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Fatima N, Khan MI, Jawed H, Qureshi U, Ul-Haq Z, Hafizur RM, Shah TA, Dauelbait M, Bin Jardan YA, Shazly GA. Cinnamaldehyde ameliorates diabetes-induced biochemical impairments and AGEs macromolecules in a pre-clinical model of diabetic nephropathy. BMC Pharmacol Toxicol 2024; 25:85. [PMID: 39543757 PMCID: PMC11566217 DOI: 10.1186/s40360-024-00811-0] [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: 09/24/2024] [Accepted: 11/01/2024] [Indexed: 11/17/2024] Open
Abstract
PURPOSE Cinnamaldehyde, has various therapeutic potentials including glucose-lowering effect, and insulinotropic effect; however, its glycation inhibitory mechanism is not known yet. In this study, we explored the effects of cinnamaldehyde for its AGEs inhibitory mechanism in a streptozotocin-complete Freund's adjuvant (STZ-CFA) induced diabetic nephropathy (DN) rat model. METHODS Pre-clinical DN model was developed by the administration of multiple low doses of STZ-CFA in rats, mainly characterized by abnormal blood parameters and nephrotic damages. Diabetes-related systemic profile and histopathological hallmarks were evaluated using biochemical assays, microscopic imaging, immunoblot, and real-time PCR analyses, supported by cinnamaldehyde-albumin interaction assessed using STD-NMR and in silico site-directed interactions in the presence of glucose. RESULTS Cinnamaldehyde-treatment significantly reversed DN hallmarks, fasting blood glucose (FBG), serum insulin, glycated hemoglobin (HbA1c), urinary microalbumin, and creatinine contrasted to non-treated DN rats and aminoguanidine, a positive reference advanced glycation end products (AGEs) inhibitor. The pathological depositions of AGEs, receptor for advanced glycation end products (RAGE), and carboxymethyl lysine (CML), and transcriptional levels of AGE-RAGE targeted immunomodulatory factors (IL1β, TNF-α, NF-κB, TGF-β) were significantly improved in cinnamaldehyde treated rats as compared to aminoguanidine. Cinnamaldehyde post-treatment improved pancreatic pathology and systemic glycemic index (0.539 ± 0.01 vs. 0.040 ± 0.001, P < 0.001) in DN rats. Subsequently, in silico profiling of cinnamaldehyde defined the competitive binding inhibition with glucose in AGE and RAGE receptors that was further confirmed by in vitro STD-NMR analysis. CONCLUSION These findings suggest potential role of cinnamaldehyde in reversing STZ-induced diabetic nephropathic impairments; therefore, appears promising candidate for further pharmacological explorations towards diabetes-associated complications.
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Affiliation(s)
- Noor Fatima
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan.
| | - M Israr Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Hira Jawed
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Urooj Qureshi
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Zaheer Ul-Haq
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Rahman M Hafizur
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan.
- Department of Biochemistry and Molecular Biology, Dhaka International University (DIU), Satarkul, Badda, Dhaka, 1212, Bangladesh.
- Daffodil International University, Birulia, Savar, Dhaka, 1216, Bangladesh.
| | - Tawaf Ali Shah
- College of agriculture of Agriculture Engineering and Food Science, Shandong University of Technology, Zibo, 255000, China
| | - Musaab Dauelbait
- Department of Scientific Translation, Faculty of Translation, Khartoum, 11111, Sudan.
| | - Yousef A Bin Jardan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 11451, Riyadh, Saudi Arabia
| | - Gamal A Shazly
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 11451, Riyadh, Saudi Arabia
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Lin YC, Lai TS, Chen YT, Chou YH, Chen YM, Hung KY, Tu YK. Comparative efficacy and choice of lipid-lowering drugs for cardiovascular and kidney outcomes in patients with chronic kidney disease: A systematic review and network meta-analysis. J Formos Med Assoc 2024:S0929-6646(24)00474-1. [PMID: 39389802 DOI: 10.1016/j.jfma.2024.09.037] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/07/2024] [Accepted: 09/27/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND The effect of exact classes of lipid-lowering drugs (LLDs) on preventing major adverse cardiovascular events (MACEs) and poor renal outcomes is not well characterized in the chronic kidney disease (CKD) population. METHODS We performed a frequentist random-effects network meta-analysis of randomized controlled trials (RCTs) to evaluate the protective effect of the LLDs in non-dialysis CKD patients. The PubMed, Embase, Web of Science, and Cochrane Library databases were systematically searched for relevant trials published before March 31, 2024. The primary outcome was the incidence of MACEs. The secondary outcomes comprised all-cause mortality, end-stage kidney disease, changes in estimated glomerular filtration rate (eGFR) and proteinuria, and safety. RESULTS Forty-nine eligible RCTs with 77,826 participants with non-dialysis CKD were included. With moderate confidence in the evidence, rosuvastatin and atorvastatin showed statistically significantly more efficacy in reducing the risk of MACE, with a pooled risk ratio of 0.55 (95% CI 0.33-0.91) for rosuvastatin and 0.67 (0.49-0.90) for atorvastatin, respectively, compared with the control group. For the change in the eGFR, atorvastatin (mean difference [MD], 1.40; 95% CI, 0.61 to 2.18), rosuvastatin (MD, 1.73; 95% CI, 0.63 to 2.83), and statin plus ezetimibe (MD, 2.35; 95% CI, 0.44 to 4.26) showed statistically significant increases in the mean eGFR. CONCLUSION In patients with non-dialysis CKD, there is sufficient evidence to show that rosuvastatin and atorvastatin were statistically significantly more effective and preferable in reducing the risk of MACE and increasing the mean eGFR compared with the control group.
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Affiliation(s)
- Yi-Chih Lin
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan
| | - Tai-Shuan Lai
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - Yi-Ting Chen
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Hsiang Chou
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yung-Ming Chen
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kuan-Yu Hung
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Kang Tu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan; Health Data Research Center, National Taiwan University, Taipei, Taiwan.
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Hua Y, Yin Z, Li M, Sun H, Shi B. Correlation between circulating advanced glycation end products and thioredoxin-interacting protein levels and renal fat content in type 2 diabetes mellitus patients. Diabetol Metab Syndr 2024; 16:144. [PMID: 38951835 PMCID: PMC11218298 DOI: 10.1186/s13098-024-01361-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 05/27/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND This study sought to explore the clinical relevance of the associations of serum levels of advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), and thioredoxin-interacting protein (TXNIP) with the renal fat fraction (RFF) in individuals with type 2 diabetes mellitus (T2DM). METHODS A total of 133 patients with T2DM were enrolled in the study. RFF, which represents the renal fat level, was determined utilizing Dixon magnetic resonance imaging (MRI). Serum levels of AGEs, sRAGE, TXNIP, and other biochemical parameters were measured in patients who fasted. RESULTS RFF in T2DM patients was positively correlated with the fasting levels of C-peptide (CP), triglycerides (TG), AGEs, TXNIP, and sRAGE (P < 0.05) and negatively correlated with the high-density lipoprotein cholesterol (HDL-c) level (P < 0.05). Pearson's correlation analysis indicated that the serum levels of AGEs, sRAGE, and TXNIP were interrelated and positively correlated (P < 0.05). Then, all patients were assigned to four groups according to the RFF quartile. The HC, CP, TG, AGEs, sRAGE, TXNIP, and DKD percentages tended to increase as the RFF quartiles increased, while the HDL-c level tended to decrease (p for trend < 0.05). Next, multiple linear regression analysis was performed using RFF as the dependent variable. After controlling for covariates related to RFF, the results showed that the serum levels of AGEs and TXNIP were still significantly correlated with RFF. CONCLUSION These results suggest that circulating AGEs and TXNIP levels may be associated with ectopic fat accumulation in the kidneys of T2DM patients and may serve as indicators of the severity of renal fat deposition.
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Affiliation(s)
- Yulin Hua
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Zaifei Yin
- Department of Endocrinology and Metabolism, Suzhou Dushu Lake Hospital, The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Mingming Li
- Department of Endocrinology and Metabolism, Suzhou Dushu Lake Hospital, The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Hong Sun
- Department of Endocrinology and Metabolism, Suzhou Dushu Lake Hospital, The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University, Suzhou, Jiangsu, 215123, China.
| | - Bimin Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China.
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Parwani K, Mandal P. Advanced glycation end products and insulin resistance in diabetic nephropathy. VITAMINS AND HORMONES 2024; 125:117-148. [PMID: 38997162 DOI: 10.1016/bs.vh.2024.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Insulin resistance is a central hallmark that connects the metabolic syndrome and diabetes to the resultant formation of advanced glycation end products (AGEs), which further results in the complications of diabetes, including diabetic nephropathy. Several factors play an important role as an inducer to diabetic nephropathy, and AGEs elicit their harmful effects via interacting with the receptor for AGEs Receptor for AGEs, by induction of pro-inflammatory cytokines, oxidative stress, endoplasmic reticulum stress and fibrosis in the kidney tissues leading to the loss of renal function. Insulin resistance results in the activation of other alternate pathways governed by insulin, which results in the hypertrophy of the renal cells and tissue remodeling. Apart from the glucose uptake and disposal, insulin dependent PI3K and Akt also upregulate the expression of endothelial nitric oxide synthase, that results in increasing the bioavailability of nitric oxide in the vascular endothelium, which further results in tissue fibrosis. Considering the global prevalence of diabetic nephropathy, and the impact of protein glycation, various inhibitors and treatment avenues are being developed, to prevent the progression of diabetic complications. In this chapter, we discuss the role of glycation in insulin resistance and further its impact on the kidney.
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Affiliation(s)
- Kirti Parwani
- Department of Biological Sciences, P. D. Patel Institute of Applied Sciences, Charotar University of Science & Technology, Gujarat, India
| | - Palash Mandal
- Department of Biological Sciences, P. D. Patel Institute of Applied Sciences, Charotar University of Science & Technology, Gujarat, India.
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Kunnel S, Chakraborty I, Govindaraju I, Mal SS, Mazumder N. Impact of dietary advanced glycation end products (dAGEs) in processed foods on health. ADVANCED BIOPHYSICAL TECHNIQUES FOR POLYSACCHARIDES CHARACTERIZATION 2024:309-325. [DOI: 10.1016/b978-0-443-14042-6.00013-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Xi K, Zhang M, Li M, Tang Q, Zhao Q, Chen W. Unveiling the mechanisms of nephrotoxicity caused by nephrotoxic compounds using toxicological network analysis. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 34:102075. [PMID: 38074898 PMCID: PMC10709196 DOI: 10.1016/j.omtn.2023.102075] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/08/2023] [Indexed: 10/16/2024]
Abstract
Billions of people worldwide have experienced irreversible kidney injuries, which is mainly attributed to the complexity of drug-induced nephrotoxicity. Consequently, there is an urgent need for uncovering the mechanisms of nephrotoxicity caused by compounds. In the present study, a network-based methodology was applied to explore the mechanisms of nephrotoxicity induced by specific compounds. Initially, a total of 42 nephrotoxic compounds and 60 kinds of syndromes associated with nephrotoxicity were collected from public resources. Afterward, network localization and separation algorithms were used to map the targets of compounds and diseases into the human interactome. By doing so, 199 statistically significant nephrotoxic networks displaying the interaction between compound targets and disease genes were obtained, which played pivotal roles in compounds-induced nephrotoxicity. Subsequently, enrichment analysis pinpointed core Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways that highlight commonalities in nephrotoxicity induced by nephrotoxic compounds. It was found that nephrotoxic compounds primarily induce nephrotoxicity by mediating the advanced glycosylation end products-receptor for advanced glycosylation end products signaling pathway in diabetic complications, human cytomegalovirus infection, lipid and atherosclerosis, Kaposi sarcoma-associated herpesvirus infection, apoptosis, and the phosphatidylinositol 3-kinase-Akt pathways. These results provide valuable insights for preventing drug-induced nephrotoxicity. Furthermore, the approaches we used are also helpful in conducting research on other kinds of toxicities.
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Affiliation(s)
- Kexing Xi
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Mengqing Zhang
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Mingrui Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qiang Tang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qi Zhao
- School of Computer Science and Software Engineering, University of Science and Technology Liaoning, Anshan 114051, China
| | - Wei Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
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Lin YC, Tsao HM, Lai TS, Chen YT, Chou YH, Lin SL, Chen YM, Hung KY, Tu YK. Effect of Lipid-Lowering Drugs on Renal and Cardiovascular Outcomes in Patients with Chronic Kidney Disease and Dyslipidemia: A Retrospective Cohort Study. Clin Pharmacol Ther 2023; 114:1366-1374. [PMID: 37750432 DOI: 10.1002/cpt.3060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/16/2023] [Indexed: 09/27/2023]
Abstract
The effects of lipid-lowering drugs (LLDs) on cardiovascular and renal outcomes in patients with advanced chronic kidney disease (CKD) and dyslipidemia are not completely understood. We conducted a retrospective cohort study to evaluate the effect of LLDs on end-stage kidney disease (ESKD), major adverse cardiovascular events (MACEs), and mortality in adult patients with CKD stage 3b, 4, or 5, and dyslipidemia. Participants were recruited between January 1, 2008, and December 31, 2018, and classified as LLD or non-LLD users; the final follow-up date was December 31, 2020. The primary outcome was time to ESKD or death due to renal failure. Sub-distribution hazard regression models adjusted for multivariables, including time-varying lipid profile covariates, were used for the analysis. Among the 6,740 participants, 4,280 patients with CKD and dyslipidemia, including 872 using LLDs and 3,408 not using LLDs, completed the primary analysis. The multivariable analyses showed that LLD users had a significantly lower risk of time to the composite renal outcome (adjusted hazard ratio [aHR], 0.76, 95% confidence interval [CI], 0.65-0.89), and MACE incidence (aHR, 0.75, 95% CI, 0.62-0.93) than did non-LLD users. After adjusting for time-varying covariates of the lipid profile, there was a significant difference in the composite renal outcome (aHR, 0.78, 95% CI, 0.65-0.93) and MACEs (aHR, 0.77, 95% CI, 0.60-0.98). Among adult patients with advanced CKD and dyslipidemia, LLD users had a significantly lower risk of composite renal outcomes and MACEs than non-LLD users. In addition to reducing lipid profile, the use of LLD is associated with renal and cardiovascular protective effects.
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Affiliation(s)
- Yi-Chih Lin
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan
| | - Hsiao-Mei Tsao
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tai-Shuan Lai
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Ting Chen
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Division of Blood Purification, Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Hsiang Chou
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shuei-Liong Lin
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan
| | - Yung-Ming Chen
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kuan-Yu Hung
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Kang Tu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
- Health Data Research Center, National Taiwan University, Taipei, Taiwan
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Berdowska I, Matusiewicz M, Fecka I. Methylglyoxal in Cardiometabolic Disorders: Routes Leading to Pathology Counterbalanced by Treatment Strategies. Molecules 2023; 28:7742. [PMID: 38067472 PMCID: PMC10708463 DOI: 10.3390/molecules28237742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/13/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Methylglyoxal (MGO) is the major compound belonging to reactive carbonyl species (RCS) responsible for the generation of advanced glycation end products (AGEs). Its upregulation, followed by deleterious effects at the cellular and systemic levels, is associated with metabolic disturbances (hyperglycemia/hyperinsulinemia/insulin resistance/hyperlipidemia/inflammatory processes/carbonyl stress/oxidative stress/hypoxia). Therefore, it is implicated in a variety of disorders, including metabolic syndrome, diabetes mellitus, and cardiovascular diseases. In this review, an interplay between pathways leading to MGO generation and scavenging is addressed in regard to this system's impairment in pathology. The issues associated with mechanistic MGO involvement in pathological processes, as well as the discussion on its possible causative role in cardiometabolic diseases, are enclosed. Finally, the main strategies aimed at MGO and its AGEs downregulation with respect to cardiometabolic disorders treatment are addressed. Potential glycation inhibitors and MGO scavengers are discussed, as well as the mechanisms of their action.
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Affiliation(s)
- Izabela Berdowska
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | | | - Izabela Fecka
- Department of Pharmacognosy and Herbal Medicines, Wroclaw Medical University, 50-556 Wroclaw, Poland
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Waseem R, Khan T, Shamsi A, Shahid M, Kazim SN, Hassan MI, Islam A. Inhibitory potential of N-acetylaspartate against protein glycation, AGEs formation and aggregation: Implication of brain osmolyte in glycation-related complications. Int J Biol Macromol 2023:125405. [PMID: 37336383 DOI: 10.1016/j.ijbiomac.2023.125405] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 06/11/2023] [Accepted: 06/13/2023] [Indexed: 06/21/2023]
Abstract
Protein glycation and aggregation have a pivotal role in many diseases including diabetes and neurodegenerative disorders. N-acetyl aspartate (NAA), an osmolyte derived from L-aspartic acid, is one of the most abundant metabolites in the mammalian brain. Although NAA is supposed to be a substitute for a neuronal marker, its function is not fully elucidated. Herein, we have investigated the effect of NAA on glycation, AGEs formation and aggregation of irisin. AGE-specific fluorescence showed the strong inhibition of AGEs formation in the presence of NAA, demonstrating its anti-glycating property. The aggregates present in MG-modified irisin were also reduced by NAA, which was confirmed by Thioflavin T fluorescence and fluorescence microscopy. Further, for the explanation of the strong anti-glycating potential of NAA, the interaction between irisin and NAA was also examined. Interaction studies involving steady-state fluorescence and molecular docking demonstrated that hydrogen bonding and salt bridges by NAA stabilize the irisin. It was found that glycation-prone residues i.e., lysine and arginine are specifically involved in the interaction which might prevent them from getting modified during the process of glycation. This study for the first time reported the antiglycating potential of NAA which can be implicated in the therapeutic management of various glycation-related complications.
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Affiliation(s)
- Rashid Waseem
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Tanzeel Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Anas Shamsi
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, United Arab Emirates
| | - Mohammad Shahid
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Syed Naqui Kazim
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Asimul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
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Kim Y. Blood and Tissue Advanced Glycation End Products as Determinants of Cardiometabolic Disorders Focusing on Human Studies. Nutrients 2023; 15:nu15082002. [PMID: 37111220 PMCID: PMC10144557 DOI: 10.3390/nu15082002] [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: 04/04/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 04/29/2023] Open
Abstract
Cardiometabolic disorders are characterised by a cluster of interactive risk determinants such as increases in blood glucose, lipids and body weight, as well as elevated inflammation and oxidative stress and gut microbiome changes. These disorders are associated with onset of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). T2DM is strongly associated with CVD. Dietary advanced glycation end products (dAGEs) attributable from modern diets high in sugar and/or fat, highly processed foods and high heat-treated foods can contribute to metabolic etiologies of cardiometabolic disorders. This mini review aims to determine whether blood dAGEs levels and tissue dAGEs levels are determinants of the prevalence of cardiometabolic disorders through recent human studies. ELISA (enzyme-linked immunosorbent assay), high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) for blood dAGEs measurement and skin auto fluorescence (SAF) for skin AGEs measurement can be used. Recent human studies support that a diet high in AGEs can negatively influence glucose control, body weight, blood lipid levels and vascular health through the elevated oxidative stress, inflammation, blood pressure and endothelial dysfunction compared with a diet low in AGEs. Limited human studies suggested a diet high in AGEs could negatively alter gut microbiota. SAF could be considered as one of the predictors affecting risks for cardiometabolic disorders. More intervention studies are needed to determine how dAGEs are associated with the prevalence of cardiometabolic disorders through gut microbiota changes. Further human studies are conducted to find the association between CVD events, CVD mortality and total mortality through SAF measurement, and a consensus on whether tissue dAGEs act as a predictor of CVD is required.
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Affiliation(s)
- Yoona Kim
- Department of Food and Nutrition, Institute of Agriculture and Life Science, Gyeongsang National University, 501 Jinju-daero, Jinju 52828, Gyeongsangnam-do, Republic of Korea
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Zhou X, Xu C, Dong J, Liao L. Role of renal tubular programed cell death in diabetic kidney disease. Diabetes Metab Res Rev 2023; 39:e3596. [PMID: 36401596 PMCID: PMC10078574 DOI: 10.1002/dmrr.3596] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 09/22/2022] [Accepted: 10/10/2022] [Indexed: 11/21/2022]
Abstract
The pathogenic mechanism of diabetic kidney disease (DKD) is involved in various functions; however, its inadequate characterisation limits the availability of effective treatments. Tubular damage is closely correlated with renal function and is thought to be the main contributor to the injury observed in early DKD. Programed cell death (PCD) occurs during the biological development of the living body. Accumulating evidence has clarified the fundamental role of abnormalities in tubular PCD during DKD pathogenesis. Among PCD types, classical apoptosis, autophagic cell death, and pyroptosis are the most studied and will be the focus of this review. Our review aims to elucidate the current knowledge of the mechanism of DKD and the potential therapeutic potential of drugs targeting tubular PCD pathways in DKD.
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Affiliation(s)
- Xiaojun Zhou
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, China
- Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Chunmei Xu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Provincial Hospital, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Jianjun Dong
- Division of Endocrinology, Department of Internal Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Lin Liao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, China
- Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
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12
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Parwani K, Mandal P. Role of advanced glycation end products and insulin resistance in diabetic nephropathy. Arch Physiol Biochem 2023; 129:95-107. [PMID: 32730131 DOI: 10.1080/13813455.2020.1797106] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
Abstract
Metabolic syndrome (MetS), i.e. a cluster of physiological and biochemical abnormalities can lead to diabetic nephropathy (DN). Insulin resistance, impaired fasting glucose are the main signs and symptoms of MetS. Excess sugar can induce various substantial structural changes like formation of advanced glycation end products (AGEs). AGEs are formed due to reaction of reducing sugars with amino groups of proteins, lipids and nucleic acids. AGEs when bound to the receptor for advanced glycation end products (RAGE) activate increased production of pro-inflammatory markers like interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α) along with induction of endoplasmic reticulum (ER) stress. Accumulation of AGEs, enhanced reactive oxygen species (ROS) generation and activation of protein kinase C (PKC), are considered to induce glomerular hypertrophy, podocyte apoptosis, therefore contributing to the development and progression of DN. In this review, we decipher different biochemical and physiological factors that link AGEs and DN.
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Affiliation(s)
- Kirti Parwani
- Department of Biological Sciences, P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, Gujarat 388421, India
| | - Palash Mandal
- Department of Biological Sciences, P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, Gujarat 388421, India
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13
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Sun H, Chen J, Hua Y, Zhang Y, Liu Z. New insights into the role of empagliflozin on diabetic renal tubular lipid accumulation. Diabetol Metab Syndr 2022; 14:121. [PMID: 35999610 PMCID: PMC9396853 DOI: 10.1186/s13098-022-00886-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 08/04/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Glucose cotransporter (SGLT) 2 suppression provides potent renal protective effect during diabetic kidney disease (DKD). This work aimed to explore how empagliflozin (EMPA, the selective and strong inhibitor of SGLT2) affected renal lipid deposition among patients undergoing type 2 diabetes mellitus (T2DM), a T2DM mouse model and human renal proximal tubular epithelial (HK-2) cells. METHODS This work divided subjects as 3 groups: non-diabetic volunteers, patients treated with metformin and those treated with metformin plus EMPA. In an in vivo study, EMPA was adopted for treating db/db mice that were raised with the basal diet or the high-advanced glycation end products (AGEs) diet. In addition, AGEs and/or EMPA was utilized to treat HK-2 cells in vitro. RESULTS Results showed that diabetic patients treated with metformin plus EMPA had lower AGEs levels and renal fat fraction (RFF) than those treated with metformin. Moreover, a significant and positive association was found between AGEs and RFF. Results from the basic study showed that EMPA decreased cholesterol level, tubular lipid droplets, and protein levels related to cholesterol metabolism in AGEs-mediated HK-2 cells, kidneys of db/db mice and those fed with the high-AGEs diet. Additionally, EMPA decreased AGEs levels in serum while inhibiting the expression of receptor of AGEs (RAGE) in vitro and in vivo. CONCLUSION EMPA inhibited the AGEs-RAGE pathway, thereby alleviating diabetic renal tubular cholesterol accumulation.
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Affiliation(s)
- Hong Sun
- Department of Endocrinology and Metabolism, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou, Jiangsu, China.
| | - Juan Chen
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yulin Hua
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yuyang Zhang
- The First Clinical Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Zheng Liu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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Cui Q, Du H, Ma Y, Wang T, Zhu H, Zhu L, Pan S, Min N, Wang X, Liu Z. Matrine inhibits advanced glycation end products-induced macrophage M1 polarization by reducing DNMT3a/b-mediated DNA methylation of GPX1 promoter. Eur J Pharmacol 2022; 926:175039. [PMID: 35597264 DOI: 10.1016/j.ejphar.2022.175039] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 11/20/2022]
Abstract
Advanced glycation end products (AGEs) are characterized diabetic metabolites inducing macrophage M1 polarization which is crucial in diabetes-exacerbated atherosclerosis. Matrine was proved anti-atherosclerotic. The current study was aimed to investigate the inhibitory effects of matrine on AGEs- induced macrophage M1 polarization and underlying molecular mechanisms. Primary mouse macrophages were exposed to AGEs. Receptor for AGEs (RAGE) and toll-like receptor 4 (TLR4) were over-expressed by vectors. Matrine was used to treat these cells. Inducible nitric oxide synthase (iNOS) expression and pro-inflammatory cytokine production were used to evaluate macrophage M1 polarization. Oxidative stress was assessed by intracellular reactive oxygen species (ROS) generation, total antioxidant capacity (TAC) and malondialdehyde (MDA) contents. Relative mRNA expression level was determined by real-time PCR. Western blotting was used to evaluate protein and protein phosphorylation levels. Bisulfite sequencing PCR (BSP) was used to evaluate DNA methylation. Matrine reduced AGEs exposure-elevated expressions of DNA methyltransferase (DNA MTase, DNMT)3a and DNMT3b in macrophages which were not affected by RAGE or TLR4 over expressions. DNA methylation rate of GPX1 promoter was reduced from 97.22% to 66.67% in AGEs- exposed macrophages treated by matrine. GPX1 expression was up-regulated by matrine, which further suppressed AGEs/RAGE-mediated oxidative stress. Thus, the activation of down-stream TLR4/STAT1 signaling pathway was inhibited by matrine treatment which eventually suppressed AGEs- induced macrophage M1 polarization. However, these effects of matrine were impaired by RAGE and TLR4 overexpression. Results from this study suggested that matrine inhibited AGEs- induced macrophage M1 polarization by suppressing RAGE-induced oxidative stress-mediated TLR4/STAT1 signaling pathway. Matrine exerted anti-oxidant effects via increasing GPX1 expression by inhibiting DNMT3a/b-induced GPX1 promoter DNA methylation.
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Affiliation(s)
- Qianwei Cui
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Haixia Du
- Rocket Force University of Engineering, Xi'an, 710025, China
| | - Yanpeng Ma
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Ting Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Haitao Zhu
- Department of Pediatrics, Northwest Women's and Children's Hospital, Xi'an, 710061, China
| | - Ling Zhu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Shuo Pan
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Ningbin Min
- Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Department of Cardiology, Heyang County Hospital, Heyang, 715300, China.
| | - Xiqiang Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, 710072, China.
| | - Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Cardiovascular Research Center, Shaanxi Provincial People's Hospital, Xi'an, 710068, China; Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, 710072, China.
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Ma Y, Zhou Q, Zhao P, Lv X, Gong C, Gao J, Liu J. Effect of transferrin glycation induced by high glucose on HK-2 cells in vitro. Front Endocrinol (Lausanne) 2022; 13:1009507. [PMID: 36778593 PMCID: PMC9909336 DOI: 10.3389/fendo.2022.1009507] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 12/19/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND AND OBJECTIVE Glycation is a common post-transcriptional modification of proteins. Previous studies have shown that advanced glycation end modified transferrin (AGE-Tf) levels in diabetic rat kidney tissues were increased; however, its role in diabetic nephropathy remains unclear. In this study, differences in glycation degree and Tf sites induced by differing high glucose concentrations in vitro and the effect on total iron binding capacity (TIBC) were observed. Moreover, the effect of AGE-Tf on human renal tubular epithelial cells (HK-2) was investigated. METHODS In vitro Tf was incubated with increasing glucose concentrations (0 mM, 5.6 mM, 11.1 mM, 33.3 mM, 100 mM, 500 mM, and 1,000 mM) for AGE-Tf. Differences in AGE-Tf glycation degree and TIBC level were analyzed via colorimetric method. The AGE-Tf glycation sites were identified with LC-MS/MS. HK-2 cells were treated with AGE-Tf prepared with different glucose concentrations (33.3 mM and 500 mM) in vitro. The effects of AGE-Tf on HK-2 cell viability, proliferation, oxidative stress index, and Tf receptor expression levels were then observed. RESULTS With increasing glucose concentrations (100 mM, 500 mM, and 1,000 mM) in vitro, Tf glycation degree was significantly increased. The TIBC levels of AGE-Tf were decreased significantly with increasing glucose concentrations (33.3 mM, 100 mM, 500 mM, and 1,000 mM). Four glycated modification sites in Tf and 17 glycated modification sites were detected in AGE-Tf (500 mM) by LC-MS/MS. The structural types of AGEs were CML, G-H1, FL-1H2O, FL, and MG-H1. No significant differences were found in the survival rate of HK-2 cells among the AGE-Tf (500 mM), AGE-Tf (33.3 mM), and Tf groups (all p > 0.05). The apoptosis rate of HK-2 cells in the AGE-Tf (500 mM) group was significantly higher than that in the AGE-Tf (33.3 mM) group. Additionally, both of them were significantly higher than that in the Tf group (both p < 0.05). The MDA levels of HK-2 cells in the AGE-Tf (500 mM) and AGE-Tf (33.3 mM) groups were higher than that in the Tf group, but not significantly (both p > 0.05). The T-AOC level of HK-2 in the AGE-Tf (500 mM) group was significantly lower than that in the AGE-Tf (33.3 mM) and Tf groups (both p < 0.001). The GSH level of HK-2 cells in the AGE-Tf (500 mM) group was significantly lower than that in the Tf group (p < 0.05). The expression level of TfR in the AGE-Tf (500 mM) group was also significantly lower than that in the Tf group (p < 0.05). CONCLUSION The degree and sites of Tf glycation were increased in vitro secondary to high-glucose exposure; however, the binding ability of Tf to iron decreased gradually. After HK-2 was stimulated by AGE-Tf in vitro, the apoptosis of cells was increased, antioxidant capacity was decreased, and TfR expression levels were downregulated.
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Affiliation(s)
- Yanqi Ma
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Qikai Zhou
- Tianjin Normal University, Tianjin, China
| | - Pingping Zhao
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Xiaoyu Lv
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Caixia Gong
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Jie Gao
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Jingfang Liu
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- *Correspondence: Jingfang Liu,
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16
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Diabetic nephropathy: A twisted thread to unravel. Life Sci 2021; 278:119635. [PMID: 34015285 DOI: 10.1016/j.lfs.2021.119635] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 12/18/2022]
Abstract
Diabetic nephropathy (DN), a persistent microvascular problem of diabetes mellitus is described as an elevated level of albumin excretion in urine and impaired renal activity. The morbidity and mortality of type-1 diabetics and type-2 diabetics due to end stage renal disease is also a result of the increased prevalence of DN. DN typically occurs as a consequence of an association among metabolic and hemodynamic variables, activating specific pathways leading to renal injury. According to current interventions, intensive glucose regulation decreases the threat of DN incidence and growth, and also suppressing the renin-angiotensin system (RAS) is a significant goal for hemodynamic and metabolism-related deformities in DN. However, the pathogenesis of DN is multifactorial so novel approaches other than glucose and blood pressure control are required for treatment. This review briefly summarizes the reported pathogenesis of DN, current interventions for its treatment, and possible novel interventions to unweave the thread of DN.
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Paul S, Ali A, Katare R. Molecular complexities underlying the vascular complications of diabetes mellitus - A comprehensive review. J Diabetes Complications 2020; 34:107613. [PMID: 32505477 DOI: 10.1016/j.jdiacomp.2020.107613] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/27/2020] [Accepted: 04/18/2020] [Indexed: 12/19/2022]
Abstract
Diabetes is a chronic disease, characterized by hyperglycemia, which refers to the elevated levels of glucose in the blood, due to the inability of the body to produce or use insulin effectively. Chronic hyperglycemia levels lead to macrovascular and microvascular complications. The macrovascular complications consist of peripheral artery disease (PAD), cardiovascular diseases (CVD) and cerebrovascular diseases, while the microvascular complications comprise of diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy and diabetic neuropathy. Vascular endothelial dysfunction plays a crucial role in mediating both macrovascular and microvascular complications under hyperglycemic conditions. In diabetic microvasculature, the intracellular hyperglycemia causes damage to the vascular endothelium through - (i) activation of four biochemical pathways, namely the Polyol pathway, protein kinase C (PKC) pathway, advanced glycation end products (AGE) pathway and hexosamine pathway, all of which commutes glucose and its intermediates leading to overproduction of reactive oxygen species, (ii) dysregulation of growth factors and cytokines, (iii) epigenetic changes which concern the changes in DNA as a response to intracellular changes, and (iv) abnormalities in non-coding RNAs, specifically microRNAs. This review will focus on gaining an understanding of the molecular complexities underlying the vascular complications in diabetes mellitus, to increase our understanding towards the development of new mechanistic therapeutic strategies to prevent or treat diabetes-induced vascular complications.
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Affiliation(s)
- Shalini Paul
- Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand
| | - Azam Ali
- Centre for Bioengineering and Nanomedicine (Dunedin), University of Otago, Dunedin, New Zealand
| | - Rajesh Katare
- Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand.
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Piccirillo F, Carpenito M, Verolino G, Chello C, Nusca A, Lusini M, Spadaccio C, Nappi F, Di Sciascio G, Nenna A. Changes of the coronary arteries and cardiac microvasculature with aging: Implications for translational research and clinical practice. Mech Ageing Dev 2019; 184:111161. [PMID: 31647940 DOI: 10.1016/j.mad.2019.111161] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 12/28/2022]
Abstract
Aging results in functional and structural changes in the cardiovascular system, translating into a progressive increase of mechanical vessel stiffness, due to a combination of changes in micro-RNA expression patterns, autophagy, arterial calcification, smooth muscle cell migration and proliferation. The two pivotal mechanisms of aging-related endothelial dysfunction are oxidative stress and inflammation, even in the absence of clinical disease. A comprehensive understanding of the aging process is emerging as a primary concern in literature, as vascular aging has recently become a target for prevention and treatment of cardiovascular disease. Change of life-style, diet, antioxidant regimens, anti-inflammatory treatments, senolytic drugs counteract the pro-aging pathways or target senescent cells modulating their detrimental effects. Such therapies aim to reduce the ineluctable burden of age and contrast aging-associated cardiovascular dysfunction. This narrative review intends to summarize the macrovascular and microvascular changes related with aging, as a better understanding of the pathways leading to arterial aging may contribute to design new mechanism-based therapeutic approaches to attenuate the features of vascular senescence and its clinical impact on the cardiovascular system.
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Affiliation(s)
| | | | | | - Camilla Chello
- Dermatology, Università "La Sapienza" di Roma, Rome, Italy
| | | | - Mario Lusini
- Cardiovascular surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | | | - Francesco Nappi
- Cardiac surgery, Centre Cardiologique du Nord de Saint Denis, Paris, France
| | | | - Antonio Nenna
- Cardiovascular surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
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Gkaliagkousi E, Nikolaidou B, Gavriilaki E, Lazaridis A, Yiannaki E, Anyfanti P, Zografou I, Markala D, Douma S. Increased erythrocyte- and platelet-derived microvesicles in newly diagnosed type 2 diabetes mellitus. Diab Vasc Dis Res 2019; 16:458-465. [PMID: 31046456 DOI: 10.1177/1479164119844691] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AIM To investigate the thrombotic microenvironment in early stages of type 2 diabetes mellitus measuring platelet-derived, endothelial-derived and erythrocyte-derived microvesicles. METHODS We recruited 50 newly diagnosed type 2 diabetes mellitus patients who did not receive glucose-lowering treatment except for metformin and 25 matched non-type 2 diabetes mellitus volunteers. Microvesicles were measured with flow cytometry, glycated haemoglobin with high-performance liquid chromatography and advanced glycation end products with enzyme-linked immunosorbent assay. RESULTS Type 2 diabetes mellitus patients showed significantly higher levels of platelet-derived microvesicles [195/μL (115-409) vs 110/μL (73-150), p = 0.001] and erythrocyte-derived microvesicles [26/μL (9-100) vs 9/μL (4-25), p = 0.007] compared to non-type 2 diabetes mellitus individuals. Platelet-derived microvesicles were positively associated with fasting blood glucose (p = 0.026) and glycated haemoglobin (p = 0.002). Erythrocyte-derived microvesicles were also positively associated with fasting blood glucose (p = 0.018) but not with glycated haemoglobin (p = 0.193). No significant association was observed between platelet-derived microvesicles (p = 0.126) or erythrocyte-derived microvesicles (p = 0.857) and advanced glycation end products. Erythrocyte-derived microvesicles predicted the presence of type 2 diabetes mellitus, independently of platelet-derived microvesicles. CONCLUSION In newly diagnosed type 2 diabetes mellitus, ongoing atherothrombosis is evident during the early stages as evidenced by increased microvesicles levels. Furthermore, the association with glycemic profile suggests that microvesicles represent not only a novel mechanism by which hyperglycemia amplifies thrombotic tendency in type 2 diabetes mellitus but also early markers of thrombosis highlighting the need for earlier management of hyperglycemia.
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Affiliation(s)
- Eugenia Gkaliagkousi
- 1 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Barbara Nikolaidou
- 1 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleni Gavriilaki
- 1 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonios Lazaridis
- 1 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Efthalia Yiannaki
- 2 Department of Hematology, Theagenion Cancer Center, Thessaloniki, Greece
| | - Panagiota Anyfanti
- 1 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioanna Zografou
- 3 2nd Propedeutic Department of Internal Medicine, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitra Markala
- 2 Department of Hematology, Theagenion Cancer Center, Thessaloniki, Greece
| | - Stella Douma
- 1 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Yang T, Shu F, Yang H, Heng C, Zhou Y, Chen Y, Qian X, Du L, Zhu X, Lu Q, Yin X. YY1: A novel therapeutic target for diabetic nephropathy orchestrated renal fibrosis. Metabolism 2019; 96:33-45. [PMID: 31028762 DOI: 10.1016/j.metabol.2019.04.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 04/01/2019] [Accepted: 04/19/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Renal fibrosis promotes the development of diabetic nephropathy (DN). A growing number of studies have reported that Yin Yang 1 (YY1), which is involved in cellular proliferation and differentiation, plays a crucial role in the pathogenesis of many diseases, such as pulmonary fibrosis, hepatic steatosis and cancer. METHODS We detected the expression of YY1 under various glucose concentration and time gradient conditions. Rapamycin was used to verify the mTORC1/p70S6K/YY1 signaling pathway in HK-2 cells. We used db/db mice to examine the connection between renal fibrosis and YY1. A luciferase assay and chromatin immunoprecipitation (ChIP) assay were used to identify whether YY1 directly regulated α-SMA by binding to the α-SMA promoter. RNA silencing and overexpression were performed by using a YY1 expression/knockdown plasmid to investigate the function of YY1 in renal fibrosis of DN. RESULTS YY1 expression and subsequent nuclear translocation were upregulated in a glucose- and time-dependent manner via the mTORC1/p70S6K signaling pathway in HK-2 cells. YY1 expression and nuclear translocation was significantly upregulated in db/db mice. Furthermore, YY1 upregulated α-SMA expression and activity in high-glucose-cultured HK-2 cells. Overexpression of YY1 promoted renal fibrosis in db/m mice mainly by upregulating α-SMA expression and inducing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Finally, downregulation of YY1 reversed renal fibrosis by improving EMT in vivo and in vitro. CONCLUSIONS These results reveal that upregulation of YY1 plays a critical role in HG-induced deregulation of EMT-associated protein expression, which finally results in renal fibrosis of DN. Therefore, decreasing YY1 expression might represent a new therapeutic target for diabetic nephropathy-induced renal fibrosis.
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Affiliation(s)
- Tingting Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Fanglin Shu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Hao Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Cai Heng
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Yi Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Yibing Chen
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xuan Qian
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Lei Du
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xia Zhu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
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Nabi R, Alvi SS, Saeed M, Ahmad S, Khan MS. Glycation and HMG-CoA Reductase Inhibitors: Implication in Diabetes and Associated Complications. Curr Diabetes Rev 2019; 15:213-223. [PMID: 30246643 DOI: 10.2174/1573399814666180924113442] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 07/17/2018] [Accepted: 09/19/2018] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Diabetes Mellitus (DM) acts as an absolute mediator of cardiovascular risk, prompting the prolonged occurrence, size and intricacy of atherosclerotic plaques via enhanced Advanced Glycation Endproducts (AGEs) formation. Moreover, hyperglycemia is associated with enhanced glyco-oxidized and oxidized Low-Density Lipoprotein (LDL) possessing greater atherogenicity and decreased the ability to regulate HMG-CoA reductase (HMG-R). Although aminoguanidine (AG) prevents the AGE-induced protein cross-linking due to its anti-glycation potential, it exerts several unusual pharmaco-toxicological effects thus restraining its desirable therapeutic effects. HMG-R inhibitors/ statins exhibit a variety of beneficial impacts in addition to the cholesterol-lowering effects. OBJECTIVE Inhibition of AGEs interaction with receptor for AGEs (RAGE) and glyco-oxidized-LDL by HMG-R inhibitors could decrease LDL uptake by LDL-receptor (LDL-R), regulate cholesterol synthesis via HMG-R, decrease oxidative and inflammatory stress to improve the diabetes-associated complications. CONCLUSION Current article appraises the pathological AGE-RAGE concerns in diabetes and its associated complications, mainly focusing on the phenomenon of both circulatory AGEs and those accumulating in tissues in diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy, discussing the potential protective role of HMG-R inhibitors against diabetic complications.
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Affiliation(s)
- Rabia Nabi
- Clinical Biochemistry & Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, 226026, U.P, India
| | - Sahir Sultan Alvi
- Clinical Biochemistry & Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, 226026, U.P, India
| | - Mohammad Saeed
- Department of Clinical Lab. Sciences, College of Applied Medical Sciences, University of Hail, Hail, Saudi Arabia
| | - Saheem Ahmad
- Laboratory of Glycation Biology and Metabolic Disorders, Department of Biosciences, Integral University Lucknow, 226026, U.P, India
| | - Mohammad Salman Khan
- Clinical Biochemistry & Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, 226026, U.P, India
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22
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Yamagishi SI. Sex disparity in cardiovascular mortality rates associated with diabetes. Diabetes Metab Res Rev 2018; 34:e3059. [PMID: 30098301 DOI: 10.1002/dmrr.3059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 08/02/2018] [Accepted: 08/02/2018] [Indexed: 11/12/2022]
Affiliation(s)
- Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
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23
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Nabi R, Alvi SS, Khan RH, Ahmad S, Ahmad S, Khan MS. Antiglycation study of HMG-R inhibitors and tocotrienol against glycated BSA and LDL: A comparative study. Int J Biol Macromol 2018; 116:983-992. [DOI: 10.1016/j.ijbiomac.2018.05.115] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 05/07/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022]
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Han WQ, Xu L, Tang XF, Chen WD, Wu YJ, Gao PJ. Membrane rafts-redox signalling pathway contributes to renal fibrosis via modulation of the renal tubular epithelial-mesenchymal transition. J Physiol 2018; 596:3603-3616. [PMID: 29863758 DOI: 10.1113/jp275952] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 05/25/2018] [Indexed: 01/27/2023] Open
Abstract
KEY POINTS Membrane rafts (MRs)-redox signalling pathway is activated in response to transforming growth factor-β1 (TGF-β1) stimulation in renal tubular cells. This pathway contributes to TGF-1β-induced epithelial-mesenchymal transition (EMT) in renal tubular cells. The the MRs-redox signalling pathway is activated in renal tubular cells isolated from angiotensin II (AngII)-induced hypertensive rats. Inhibition of this pathway attenuated renal inflammation and fibrosis in AngII-induced hypertension. ABSTRACT The membrane rafts (MRs)-redox pathway is characterized by NADPH oxidase subunit clustering and activation through lysosome fusion, V-type proton ATPase subunit E2 (encoded by the Atp6v1e2 gene) translocation and sphingomyelin phosphodiesterase 1 (SMPD1, encoded by the SMPD1 gene) activation. In the present study, we hypothesized that the MRs-redox-derived reactive oxygen species (ROS) are involved in renal inflammation and fibrosis by promoting renal tubular epithelial-mesenchymal transition (EMT). Results show that transforming growth factor-β1 (TGF-β1) acutely induced MR formation and ROS production in NRK-52E cells, a rat renal tubular cell line. In addition, transfection of Atp6v1e2 small hairpin RNAs (shRNA) and SMPD1 shRNA attenuated TGF-β1-induced changes in EMT markers, including E-cadherin, α-smooth muscle actin (α-SMA) and fibroblast-specific protein-1 (FSP-1) in NRK-52E cells. Moreover, Erk1/2 activation may be a downstream regulator of the MRs-redox-derived ROS, because both shRNAs significantly inhibited TGF-β1-induced Erk1/2 phosphorylation. Further in vivo study shows that the renal tubular the MRs-redox signalling pathway was activated in angiotensin II (AngII)-induced hypertension, as indicated by the increased NADPH oxidase subunit Nox4 fraction in the MR domain, SMPD1 activation and increased ROS content in isolated renal tubular cells. Finally, renal transfection of Atp6v1e2 shRNA and SMPD1 shRNA significantly prevented renal fibrosis and inflammation, as indicated by the decrease of α-SMA, fibronectin, collagen I, monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1) and tumour necrosis factor-α (TNF-α) in kidneys from AngII-infused rats. It was concluded that the the MRs-redox signalling pathway is involved in TGF-β1-induced renal tubular EMT and renal inflammation/fibrosis in AngII-induced hypertension.
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Affiliation(s)
- Wei-Qing Han
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
| | - Lian Xu
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiao-Feng Tang
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
| | - Wen-Dong Chen
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
| | - Yong-Jie Wu
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
| | - Ping-Jin Gao
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
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25
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Rhee SY, Kim YS. The Role of Advanced Glycation End Products in Diabetic Vascular Complications. Diabetes Metab J 2018; 42:188-195. [PMID: 29885110 PMCID: PMC6015964 DOI: 10.4093/dmj.2017.0105] [Citation(s) in RCA: 173] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 03/29/2018] [Indexed: 01/08/2023] Open
Abstract
In cases of chronic hyperglycemia, advanced glycation end-products (AGEs) are actively produced and accumulated in the circulating blood and various tissues. AGEs also accelerate the expression of receptors for AGEs, and they play an important role in the development of diabetic vascular complications through various mechanisms. Active interventions for glucose and related risk factors may help improve the clinical course of patients by reducing AGEs. This review summarizes recent updates on AGEs that have a significant impact on diabetic vascular complications.
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Affiliation(s)
- Sang Youl Rhee
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Young Seol Kim
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea.
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26
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Mega C, Teixeira-de-Lemos E, Fernandes R, Reis F. Renoprotective Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin: A Review in Type 2 Diabetes. J Diabetes Res 2017; 2017:5164292. [PMID: 29098166 PMCID: PMC5643039 DOI: 10.1155/2017/5164292] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Accepted: 07/12/2017] [Indexed: 12/13/2022] Open
Abstract
Diabetic nephropathy (DN) is now the single commonest cause of end-stage renal disease (ESRD) worldwide and one of the main causes of death in diabetic patients. It is also acknowledged as an independent risk factor for cardiovascular disease (CVD). Since sitagliptin was approved, many studies have been carried out revealing its ability to not only improve metabolic control but also ameliorate dysfunction in various diabetes-targeted organs, especially the kidney, due to putative underlying cytoprotective properties, namely, its antiapoptotic, antioxidant, anti-inflammatory, and antifibrotic properties. Despite overall recommendations, many patients spend a long time well outside the recommended glycaemic range and, therefore, have an increased risk for developing micro- and macrovascular complications. Currently, it is becoming clearer that type 2 diabetes mellitus (T2DM) management must envision not only the improvement in glycaemic control but also, and particularly, the prevention of pancreatic deterioration and the evolution of complications, such as DN. This review aims to provide an overview of the current knowledge in the field of renoprotective actions of sitagliptin, namely, improvement in diabetic dysmetabolism, hemodynamic factors, renal function, diabetic kidney lesions, and cytoprotective properties.
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Affiliation(s)
- Cristina Mega
- Agrarian School of Viseu (ESAV), Polytechnic Institute of Viseu (IPV), 3500-606 Viseu, Portugal
- Centre for the Study of Education, Technologies and Health (CI&DETS), Polytechnic Institute of Viseu (IPV), 3500-606 Viseu, Portugal
- Institute of Pharmacology and Experimental Therapeutics and Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Edite Teixeira-de-Lemos
- Agrarian School of Viseu (ESAV), Polytechnic Institute of Viseu (IPV), 3500-606 Viseu, Portugal
- Centre for the Study of Education, Technologies and Health (CI&DETS), Polytechnic Institute of Viseu (IPV), 3500-606 Viseu, Portugal
| | - Rosa Fernandes
- Institute of Pharmacology and Experimental Therapeutics and Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CNC.IBILI Research Consortium, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Flávio Reis
- Institute of Pharmacology and Experimental Therapeutics and Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CNC.IBILI Research Consortium, University of Coimbra, 3004-504 Coimbra, Portugal
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27
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Lin CH, Cheng YC, Nicol CJ, Lin KH, Yen CH, Chiang MC. Activation of AMPK is neuroprotective in the oxidative stress by advanced glycosylation end products in human neural stem cells. Exp Cell Res 2017; 359:367-373. [PMID: 28821394 DOI: 10.1016/j.yexcr.2017.08.019] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 08/09/2017] [Accepted: 08/12/2017] [Indexed: 12/16/2022]
Abstract
Advanced glycosylation end products (AGEs) formation is correlated with the pathogenesis of diabetic neuronal damage, but its links with oxidative stress are still not well understood. Metformin, one of the most widely used anti-diabetic drugs, exerts its effects in part by activation of AMP-activated protein kinase (AMPK). Once activated, AMPK regulates many pathways central to metabolism and energy balance including, glucose uptake, glycolysis and fatty acid oxidation. AMPK is also present in neurons, but its role remains unclear. Here, we show that AGE exposure decreases cell viability of human neural stem cells (hNSCs), and that the AMPK agonist metformin reverses this effect, via AMPK-dependent downregulation of RAGE levels. Importantly, hNSCs co-treated with metformin were significantly rescued from AGE-induced oxidative stress, as reflected by the normalization in levels of reactive oxygen species. In addition, compared to AGE-treated hNSCs, metformin co-treatment significantly reversed the activity and mRNA transcript level changes of SOD1/2 and Gpx. Furthermore, hNSCs exposed to AGEs had significantly lower mRNA levels among other components of normal cellular oxidative defenses (GSH, Catalase and HO-1), which were all rescued by co-treatment with metformin. This metformin-mediated protective effect on hNSCs for of both oxidative stress and oxidative defense genes by co-treatment with metformin was blocked by the addition of an AMPK antagonist (Compound C). These findings unveil the protective role of AMPK-dependent metformin signaling during AGE mediated oxidative stress in hNSCs, and suggests patients undergoing AGE-mediated neurodegeneration may benefit from the novel therapeutic use of metformin.
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Affiliation(s)
- Chien-Hung Lin
- Department of Pediatrics, Taipei City Hospital Zhongxing Branch, Taipei 103, Taiwan
| | - Yi-Chuan Cheng
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Christopher J Nicol
- Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, and Division of Cancer Biology & Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
| | - Kuan-Hung Lin
- Graduate Institute of Biotechnology, Chinese Culture University, Taipei 111, Taiwan
| | - Chia-Hui Yen
- Department of International Business, Ming Chuan University, Taipei 111, Taiwan
| | - Ming-Chang Chiang
- Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan.
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Ohigashi M, Kobara M, Takahashi T, Toba H, Wada T, Nakata T. Pitavastatin suppresses hyperglycaemia-induced podocyte injury via bone morphogenetic protein-7 preservation. Clin Exp Pharmacol Physiol 2017; 44:378-385. [DOI: 10.1111/1440-1681.12716] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 12/05/2016] [Accepted: 12/13/2016] [Indexed: 12/14/2022]
Affiliation(s)
- Makoto Ohigashi
- Department of Clinical Pharmacology; Division of Pathological Science; Kyoto Pharmaceutical University; Kyoto Japan
| | - Miyuki Kobara
- Department of Clinical Pharmacology; Division of Pathological Science; Kyoto Pharmaceutical University; Kyoto Japan
| | - Tamotsu Takahashi
- Department of Clinical Pharmacology; Division of Pathological Science; Kyoto Pharmaceutical University; Kyoto Japan
| | - Hiroe Toba
- Department of Clinical Pharmacology; Division of Pathological Science; Kyoto Pharmaceutical University; Kyoto Japan
| | - Takehiko Wada
- Division of Nephrology, Endocrinology and Metabolism; Tokai University School of Medicine; Isezaki Japan
| | - Tetsuo Nakata
- Department of Clinical Pharmacology; Division of Pathological Science; Kyoto Pharmaceutical University; Kyoto Japan
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29
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Yamagishi SI, Nakamura N, Matsui T. Glycation and cardiovascular disease in diabetes: A perspective on the concept of metabolic memory. J Diabetes 2017; 9:141-148. [PMID: 27556881 DOI: 10.1111/1753-0407.12475] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 07/25/2016] [Accepted: 08/20/2016] [Indexed: 12/16/2022] Open
Abstract
Epidemiological studies have suggested that cumulative diabetic exposure, namely prolonged exposure to chronic hyperglycemia, contributes to the increased risk of cardiovascular disease (CVD) in diabetes. The formation and accumulation of advanced glycation end-products (AGEs) have been known to progress under hyperglycemic conditions. Because AGEs-modified collagens are hardly degraded and remain in diabetic vessels, kidneys and the heart for a long time, even after glycemic control has been achieved, AGEs could become a marker reflecting cumulative diabetic exposure. Furthermore, there is a growing body of evidence that an interaction between AGEs and the receptor for AGEs (RAGE) plays a role in the pathogenesis of CVD. In addition, AGEs induce the expression of RAGE, thus leading to sustained activation of the AGEs-RAGE axis in diabetes. Herein we review the pathological role of the AGEs-RAGE axis in CVD, focusing particularly on the phenomenon of metabolic memory, and discuss the potential clinical usefulness of measuring circulating and tissue levels of AGEs accumulation to evaluate diabetic macrovascular complications.
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Affiliation(s)
- Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Nobutaka Nakamura
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Takanori Matsui
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
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Abstract
This study is one in series determining the potential of RAGE axis (receptor for advanced glycation end products, isoforms, ligands) as a biomarker in multiple sclerosis (MS). We evaluated serum levels of RAGE ligand, the high-mobility group box (HMGB)1 in MS patients, and assessed the correlation between HMGB1 serum levels and the use of disease-modifying drugs (DMDs), and between HMGB1 serum levels and indicators of MS disease severity. HMGB1 serum levels were compared between 96 (23 males) MS patients and 34 age- and gender-matched healthy controls (HCs) using enzyme-linked immunosorbent assays. DMD-naïve MS patients had significantly higher HMGB1 serum levels compared with DMD-treated (P = 0.04) and compared with HCs (P = 0.01). HMGB1 serum levels were not significantly different between total MS patients (DMD-naïve plus DMD-treated) and HCs (P = 0.09). DMD-naïve MS patients in clinical relapse tended to have lower HMGB1 serum levels than clinically stable RRMS patients (P = 0.07). HMGB1 serum levels showed 0.65 area under the curve (95 % CI 0.55-0.95) sensitivity/specificity for MS clinical relapse. The role of HMGB1 in MS disease pathology and DMD modulation of this protein warrant further investigations.
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31
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Kumar Pasupulati A, Chitra PS, Reddy GB. Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy. Biomol Concepts 2016; 7:293-309. [PMID: 27816946 DOI: 10.1515/bmc-2016-0021] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 09/18/2016] [Indexed: 05/15/2025] Open
Abstract
Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients and a leading cause of end-stage renal disease (ESRD). Degenerative changes such as glomerular hypertrophy, hyperfiltration, widening of basement membranes, tubulointerstitial fibrosis, glomerulosclerosis and podocytopathy manifest in various degrees of proteinuria in DN. One of the key mechanisms implicated in the pathogenesis of DN is non-enzymatic glycation (NEG). NEG is the irreversible attachment of reducing sugars onto free amino groups of proteins by a series of events, which include the formation of Schiff's base and an Amadori product to yield advanced glycation end products (AGEs). AGE modification of client proteins from the extracellular matrix induces crosslinking, which is often associated with thickening of the basement membrane. AGEs activate several intracellular signaling cascades upon interaction with receptor for AGEs (RAGE), which manifest in aberrant cellular responses such as inflammation, apoptosis and autophagy, whereas other receptors such as AGE-R1, AGE-R3 and scavenger receptors also bind to AGEs and ensue endocytosis and degradation of AGEs. Elevated levels of both serum and tissue AGEs are associated with adverse renal outcome. Increased evidence supports that attenuation of AGE formation and/or inhibition of RAGE activation manifest(s) in improving renal function. This review provides insights of NEG, discusses the cellular and molecular events triggered by AGEs, which manifest in the pathogenesis of DN including renal fibrosis, podocyte epithelial-mesenchymal transition and activation of renin-angiotensin system. Therapies designed to target AGEs, such as inhibitors of AGEs formation and crosslink breakers, are discussed.
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Williams EJ, Baines KJ, Smart JM, Gibson PG, Wood LG. Rosuvastatin, lycopene and omega-3 fatty acids: A potential treatment for systemic inflammation in COPD; a pilot study. JOURNAL OF NUTRITION & INTERMEDIARY METABOLISM 2016. [DOI: 10.1016/j.jnim.2016.04.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Bhattacharjee N, Barma S, Konwar N, Dewanjee S, Manna P. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update. Eur J Pharmacol 2016; 791:8-24. [PMID: 27568833 DOI: 10.1016/j.ejphar.2016.08.022] [Citation(s) in RCA: 192] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 08/03/2016] [Accepted: 08/24/2016] [Indexed: 02/09/2023]
Abstract
Diabetic nephropathy (DN), a chronic complication of diabetes, is charecterized by glomerular hypertrophy, proteinuria, decreased glomerular filtration, and renal fibrosis resulting in the loss of renal function. Although the exact cause of DN remains unclear, several mechanisms have been postulated, such as hyperglycemia-induced renal hyper filtration and renal injury, AGEs-induced increased oxidative stress, activated PKC-induced increased production of cytokines, chemokines, and different inflammatory and apoptotic signals. Among various factors, oxidative stress has been suggested to play a major role underlying the onset and propagation of DN. It triggers several signaling pathways involved in DN, like AGEs, PKC cascade, JAK/STAT signaling, MAPK, mTOR, and SMAD. Oxidative stress-induced activation of both inflammatory and apoptotic signals are two major problems in the pathogenesis of DN. The FDA approved pharmacotherapeutic agents affecting against polyol pathway principally include anti-oxidants, like α-lipoic acid, vitamin E, and vitamin C. Kremezin and benfotiamine are the FDA approved AGEs inhibitors, another therapeutic target against DN. Ruboxistaurin, telmizartan, rapamycin, fenofibrate, aliskiren, and manidipine are some FDA approved pharmacotherapeutics effective against DN via diverse mechanisms. Beside this, some therapeutic agents are still waiting for FDA approval and few drugs without FDA approval are also prescribed in some countries for the management of DN. Despite the medications available in the market to treat DN, the involvement of multiple mechanisms makes it difficult to choose an optimum therapeutic agent. Therefore, much research is required to find out new therapeutic agent/strategies for an adequate pharmacotherapy of DN.
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Affiliation(s)
- Niloy Bhattacharjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032, India
| | - Sujata Barma
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032, India
| | - Nandita Konwar
- Biological Science and Technology Division, CSIR-NEIST, Jorhat, Assam 785006, India
| | - Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032, India.
| | - Prasenjit Manna
- Biological Science and Technology Division, CSIR-NEIST, Jorhat, Assam 785006, India.
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Okada M, Okada Y. Effects of methanolic extracts of edible plants on RAGE in high-glucose-induced human endothelial cells. Biomed Mater Eng 2016; 25:257-66. [PMID: 26407112 DOI: 10.3233/bme-151280] [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] [Indexed: 11/15/2022]
Abstract
Advanced glycation end products' (AGEs) engagement of a cell-surface receptor for AGEs (RAGE) has been causally implicated in the pathogenesis of vascular complications in diabetic patients. Methanolic extracts from edible plants (MEEP) are naturally occurring phenolic compounds. The phenolic compounds have been reported to possess potent radical-scavenging properties. We investigated whether MEEP could inhibit high glucose-induced RAGE production through interference with reactive oxygen species generation in endothelial cells (ECs). ECs were incubated with 4.5 g/l of glucose in culture medium treated with 21 MEEP. Determination of RAGE production in the culture supernatants was performed by colorimetric ELISA. DNA damage was determined by using the 8-hydroxydeoxyguanosine ELISA kit. Because peroxynitrite radicals with stronger toxicity were produced by nitric oxide radical (NO), the NO scavenging activity of MEEP was assessed as nitrite generation. Peroxynitrite radical-dependent oxidation inhibition by MEEP was estimated by the Crow method. The results showed that four extracts reduced RAGE production. The extract from onion peel showed the highest RAGE production inhibition activity, followed by that of onion rhizome, cow pea and burdock. The results showed that RAGE production is correlated with the above-mentioned indicators. This study supports the utilization of four extracts for improved treatment of diabetic complications.
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Affiliation(s)
- Mizue Okada
- Nutrition Section, Ageing and Nutrition Research, Yms Laboratory, Gifu, Japan
| | - Yoshinori Okada
- Laboratory on Ageing and Health Management, Graduate School of Nursing and Health, Aichi Prefectural University, Nagoya, Japan
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Pinkas A, Aschner M. Advanced Glycation End-Products and Their Receptors: Related Pathologies, Recent Therapeutic Strategies, and a Potential Model for Future Neurodegeneration Studies. Chem Res Toxicol 2016; 29:707-14. [PMID: 27054356 DOI: 10.1021/acs.chemrestox.6b00034] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction between sugars and proteins, lipids, or nucleic acids. AGEs are both consumed and endogenously formed; their accumulation is accelerated under hyperglycemic and oxidative stress conditions, and they are associated with the onset and complication of many diseases, such as cardiovascular diseases, diabetes, and Alzheimer's disease. AGEs exert their deleterious effects by either accumulating in the circulation and tissues or by receptor-mediated signal transduction. Several receptors bind AGEs: some are specific and contribute to clearance of AGEs, whereas others, like the RAGE receptor, are nonspecific, associated with inflammation and oxidative stress, and considered to be mediators of the aforementioned AGE-related diseases. Although several anti-AGE compounds have been studied, understanding the underlying mechanisms of RAGE and targeting it as a therapeutic strategy is becoming increasingly desirable. For achieving these goals efficiently and expeditiously, the C. elegans model has been suggested. This model is already used for studying several human diseases and, by expressing RAGE, could also be used to study RAGE-related pathways and pathologies to facilitate the development of novel therapeutic strategies.
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Affiliation(s)
- Adi Pinkas
- Albert Einstein College of Medicine , Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Forchheimer Building, Room 209, Bronx, New York 10461, United States
| | - Michael Aschner
- Albert Einstein College of Medicine , Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Forchheimer Building, Room 209, Bronx, New York 10461, United States
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Tesarova P, Kalousova M, Zima T, Tesar V. HMGB1, S100 proteins and other RAGE ligands in cancer - markers, mediators and putative therapeutic targets. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2016; 160:1-10. [DOI: 10.5507/bp.2016.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 01/22/2016] [Indexed: 12/30/2022] Open
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Gowd V, Gurukar A, Chilkunda ND. Glycosaminoglycan remodeling during diabetes and the role of dietary factors in their modulation. World J Diabetes 2016; 7:67-73. [PMID: 26962410 PMCID: PMC4766247 DOI: 10.4239/wjd.v7.i4.67] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Revised: 11/23/2015] [Accepted: 01/04/2016] [Indexed: 02/06/2023] Open
Abstract
Glycosaminoglycans (GAGs) play a significant role in various aspects of cell physiology. These are complex polymeric molecules characterized by disaccharides comprising of uronic acid and amino sugar. Compounded to the heterogeneity, these are variously sulfated and epimerized depending on the class of GAG. Among the various classes of GAG, namely, chondroitin/dermatan sulfate, heparin/heparan sulfate, keratan sulfate and hyaluronic acid (HA), only HA is non-sulfated. GAGs are known to undergo remodeling in various tissues during various pathophysiological conditions, diabetes mellitus being one among them. These changes will likely affect their structure thereby impinging on their functionality. Till date, diabetes has been shown to affect GAGs in organs such as kidney, liver, aorta, skin, erythrocytes, etc. to name a few, with deleterious consequences. One of the mainstays in the treatment of diabetes is though dietary means. Various dietary factors are known to play a significant role in regulating glucose homeostasis. Furthermore, in recent years, there has been a keen interest to decipher the role of dietary factors on GAG metabolism. This review focuses on the remodeling of GAGs in various organs during diabetes and their modulation by dietary factors. While effect of diabetes on GAG metabolism has been worked out quite a bit, studies on the role of dietary factors in their modulation has been few and far between. We have tried our best to give the latest reports available on this subject.
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Ohsawa M, Tamura K, Wakui H, Kanaoka T, Azushima K, Uneda K, Haku S, Kobayashi R, Ohki K, Haruhara K, Kinguchi S, Toya Y, Umemura S. Effects of pitavastatin add-on therapy on chronic kidney disease with albuminuria and dyslipidemia. Lipids Health Dis 2015; 14:161. [PMID: 26645467 PMCID: PMC4673714 DOI: 10.1186/s12944-015-0164-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 12/02/2015] [Indexed: 12/24/2022] Open
Abstract
Background In non-dialysis chronic kidney disease (CKD) patients with dyslipidemia, statin therapy is recommended to prevent cardiovascular complications. Dyslipidemia has been also shown to be an independent risk factor for the progression of CKD. However, it is still unclear whether statin therapy exerts an inhibitory effect on renal deterioration in CKD patients with dyslipidemia. The purpose of the present study was to examine possible therapeutic effects of statin add-on therapy on renal function as well as parameters of lipid and glucose metabolism, arterial stiffness and oxidative stress, in comparison to diet therapy, in CKD patients with dyslipidemia. Methods This study was a randomized, open-label, and parallel-group trial consisted of a 12-months treatment period in non-dialysis CKD patients with alubuminuria and dyslipidemia. Twenty eight patients were randomly assigned either to receive diet counseling alone (diet therapy group) or diet counseling plus pitavastatin (diet-plus-statin therapy group), to achieve the LDL-cholesterol (LDL-C) target of <100 mg/dl. Results The statin treatment by pitavastatin was well tolerated in all of the patients without any significant adverse events and the average dose of pitavastatin was 1.0 ± 0.0 mg daily after treatment. After the 12-months treatment period, LDL-C was significantly lower in the diet-plus-statin therapy group compared with the diet therapy group (diet vs diet-plus-statin: LDL-C, 126 ± 5 vs 83 ± 4 mg/dL, P < 0.001). On the other hand, the diet-plus-statin therapy did not significantly reduce albuminuria or delay the decline in eGFR compared with the diet therapy, and there was no relationship between the change in LDL-C and the change in eGFR or albuminuria. However, diet therapy as well as diet-plus-statin therapy exerted similar lowering effects on the pentosidine levels (diet therapy group, baseline vs 12 months: 40 ± 4 vs 24 ± 3 ng/mL, P = 0.001; diet-plus-statin therapy, 46 ± 7 vs 34 ± 6 ng/mL, P = 0.008). Furthermore, the results of multivariate regression analysis indicated that the change in pentosidine was a significant contributor to the change in eGFR (β = −0.536, P = 0.011). Conclusions Although statin add-on therapy did not show additive renal protective effects, the diet therapy as well as the diet-plus-statin therapy could contribute to the reduction in plasma pentosidine in CKD patients with albuminuria and dyslipidemia.
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Affiliation(s)
- Masato Ohsawa
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. .,Department of Nephrology, Yokohama Hodogaya Central Hospital, Yokohama, 240-8585, Japan.
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Hiromichi Wakui
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Tomohiko Kanaoka
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Kengo Azushima
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Kazushi Uneda
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Sona Haku
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Ryu Kobayashi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Kohji Ohki
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Kotaro Haruhara
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Sho Kinguchi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Yoshiyuki Toya
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Satoshi Umemura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
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Khodeer DM, Zaitone SA, Farag NE, Moustafa YM. Cardioprotective effect of pioglitazone in diabetic and non-diabetic rats subjected to acute myocardial infarction involves suppression of AGE-RAGE axis and inhibition of apoptosis. Can J Physiol Pharmacol 2015; 94:463-76. [PMID: 27119311 DOI: 10.1139/cjpp-2015-0135] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Insulin resistance increases risk of cardiovascular diseases. This work investigated the protective effect of pioglitazone on myocardial infarction (MI) in non-diabetic and diabetic rats, focusing on its role on advanced glycated endproducts (AGEs) and cardiac apoptotic machinery. Male rats were divided into 2 experiments: experiment I and II (non-diabetic and diabetic rats) were assigned as saline, MI (isoproterenol, 85 mg/kg, daily), and MI+pioglitazone (5, 10, and 20 mg/kg). Injection of isoproterenol in diabetic rats produced greater ECG disturbances compared to non-diabetic rats. Treatment with pioglitazone (5 mg/kg) reduced the infarct size and improved some ECG findings. Pioglitazone (10 mg/kg) enhanced ECG findings, improved the histopathological picture and downregulated apoptosis in cardiac tissues. Whereas the higher dose of pioglitazone (20 mg/kg) did not improve most of the measured parameters but rather worsened some of them, such as proapoptotic markers. Importantly, a positive correlation was found between serum AGEs and cardiac AGE receptors (RAGEs) versus caspase 3 expression in the two experiments. Therefore, the current effect of pioglitazone was, at least in part, mediated through downregulation of AGE-RAGE axis and inhibition of apoptosis. Consequently, these data suggest that pioglitazone, at optimized doses, may have utility in protection from acute MI.
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Affiliation(s)
- Dina M Khodeer
- a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, 41522 Ismailia, Egypt
| | - Sawsan A Zaitone
- a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, 41522 Ismailia, Egypt
| | - Noha E Farag
- b Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Yasser M Moustafa
- a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, 41522 Ismailia, Egypt
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Mallipattu SK, Uribarri J. Advanced glycation end product accumulation: a new enemy to target in chronic kidney disease? Curr Opin Nephrol Hypertens 2015; 23:547-54. [PMID: 25160075 DOI: 10.1097/mnh.0000000000000062] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW The critical role of advanced glycation end products (AGEs) in the progression of chronic diseases and their complications has recently become more apparent. This review summarizes the recent contributions to the field of AGEs in chronic kidney disease (CKD). RECENT FINDINGS Over the past 3 decades, AGEs have been implicated in the progression of CKD, and specifically diabetic nephropathy. Although numerous in-vitro and in-vivo studies highlight the detrimental role of AGEs accumulation in tissue injury, few prospective human studies or clinical trials show that inhibiting this process ameliorates disease. Nonetheless, recent studies have focused on the novel mechanisms that contribute to end-organ injury as a result of AGEs accumulation, as well as novel targets of therapy in kidney disease. SUMMARY As the prevalence and the incidence of CKD rises in the United States, it is essential to identify therapeutic strategies that either delay the progression of CKD or improve mortality in this population. The focus of this review is on highlighting the recent studies that advance our current understanding of the mechanisms mediating AGEs-induced CKD progression, as well as novel treatment strategies that have the potential to abrogate this disease process. VIDEO ABSTRACT http://links.lww.com/CONH/A12.
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Affiliation(s)
- Sandeep K Mallipattu
- aDivision of Nephrology, Department of Medicine, Stony Brook University bDivision of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
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Effect of advanced glycosylation end products on apoptosis in human adipose tissue-derived stem cells in vitro. Cell Biosci 2015; 5:3. [PMID: 25973170 PMCID: PMC4429817 DOI: 10.1186/2045-3701-5-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Accepted: 12/24/2014] [Indexed: 12/15/2022] Open
Abstract
Background Both apoptosis and caspase-3 activity in adipose tissue-derived stem cells play an important role in the therapeutic process of diabetes patients. The purpose of this study was to investigate the effect of advanced glycation end products-human serum albumin (AGE-HSA) on apoptosis in human adipose tissue-derived stem cells (ADSCs) and to characterize the signal transduction pathways activated by AGEs that are involved in apoptosis regulation. Results AGE-HSA promoted apoptosis and caspase-3 activity in ADSCs. However, the effects of AGE-HSA were significantly attenuated by an inhibitor of p38 MAPK, but not by inhibitors of JNK MAPK or ERK MAPK. AGE-HSA also upregulated the expression of RAGE. Silencing of the RAGE gene inhibited AGE-HSA-induced apoptosis, and activation and expression of phosphorylated p38 MAPK. Conclusions These results suggest that AGE-HSA promote the apoptosis of ADSCs in vitro via a RAGE-dependent p38 MAPK pathway.
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The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent. Biochim Biophys Acta Mol Basis Dis 2015; 1852:720-31. [PMID: 25595658 DOI: 10.1016/j.bbadis.2015.01.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 01/05/2015] [Accepted: 01/08/2015] [Indexed: 12/17/2022]
Abstract
Diabetic neuronal damage results from hyperglycemia followed by increased formation of advanced glycosylation end products (AGEs), which leads to neurodegeneration, although the molecular mechanisms are still not well understood. Metformin, one of the most widely used anti-diabetic drugs, exerts its effects in part by activation of AMP-activated protein kinase (AMPK). AMPK is a critical evolutionarily conserved enzyme expressed in the liver, skeletal muscle and brain, and promotes cellular energy homeostasis and biogenesis by regulating several metabolic processes. While the mechanisms of AMPK as a metabolic regulator are well established, the neuronal role for AMPK is still unknown. In the present study, human neural stem cells (hNSCs) exposed to AGEs had significantly reduced cell viability, which correlated with decreased AMPK and mitochondria associated gene/protein (PGC1α, NRF-1 and Tfam) expressions, as well as increased activation of caspase 3 and 9 activities. Metformin prevented AGEs induced cytochrome c release from mitochondria into cytosol in the hNSCs. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. Metformin also significantly rescued hNSCs from AGE-mediated mitochondrial deficiency (lower ATP, D-loop level, mitochondrial mass, maximal respiratory function, COX activity, and mitochondrial membrane potential). Furthermore, co-treatment of hNSCs with metformin significantly blocked AGE-mediated reductions in the expression levels of several neuroprotective genes (PPARγ, Bcl-2 and CREB). These findings extend our understanding of the molecular mechanisms of both AGE-induced neuronal toxicity, and AMPK-dependent neuroprotection by metformin. This study further suggests that AMPK may be a potential therapeutic target for treating diabetic neurodegeneration.
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Moran C, Münch G, Forbes JM, Beare R, Blizzard L, Venn AJ, Phan TG, Chen J, Srikanth V. Type 2 diabetes, skin autofluorescence, and brain atrophy. Diabetes 2015; 64:279-83. [PMID: 25053588 DOI: 10.2337/db14-0506] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is associated with brain atrophy, but the mechanisms underlying this link are unknown. Advanced glycation end products (AGEs) accumulate in T2DM, resulting in inflammation, oxidative stress, and protein cross-linking, which are known contributors to neurodegeneration. We aimed to study whether tissue AGE accumulation is associated with T2DM-related brain atrophy. We performed brain magnetic resonance imaging, cognitive tests, and noninvasive skin autofluorescence (SAF; a measure of tissue AGE levels) on people aged >55 years with and without T2DM. Multivariable linear regression was used to study the relationships among T2DM, SAF, and gray matter volume (GMV). There were 486 people included in the study. T2DM was associated with greater SAF. Greater SAF, T2DM, and cognitive impairment were each associated with lower GMV independently of age, sex, and total intracranial volume. SAF partially mediated the association between T2DM and GMV. Longitudinal studies may help confirm whether tissue AGE accumulation is associated with brain atrophy in T2DM.
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Affiliation(s)
- Chris Moran
- Stroke and Ageing Research Group, Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia Neurosciences, Monash Medical Centre, Monash Health, Melbourne, Australia
| | - Gerald Münch
- Department of Pharmacology, School of Medicine, University of Western Sydney, New South Wales, Australia Molecular Medicine Research Group, University of Western Sydney, New South Wales, Australia
| | - Josephine M Forbes
- Translational Research Institute, Mater University of Queensland, Brisbane, Queensland, Australia Mater Clinical School, University of Queensland, Brisbane, Queensland, Australia
| | - Richard Beare
- Stroke and Ageing Research Group, Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia Neurosciences, Monash Medical Centre, Monash Health, Melbourne, Australia Developmental Imaging, Murdoch Children's Research Institute, Melbourne, Australia
| | - Leigh Blizzard
- Menzies Research Institute Tasmania, Hobart, Tasmania, Australia
| | - Alison J Venn
- Menzies Research Institute Tasmania, Hobart, Tasmania, Australia
| | - Thanh G Phan
- Stroke and Ageing Research Group, Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia Neurosciences, Monash Medical Centre, Monash Health, Melbourne, Australia
| | - Jian Chen
- Stroke and Ageing Research Group, Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia Neurosciences, Monash Medical Centre, Monash Health, Melbourne, Australia Developmental Imaging, Murdoch Children's Research Institute, Melbourne, Australia
| | - Velandai Srikanth
- Stroke and Ageing Research Group, Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia Neurosciences, Monash Medical Centre, Monash Health, Melbourne, Australia Menzies Research Institute Tasmania, Hobart, Tasmania, Australia
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Gugliucci A, Menini T. The axis AGE-RAGE-soluble RAGE and oxidative stress in chronic kidney disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 824:191-208. [PMID: 25039001 DOI: 10.1007/978-3-319-07320-0_14] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Chronic kidney disease (CKD) has been shown to be associated with high oxidative stress and cardiovascular disease. In this chapter our focus will be on the role of advanced glycation end products (AGE) and their receptor, RAGE in CKD progression and their role on cardiovascular complications. We provide a succinct, yet comprehensive summary of the current knowledge, the challenges and the future therapeutic avenues that are stemming out from novel recent findings. We first briefly review glycation and AGE formation and the role of the kidney in their metabolism. Next, we focus on the RAGE, its signaling and role in oxidative stress. We address the possible role of soluble RAGEs as decoys and the controversy regarding this issue. We then provide the latest information on the specific role of both AGE and RAGE in inflammation and perpetuation of kidney damage in diabetes and in CKD without diabetes, which is the main purpose of the review. Finally, we offer an update on new avenues to target the AGE-RAGE axis in CKD.
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Affiliation(s)
- Alejandro Gugliucci
- Glycation, Oxidation and Disease Laboratory, Department of Research, College of Osteopathic Medicine, Touro University-California, 1310 Club Drive, 94592, Vallejo, CA, USA,
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Wang X, Yu S, Wang CY, Wang Y, Liu HX, Cui Y, Zhang LD. Advanced glycation end products induce oxidative stress and mitochondrial dysfunction in SH-SY5Y cells. In Vitro Cell Dev Biol Anim 2014; 51:204-9. [DOI: 10.1007/s11626-014-9823-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Accepted: 09/16/2014] [Indexed: 12/17/2022]
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Abstract
Diabetic nephropathy is a significant cause of chronic kidney disease and end-stage renal failure globally. Much research has been conducted in both basic science and clinical therapeutics, which has enhanced understanding of the pathophysiology of diabetic nephropathy and expanded the potential therapies available. This review will examine the current concepts of diabetic nephropathy management in the context of some of the basic science and pathophysiology aspects relevant to the approaches taken in novel, investigative treatment strategies.
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Affiliation(s)
- Andy Kh Lim
- Department of Nephrology, Monash Medical Center, Monash Health, Clayton, VIC, Australia ; Department of General Medicine, Dandenong Hospital, Monash Health, Clayton, VIC, Australia ; Department of Medicine, Monash University, Clayton, VIC, Australia
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Popolo A, Adesso S, Pinto A, Autore G, Marzocco S. L-Arginine and its metabolites in kidney and cardiovascular disease. Amino Acids 2014; 46:2271-86. [PMID: 25161088 DOI: 10.1007/s00726-014-1825-9] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 08/13/2014] [Indexed: 12/19/2022]
Abstract
L-Arginine is a semi essential amino acid synthesised from glutamine, glutamate and proline via the intestinal-renal axis in humans and most mammals. L-Arginine degradation occurs via multiple pathways initiated by arginase, nitric-oxide synthase, Arg: glycine amidinotransferase, and Arg decarboxylase. These pathways produce nitric oxide, polyamines, proline, glutamate, creatine and agmatine with each having enormous biological importance. Several disease are associated to an L-arginine impaired levels and/or to its metabolites: in particular various L-arginine metabolites may participate in pathogenesis of kidney and cardiovascular disease. L-Arginine and its metabolites may constitute both a marker of pathology progression both the rationale for manipulating L-arginine metabolism as a strategy to ameliorate these disease. A large number of studies have been performed in experimental models of kidney disease with sometimes conflicting results, which underlie the complexity of Arg metabolism and our incomplete knowledge of all the mechanisms involved. Moreover several lines of evidence demonstrate the role of L-arg metabolites in cardiovascular disease and that L-arg administration role in reversing endothelial dysfunction, which is the leading cause of cardiovascular diseases, such as hypertension and atherosclerosis. This review will discuss the implication of the mains L-arginine metabolites and L-arginine-derived guanidine compounds in kidney and cardiovascular disease considering the more recent literature in the field.
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Affiliation(s)
- Ada Popolo
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy
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Ishibashi Y, Matsui T, Ueda S, Fukami K, Okuda S, Yamagishi SI. Irbesartan inhibits advanced glycation end product-induced increase in asymmetric dimethylarginine level in mesangial cells through its anti-oxidative properties. Int J Cardiol 2014; 176:1120-2. [PMID: 25156845 DOI: 10.1016/j.ijcard.2014.07.299] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 07/27/2014] [Indexed: 11/30/2022]
Affiliation(s)
- Yuji Ishibashi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Takanori Matsui
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Seiji Ueda
- Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Kei Fukami
- Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Seiya Okuda
- Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Sho-ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
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Tahara N, Yamagishi SI, Mizoguchi M, Tahara A, Imaizumi T. Pioglitazone decreases asymmetric dimethylarginine levels in patients with impaired glucose tolerance or type 2 diabetes. Rejuvenation Res 2014; 16:344-51. [PMID: 23777507 DOI: 10.1089/rej.2013.1434] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND AND AIMS Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is a biomarker and mediator of cardiovascular disease in patients with impaired glucose tolerance (IGT) or diabetes mellitus (DM). Advanced glycation end products (AGEs) and their receptor (RAGE) axis is involved in ADMA generation as well. However, it remains unclear whether pioglitazone could decrease ADMA levels by reducing RAGE expression in humans. DESIGN AND METHODS Forty-eight IGT or type 2 DM (T2DM) patients were assigned to receive either pioglitazone (n=29) or glimepiride (n=19) and evaluated at baseline and 16 weeks of follow-up. We compared the effects of pioglitazone and glimepride on ADMA and soluble form of RAGE (sRAGE) levels and then studied whether the changes in serum ADMA level (ΔADMA) after treatment with pioglitazone were correlated with ΔsRAGE. We further examined which Δclinical variables were independently associated with ΔADMA. RESULTS After 16-week treatments, fasting plasma glucose and glycated hemoglobin (HbA1c) values were comparably reduced in both groups. Compared with glimepiride, pioglitazone treatment significantly decreased ADMA levels and improved insulin sensitivity, while it elevated high-density lipoprotein cholesterol (HDL-C) and sRAGE values and increased body weight and waist circumference. In multiple stepwise regression analysis, log-transformed Δfibronectin were a sole independent determinant of log-transformed ΔADMA (r=-0.551, R²=0.303). CONCLUSIONS This study demonstrated that pioglitazone decreased serum ADMA levels in a glucose-lowering independent manner. Elevation of fibronectin by pioglitazone may contribute to the reduction of serum levels of ADMA in IGT or T2DM subjects, thus playing a protective role against cardiovascular disease.
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Affiliation(s)
- Nobuhiro Tahara
- 1 Department of Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine , Kurume, Japan
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Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2014; 18:1-14. [PMID: 24634591 PMCID: PMC3951818 DOI: 10.4196/kjpp.2014.18.1.1] [Citation(s) in RCA: 939] [Impact Index Per Article: 85.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 10/11/2013] [Accepted: 12/10/2013] [Indexed: 02/06/2023]
Abstract
During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.
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Affiliation(s)
- Varun Parkash Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
| | - Anjana Bali
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
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