP3 protein interaction. Ablation of the NLRP3 inflammasome or treatment with antioxidant N-acetyl-cysteine (NAC) clearly ameliorated these effects. In conclusion, our results reveal a possible mechanism for AGE-induced pancreatic islet damage upon NLRP3 inflammasome activation.
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Morioka Y, Teshigawara K, Tomono Y, Wang D, Izushi Y, Wake H, Liu K, Takahashi HK, Mori S, Nishibori M. The specific localization of advanced glycation end-products (AGEs) in rat pancreatic islets. J Pharmacol Sci 2017; 134:218-224. [DOI: 10.1016/j.jphs.2017.07.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 07/23/2017] [Accepted: 07/26/2017] [Indexed: 02/08/2023] Open
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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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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: 236] [Impact Index Per Article: 29.5] [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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Hasanvand A, Amini-Khoei H, Hadian MR, Abdollahi A, Tavangar SM, Dehpour AR, Semiei E, Mehr SE. Anti-inflammatory effect of AMPK signaling pathway in rat model of diabetic neuropathy. Inflammopharmacology 2016; 24:207-219. [PMID: 27506528 DOI: 10.1007/s10787-016-0275-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 07/29/2016] [Indexed: 02/06/2023]
Abstract
Diabetic neuropathy (DN) is characterized as Hyperglycemia activates thdisturbed nerve conduction and progressive chronic pain. Inflammatory mediators, particularly cytokines, have a determinant role in the pathogenesis of neuropathic pain. The activity of adenosine monophosphate protein kinase (AMPK), an energy charge sensor with neuroprotective properties, is decreased in diabetes. It has been reported that activation of AMPK reduces the systemic inflammation through inhibition of cytokines. In this study, we aimed to investigate the probable protective effects of AMPK on DN in a rat of diabetes. DN was induced by injection of streptozotocin (65 mg/kg, i.p.). Motor nerve conduction velocities (MNCV) of the sciatic nerve, as an electrophysiological marker for peripheral nerve damage, were measured. Plasma levels of IL-6, TNF-α, CRP were assessed as relevant markers for inflammatory response. Also, the expression of phosphorylated AMPK (p-AMPK) and non-phosphorylated (non-p-AMPK) was evaluated by western blotting in the dorsal root ganglia. Histopathological assessment was performed to determine the extent of nerve damage in sciatic nerve. Our findings showed that activation of AMPK by metformin (300 mg/kg) significantly increased the MNCV and reduced the levels of inflammatory cytokines. In addition, we showed that administration of metformin increased the expression of p-AMPK as well as decline in the level of non p-AMPK. Our results demonstrated that co-administration of dorsomorphin with metformin reversed the beneficial effects of metformin. In conclusion, the results of this study demonstrated that the activation of AMPK signaling pathway in diabetic neuropathy might be associated with the anti-inflammatory response.
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Affiliation(s)
- Amin Hasanvand
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, Iran.,Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Amini-Khoei
- Department of Pharmacology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Hadian
- Department of Physical Therapy, Rehabilitation Faculty, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Abdollahi
- Department of Pathology, Imam Khomini Complex Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Tavangar
- Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Elika Semiei
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahram Ejtemaei Mehr
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, Iran. .,Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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44
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Watanabe M, Kawai Y, Kitayama M, Akao H, Motoyama A, Wakasa M, Saito R, Aoki H, Fujibayashi K, Tsuchiya T, Nakanishi H, Saito K, Takeuchi M, Kajinami K. Diurnal glycemic fluctuation is associated with severity of coronary artery disease in prediabetic patients: Possible role of nitrotyrosine and glyceraldehyde-derived advanced glycation end products. J Cardiol 2016; 69:625-631. [PMID: 27470137 DOI: 10.1016/j.jjcc.2016.07.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 06/10/2016] [Accepted: 07/04/2016] [Indexed: 11/18/2022]
Abstract
BACKGROUND Glucose fluctuation (GF) is a risk factor for coronary artery disease (CAD). However, it remains unknown whether specific indices of GF are risk factors for CAD. Therefore, we evaluated the relationship between GF, as determined by a continuous glucose monitoring system (CGMS) or the glucose level at 2h after a 75-g oral glucose tolerance test (75g OGTT 120), and the severity of CAD in prediabetic patients. We also evaluated whether nitrotyrosine (NT) and glyceraldehyde-derived advanced glycation end-products (Glycer-AGE) were induced by GF. METHODS Twenty-eight prediabetic patients underwent coronary angiography (CAG), and the Gensini score and the SYNTAX score were evaluated as the severity of CAD, while the mean amplitude of glycemic excursions (MAGE) by CGMS and 75g OGTT 120 were evaluated. Serum NT and Glycer-AGE were measured. RESULTS The MAGE was closely associated with the Gensini score (r=0.742, p<0.001) and the SYNTAX score (r=0.776, p<0.001), respectively. The 75g OGTT 120 was not associated with the Gensini score (r=0.36, p=0.06), but it was significantly associated with the SYNTAX score (r=0.413, p=0.036). Multiple linear regression analysis showed that the MAGE was the only independent determinant for the severity of CAD. The levels of NT and Glycer-AGE were significantly higher in the high MAGE group than in the low MAGE group. CONCLUSIONS Diurnal GF is associated with the severity of CAD, even in prediabetic patients. GF, NT, and Glycer-AGE may play a pathological role in the progression of CAD.
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Affiliation(s)
- Makoto Watanabe
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | - Yasuyuki Kawai
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan.
| | | | - Hironubu Akao
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | - Atsushi Motoyama
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | - Minoru Wakasa
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | - Ryuhei Saito
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | - Hirofumi Aoki
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
| | | | | | - Hiroaki Nakanishi
- Department of Forensic Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Kazuyuki Saito
- Department of Forensic Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan
| | - Kouji Kajinami
- Department of Cardiology, Kanazawa Medical University, Ishikawa, Japan
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45
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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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46
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Colzani M, De Maddis D, Casali G, Carini M, Vistoli G, Aldini G. Reactivity, Selectivity, and Reaction Mechanisms of Aminoguanidine, Hydralazine, Pyridoxamine, and Carnosine as Sequestering Agents of Reactive Carbonyl Species: A Comparative Study. ChemMedChem 2016; 11:1778-89. [DOI: 10.1002/cmdc.201500552] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 01/19/2016] [Indexed: 11/05/2022]
Affiliation(s)
- Mara Colzani
- Department of Pharmaceutical Sciences; Università degli Studi di Milano; via Mangiagalli, 25 20133 Milano Italy
| | - Danilo De Maddis
- Department of Pharmaceutical Sciences; Università degli Studi di Milano; via Mangiagalli, 25 20133 Milano Italy
| | - Gaia Casali
- Department of Pharmaceutical Sciences; Università degli Studi di Milano; via Mangiagalli, 25 20133 Milano Italy
| | - Marina Carini
- Department of Pharmaceutical Sciences; Università degli Studi di Milano; via Mangiagalli, 25 20133 Milano Italy
| | - Giulio Vistoli
- Department of Pharmaceutical Sciences; Università degli Studi di Milano; via Mangiagalli, 25 20133 Milano Italy
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences; Università degli Studi di Milano; via Mangiagalli, 25 20133 Milano Italy
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47
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Feng L, Zhu MM, Bu WQ, Wang CF, Zheng ZG, Wang RS, Jia XB, Zhu Q. The C-terminal tails of 4,4'-diphenylmethane-bis(methyl) carbamate are essential for binding to receptor for advanced glycation end products to attenuate advanced glycation end products-induced inflammation and apoptosis responses in human umbilical vein endothelial cells. ACTA ACUST UNITED AC 2016; 68:93-106. [PMID: 26806697 DOI: 10.1111/jphp.12499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 11/01/2015] [Indexed: 01/05/2023]
Abstract
OBJECTIVES A novel compound 4,4'-diphenylmethane-bis(methyl) carbamate (CM1) was shown to possess preventive activity on AGEs-induced human umbilical vein endothelial cells (HUVECs) damage via binding to RAGE. However, the underlying structural basis of CM1 on binding to RAGE was not fully understood. METHODS In the present study, CM1 analogues were designed and synthesized to compare the activity differences on inhibiting AGEs-induced inflammatory response including TGF-β1, RAGE protein expression in HUVECs, and macrophages migration and adhesion to HUVECs. In addition, the cell viability and anti-apoptosis activities of CM1 analogues were also examined. KEY FINDINGS These results indicated that CM1 had higher activities on preventing AGEs-induced HUVECs damage (inflammation, cell viability and apoptosis) than other analogues. The bioaffinity assay was conducted by CMC and demonstrated that the IC50 and dissociation equilibrium constants (Kd) of CM1 were lower whereas the Bmax was higher than other analogues. The incubation of RAGE protein with CM1 analogues by equilibrium dialysis method showed CM1 had a stronger binding rate than other CM1 analogues. CONCLUSION Our findings suggested that the C-terminal tails (methoxycarbonyl groups) of CM1 were the active groups for binding to RAGE and then led to the attenuation on RAGE-mediated endothelial dysfunction.
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Affiliation(s)
- Liang Feng
- Key Laboratory of Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu, Nanjing, China.,State Key Laboratory of Quality Research in Chinese Medicine, Biotechnology Labortory of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China
| | - Mao-mao Zhu
- Key Laboratory of Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu, Nanjing, China
| | - Wei-quan Bu
- Key Laboratory of Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu, Nanjing, China.,Jiangsu Provincial Combine Traditional Chinese and Western Medicine Hospital, Jiangsu, Nanjing, China
| | - Chun-fei Wang
- Key Laboratory of Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu, Nanjing, China
| | - Zhao-guang Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Biotechnology Labortory of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China
| | - Ru-shang Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Biotechnology Labortory of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China.,Institute of Conson Co. for Chinese Medicine in Kidiney Diseases and Consun Pharmaceutical Group, Guangzhou, China
| | - Xiao-bin Jia
- Key Laboratory of Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu, Nanjing, China
| | - Quan Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, Biotechnology Labortory of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China.,Institute of Conson Co. for Chinese Medicine in Kidiney Diseases and Consun Pharmaceutical Group, Guangzhou, China
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48
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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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49
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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: 28] [Impact Index Per Article: 2.8] [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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50
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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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