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Bellos I, Marinaki S, Lagiou P, Benetou V. Galectin-3 in chronic kidney disease. Clin Chim Acta 2024; 559:119727. [PMID: 38750780 DOI: 10.1016/j.cca.2024.119727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 05/10/2024] [Accepted: 05/12/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND AND AIMS High serum galectin-3 has been associated with adverse outcomes among dialysis patients, although its prognostic role remains unclear among individuals with earlier-stage chronic kidney disease. The present systematic review aims to evaluate the association of serum galectin-3 with survival, cardiovascular disease and kidney disease progression among non-dialysis chronic kidney disease patients. METHODS PubMed, Scopus, Web of Science, CENTRAL and Google Scholar were systematically searched till November 10, 2023. All observational studies assessing the prognostic role of serum galectin-3 in patients with non-dialysis chronic kidney disease were included. RESULTS Overall, 12 studies (10 cohort, 2 cross-sectional) were included, comprising 9,349 patients. The endpoint of survival was assessed in 5 studies, indicating a significant association between increasing serum galectin-3 levels and higher all-cause mortality risk (Hazard ratio per unit: 1.22, 95 % confidence intervals-CI: 1.05-1.41, ≥6 ng/mL: 2.66, 95 % CI: 1.68-4.23). Current evidence coming from 4 studies was inconclusive regarding the potential link of galectin-3 and kidney function decline, yielding conflicting results. No significant associations between serum galectin-3 and heart failure, cardiovascular events or death were consistently reported. CONCLUSIONS This systematic review supports the prognostic role of galectin-3 in chronic kidney disease, as its increased serum values may be associated with higher all-cause mortality risk. No clear role could be supported for serum galectin-3 regarding the prediction of cardiovascular disease or kidney disease progression.
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Affiliation(s)
- Ioannis Bellos
- Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Medical School, Athens, Greece; Department of Nephrology and Renal Transplantation, Laiko General Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
| | - Smaragdi Marinaki
- Department of Nephrology and Renal Transplantation, Laiko General Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Pagona Lagiou
- Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Vassiliki Benetou
- Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Medical School, Athens, Greece
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Beniwal A, Jain JC, Jain A. Lipids: A Major Culprit in Diabetic Nephropathy. Curr Diabetes Rev 2024; 20:60-69. [PMID: 38018185 DOI: 10.2174/0115733998259273231101052549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/13/2023] [Accepted: 09/28/2023] [Indexed: 11/30/2023]
Abstract
The pathophysiology of diabetic nephropathy (DN) is too complex and involves a variety of pathways and mediators. Hyperglycaemia and dyslipidemia are identified as major risk factors for diabetic nephropathy. Various studies revealed the fact that dyslipidemia is a major contributor to the process of diabetic nephropathy. Dyslipidemia refers to abnormal lipid levels. Lipids like LDL, free fatty acids, abnormal lipoproteins, ceramides, etc., are unsafe for kidneys. They target proximal tubular epithelial cells, podocytes, and tubulointerstitial tissues through biochemical changes, especially by enhancing the release of reactive oxygen species (ROS) and lipid peroxidation, endorsing tissue inflammation and mitochondrial damage, which give rise to nephropathy. Major lipid targets identified are SREBP1, LXR, FXR PPAR, CD-36, PKc, AGE/RAGE pathway, and ferroptosis. The drug acting on these targets has shown improvement in DN patients. Various preclinical and clinical studies support the fact that hyperlipidemic agents are promising targets for DN. Therefore, in conjunction with other standard therapies, drugs acting on dyslipidemia can be added as a part of the regimen in order to prevent the incidence of ESRD and CVD.
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Affiliation(s)
- Ankita Beniwal
- College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Jasmine Chaudhary Jain
- College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Akash Jain
- College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
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Garza-Campos A, Prieto-Correa JR, Domínguez-Rosales JA, Hernández-Nazará ZH. Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer. World J Diabetes 2023; 14:977-994. [PMID: 37547586 PMCID: PMC10401444 DOI: 10.4239/wjd.v14.i7.977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/31/2023] [Accepted: 04/17/2023] [Indexed: 07/12/2023] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are chronic pathologies with a high incidence worldwide. They share some pathological mechanisms, including hyperinsulinemia, the production and release of hormones, and hyperglycemia. The above, over time, affects other systems of the human body by causing tissue hypoxia, low-grade inflammation, and oxidative stress, which lay the pathophysiological groundwork for cancer. The leading causes of death globally are T2DM and cancer. Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death (i.e., damage-associated molecular patterns) such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products (RAGE) - a multiligand receptor involved in inflammatory and metabolic and neoplastic processes. This review analyzes the latest advanced reports on the role of RAGE in the development of obesity, T2DM, and cancer, with an aim to understand the intracellular signaling mechanisms linked with cancer initiation. This review also explores inflammation, oxidative stress, hypoxia, cellular senescence, RAGE ligands, tumor microenvironment changes, and the “cancer hallmarks” of the leading tumors associated with T2DM. The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.
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Affiliation(s)
- Andrea Garza-Campos
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Roberto Prieto-Correa
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Alfredo Domínguez-Rosales
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Zamira Helena Hernández-Nazará
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
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Association between Endothelial Cell-Specific Molecule 1 and Galectin-3 in Patients with ST-Segment Elevation Myocardial Infarction: A Pilot Study. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1723309. [PMID: 36388167 PMCID: PMC9646309 DOI: 10.1155/2022/1723309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 09/22/2022] [Indexed: 11/07/2022]
Abstract
The biomarkers galectin-3 (Gal-3) and endothelial cell-specific molecule 1 (ESM-1) reflect endothelial function and inflammation. As a consequence, they play an important role in both the diagnosis and characterization of ST-segment elevation myocardial infarction (STEMI). However, no prior study has explored the association between ESM-1 and Gal-3 in STEMI patients. This study is aimed at determining the ESM-1 and Gal-3 levels in the serum of STEMI patients and then exploring the correlation between the levels of these two biomarkers and their clinical significance in STEMI patients. The participants were divided into two groups: the ST group comprised 35 hospitalized STEMI patients while the control group comprised 24 people with normal coronary arteries. In all the patients, venous blood was taken from the middle of the antecubital fossa. The serum ESM-1 and Gal-3 concentrations were determined using an enzyme-linked immunosorbent assay. The results revealed that the ESM-1 and Gal-3 levels in the STEMI patients were 1.6 and 2.8 times higher, respectively, when compared with the controls (P < 0.001). Moreover, the ESM-1 and Gal-3 levels exhibited a positive linear correlation (r = 0.758, P < 0.001) in the acute STEMI patients. In conclusion, the ESM-1 and Gal-3 levels were found to be significantly elevated and correlated in the STEMI patients. Thus, combining these two biomarkers of endothelial dysfunction and inflammation might be useful for the diagnosis and assessment of STEMI.
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Glycation-Associated Diabetic Nephropathy and the Role of Long Noncoding RNAs. Biomedicines 2022; 10:biomedicines10102623. [PMID: 36289886 PMCID: PMC9599575 DOI: 10.3390/biomedicines10102623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 11/16/2022] Open
Abstract
The glycation of various biomolecules is the root cause of many pathological conditions associated with diabetic nephropathy and end-stage kidney disease. Glycation imbalances metabolism and increases renal cell injury. Numerous therapeutic measures have narrowed down the adverse effects of endogenous glycation, but efficient and potent measures are miles away. Recent advances in the identification and characterization of noncoding RNAs, especially the long noncoding RNAs (lncRNAs), have opened a mammon of new biology to explore the mitigations for glycation-associated diabetic nephropathy. Furthermore, tissue-specific distribution and condition-specific expression make lncRNA a promising key for second-generation therapeutic interventions. Though the techniques to identify and exemplify noncoding RNAs are rapidly evolving, the lncRNA study encounters multiple methodological constraints. This review will discuss lncRNAs and their possible involvement in glycation and advanced glycation end products (AGEs) signaling pathways. We further highlight the possible approaches for lncRNA-based therapeutics and their working mechanism for perturbing glycation and conclude our review with lncRNAs biology-related future opportunities.
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Arivazhagan L, López-Díez R, Shekhtman A, Ramasamy R, Schmidt AM. Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) - Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease. Front Cardiovasc Med 2022; 9:937071. [PMID: 35811725 PMCID: PMC9263181 DOI: 10.3389/fcvm.2022.937071] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 05/30/2022] [Indexed: 12/25/2022] Open
Abstract
Obesity and non-alcoholic fatty liver disease (NAFLD) are on the rise world-wide; despite fervent advocacy for healthier diets and enhanced physical activity, these disorders persist unabated and, long-term, are major causes of morbidity and mortality. Numerous fundamental biochemical and molecular pathways participate in these events at incipient, mid- and advanced stages during atherogenesis and impaired regression of established atherosclerosis. It is proposed that upon the consumption of high fat/high sugar diets, the production of receptor for advanced glycation end products (RAGE) ligands, advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), contribute to the development of foam cells, endothelial injury, vascular inflammation, and, ultimately, atherosclerosis and its consequences. RAGE/Diaphanous-1 (DIAPH1) increases macrophage foam cell formation; decreases cholesterol efflux and causes foam cells to produce and release damage associated molecular patterns (DAMPs) molecules, which are also ligands of RAGE. DAMPs stimulate upregulation of Interferon Regulatory Factor 7 (IRF7) in macrophages, which exacerbates vascular inflammation and further perturbs cholesterol metabolism. Obesity and NAFLD, characterized by the upregulation of AGEs, ALEs and DAMPs in the target tissues, contribute to insulin resistance, hyperglycemia and type two diabetes. Once in motion, a vicious cycle of RAGE ligand production and exacerbation of RAGE/DIAPH1 signaling ensues, which, if left unchecked, augments cardiometabolic disease and its consequences. This Review focuses on RAGE/DIAPH1 and its role in perturbation of metabolism and processes that converge to augur cardiovascular disease.
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Affiliation(s)
- Lakshmi Arivazhagan
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
| | - Raquel López-Díez
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY, United States
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States,*Correspondence: Ann Marie Schmidt
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Bayarsaikhan G, Bayarsaikhan D, Lee J, Lee B. Targeting Scavenger Receptors in Inflammatory Disorders and Oxidative Stress. Antioxidants (Basel) 2022; 11:936. [PMID: 35624800 PMCID: PMC9137717 DOI: 10.3390/antiox11050936] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/04/2022] [Accepted: 05/07/2022] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress and inflammation cannot be considered as diseases themselves; however, they are major risk factors for the development and progression of the pathogenesis underlying many illnesses, such as cancer, neurological disorders (including Alzheimer's disease and Parkinson's disease), autoimmune and metabolic disorders, etc. According to the results obtained from extensive studies, oxidative stress-induced biomolecules, such as advanced oxidation protein products, advanced glycation end products, and advanced lipoxidation end products, are critical for an accelerated level of inflammation and oxidative stress-induced cellular damage, as reflected in their strong affinity to a wide range of scavenger receptors. Based on the limitations of antioxidative and anti-inflammatory molecules in practical applications, targeting such interactions between harmful molecules and their cellular receptors/signaling with advances in gene engineering technology, such as CRISPR or TALEN, may prove to be a safe and effective alternative. In this review, we summarize the findings of recent studies focused on the deletion of scavenger receptors under oxidative stress as a development in the therapeutic approaches against the diseases linked to inflammation and the contribution of advanced glycation end products (AGEs), advanced lipid peroxidation products (ALEs), and advanced oxidation protein products (AOPPs).
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Affiliation(s)
- Govigerel Bayarsaikhan
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea; (G.B.); (D.B.); (J.L.)
| | - Delger Bayarsaikhan
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea; (G.B.); (D.B.); (J.L.)
| | - Jaewon Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea; (G.B.); (D.B.); (J.L.)
| | - Bonghee Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea; (G.B.); (D.B.); (J.L.)
- Department of Anatomy and Cell Biology, Graduate School of Medicine, Gachon University, Incheon 405-760, Korea
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Association of dietary intake, medication and anthropometric indices with serum levels of advanced glycation end products, caspase-3, and matrix metalloproteinase-9 in diabetic patients. J Diabetes Metab Disord 2021; 20:719-725. [PMID: 34222087 DOI: 10.1007/s40200-021-00803-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/20/2021] [Indexed: 10/21/2022]
Abstract
Background and objective Increased serum levels of advanced glycation end products (AGEs), caspase-3 (Cas-3) and matrix metalloproteinase-9 (MMP-9) have been reported in diabetic patients. This study aimed to evaluate association of anthropometric, dietary, and therapeutic factors with serum levels of methylglyoxal (MGO), carboxymethyl lysine (CML), pentosidine (Pen), Cas-3, and MMP-9 in diabetic patients. Methods The current study included 36 diabetic subjects. Dietary intake of the participants was assessed using three-day 24-h recall survey and anthropometric indices were measured. Demographic factors and medication intake of every subject were obtained. Serum levels of CML, MGO, Pen, MMP-9, and Cas-3 were measured using ELISA method. Results Gliclazide consumption was positively correlated with MMP-9 and Cas-3, but not AGEs levels. Females had higher MGO level compared with males. Further, CML levels were negatively correlated with BMI and WHR. Dietary protein intake was positively correlated with MMP-9, Cas-3, and MGO levels. As well as dietary energy and fat intake had significant positive relationship with serum Cas-3 concentration. Conclusion It is concluded that anthropometric characteristics, dietary intake, and therapeutic medications are possible factors that may determine the circulating levels of AGEs, MMP-9, and Cas-3 in patients with diabetes.
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Sun Z, Zhang L, Li L, Shao C, Liu J, Zhou M, Wang Z. Galectin-3 mediates cardiac remodeling caused by impaired glucose and lipid metabolism through inhibiting two pathways of activating Akt. Am J Physiol Heart Circ Physiol 2021; 320:H364-H380. [PMID: 33275526 DOI: 10.1152/ajpheart.00523.2020] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023]
Abstract
Pathological cardiac remodeling is a leading cause of mortality in patients with diabetes. Given the glucose and lipid metabolism disorders (GLDs) in patients with diabetes, it is urgent to conduct a comprehensive study of the myocardial damage under GLDs and find key mechanisms. Apolipoprotein E knockout (ApoE-/-) mice, low-density lipoprotein receptor heterozygote (Ldlr+/-) Syrian golden hamsters, or H9C2 cells were used to construct GLDs models. GLDs significantly promoted cardiomyocyte fibrosis, apoptosis, and hypertrophy in vivo and in vitro, but inhibition of galectin-3 (Gal-3) could significantly reverse this process. Then, the signal transmission pathways were determined. It was found that GLDs considerably inhibited the phosphorylation of Akt at Thr308/Ser473, whereas the silencing of Gal-3 could reverse the inhibition of Akt activity through phosphoinositide 3-kinase-AktThr308 (PI3K-AktThr308) and AMP-activated protein kinase-mammalian target of rapamycin complex 2-AktSer473 (AMPK-mTOR2-AktSer473) pathways. Finally, the PI3K, mTOR, AMPK inhibitor, and Akt activator were used to investigate the role of pathways in regulating cardiac remodeling. Phospho-AktThr308 could mediate myocardial fibrosis, whereas myocardial apoptosis and hypertrophy were regulated by both phospho-AktThr308 and phospho-AktSer473. In conclusion, Gal-3 was an important regulatory factor in GLDs-induced cardiac remodeling, and Gal-3 could suppress the phosphorylation of Akt at different sites in mediating cardiomyocyte fibrosis, apoptosis, and hypertrophy.NEW & NOTEWORTHY Studies on the pathogenesis of diabetic cardiac remodeling are highly desired. Glucose and lipid metabolism are both disordered in diabetes. Glucose and lipid metabolism disturbances promote myocardial fibrosis, apoptosis, and hypertrophy through galectin-3. Galectin-3 promotes cardiac remodeling by inhibiting phosphorylation of AktThr308 or AktSer473. The present study finds that glucose and lipid metabolism disorders are important causes for myocardial damage and provides novel ideas for the prevention and treatment of diabetic cardiac remodeling.
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Affiliation(s)
- Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lili Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lihua Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jia Liu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Mengxue Zhou
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Galectin-3 as a Next-Generation Biomarker for Detecting Early Stage of Various Diseases. Biomolecules 2020; 10:biom10030389. [PMID: 32138174 PMCID: PMC7175224 DOI: 10.3390/biom10030389] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/28/2020] [Accepted: 03/01/2020] [Indexed: 12/11/2022] Open
Abstract
Galectin-3 is a β-galactoside-binding lectin which is important in numerous biological activities in various organs, including cell proliferation, apoptotic regulation, inflammation, fibrosis, and host defense. Galectin-3 is predominantly located in the cytoplasm and expressed on the cell surface, and then often secreted into biological fluids, like serum and urine. It is also released from injured cells and inflammatory cells under various pathological conditions. Many studies have revealed that galectin-3 plays an important role as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease, viral infection, autoimmune disease, neurodegenerative disorders, and tumor formation. In particular, it has been recognized that galectin-3 is extremely useful for detecting many of these diseases in their early stages. The purpose of this article is to review and summarize the recent literature focusing on the biomarker characteristics and long-term outcome predictions of galectin-3, in not only patients with various types of diseases, but associated animal models.
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Wang Z, Zhang L, Sun Z, Shao C, Li Y, Bao Z, Jing L, Geng Y, Gu W, Pang Q, Li L, Yan J. Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque. Heart Lung Circ 2019; 29:112-117. [PMID: 31230870 DOI: 10.1016/j.hlc.2019.04.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 04/06/2019] [Accepted: 04/22/2019] [Indexed: 01/11/2023]
Abstract
Vascular calcification is a key character of advanced plaque in diabetic atherosclerosis. Microcalcification induces plaque rupture, whereas macrocalcification contributes to plaque stability. However, there is still no clear explanation for the formation and transition of these two types of calcification. Based on existing work and the latest international progress, this article provides a brief review of four aspects: calcification transition in plaque; matrix vesicle-mediated calcification transition in plaque; regulation mechanism of matrix vesicle-mediated calcification transition in diabetic plaque; and proposal of a new hypothesis, which may offer a new perspective on the study of the mechanism of calcification transition in plaque.
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Affiliation(s)
- Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
| | - Lili Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Yukun Li
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Zhengyang Bao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Lele Jing
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Yue Geng
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Wen Gu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Qiwen Pang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Lihua Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
| | - Jinchuan Yan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
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Kosmeri C, Siomou E, Vlahos AP, Milionis H. Review shows that lipid disorders are associated with endothelial but not renal dysfunction in children. Acta Paediatr 2019; 108:19-27. [PMID: 30066344 DOI: 10.1111/apa.14529] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 06/14/2018] [Accepted: 07/30/2018] [Indexed: 02/02/2023]
Abstract
AIM We undertook this review to assess the effects of lipid metabolism abnormalities on endothelial and renal function in children. METHODS A search of relevant literature published in English from January 1988 to May 2018 was performed, and this included randomised controlled trials, observational cohort studies, systematic reviews and case reports. RESULTS The search process identified 2324 relevant studies and 29 were finally included. Noninvasive ultrasound markers of endothelial dysfunction, such as flow-mediated dilation and carotid intima-media thickness, were impaired in children with dyslipidaemia. Dietary interventions and statin therapy reversed the effects of dyslipidaemia on endothelial function in children. Most data from adult studies failed to prove a causative relationship between dyslipidaemia and renal disease progression or a beneficial effect of lipid-lowering treatment on renal outcomes. The limited paediatric data did not indicate dyslipidaemia as an independent risk factor for renal dysfunction, which was mainly estimated by cystatin C levels or proteinuria. Therefore, further investigation is needed to clarify a potential relationship. CONCLUSION In view of limited available paediatric evidence, dyslipidaemia may be adversely associated with endothelial function. However, the association between lipid metabolism disorders and renal function in childhood needs to be further investigated.
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Affiliation(s)
- Chrysoula Kosmeri
- Child Health Department School of Health Sciences Faculty of Medicine University of Ioannina Ioannina Greece
| | - Ekaterini Siomou
- Child Health Department School of Health Sciences Faculty of Medicine University of Ioannina Ioannina Greece
| | - Antonios P. Vlahos
- Child Health Department School of Health Sciences Faculty of Medicine University of Ioannina Ioannina Greece
| | - Haralampos Milionis
- Department of Internal Medicine School of Health Sciences Faculty of Medicine University of Ioannina Ioannina Greece
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Mol M, Degani G, Coppa C, Baron G, Popolo L, Carini M, Aldini G, Vistoli G, Altomare A. Advanced lipoxidation end products (ALEs) as RAGE binders: Mass spectrometric and computational studies to explain the reasons why. Redox Biol 2018; 23:101083. [PMID: 30598328 PMCID: PMC6859533 DOI: 10.1016/j.redox.2018.101083] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/06/2018] [Accepted: 12/15/2018] [Indexed: 12/27/2022] Open
Abstract
Advanced Lipoxidation End-products (ALEs) are modified proteins that can act as pathogenic factors in several chronic diseases. Several molecular mechanisms have so far been considered to explain the damaging action of ALEs and among these a pathway involving the receptor for advanced glycation end products (RAGE) should be considered. The aim of the present work is to understand if ALEs formed from lipid peroxidation derived reactive carbonyl species (RCS) are able to act as RAGE binders and also to gain a deeper insight into the molecular mechanisms involved in the protein-protein engagement. ALEs were produced in vitro, by incubating human serum albumin (HSA) with 4-hydroxy-trans− 2-nonenal (HNE), acrolein (ACR) and malondialdehyde (MDA). The identification of ALEs was performed by MS. ALEs were then subjected to the VC1 Pull-Down assay (VC1 is the ligand binding domain of RAGE) and the enrichment factor (the difference between the relative abundance in the enriched sample minus the amount in the untreated one) as an index of affinity, was determined. Computation studies were then carried out to explain the factors governing the affinity of the adducted moieties and the site of interaction on adducted HSA for VC1-binding. The in silico analyses revealed the key role played by those adducts which strongly reduce the basicity of the modified residues and thus occur at their neutral state at physiological conditions (e.g. the MDA adducts, dihydropyridine-Lysine (DHPK) and N-2-pyrimidyl-ornithine (NPO), and acrolein derivatives, N-(3-formyl-3,4-dehydro-piperidinyl) lysine, FDPK). These neutral adducts become unable to stabilize ion-pairs with the surrounding negative residues which thus can contact the RAGE positive residues. In conclusion, ALEs derived from lipid peroxidation-RCS are binders of RAGE and this affinity depends on the effect of the adduct moiety to reduce the basicity of the target amino acid and on the acid moieties surrounding the aminoacidic target.
A wide set of ALEs-HSA was obtained by in vitro incubation of HSA with different RCS. ALEs-HSA before and after VC1 enrichment were fully characterized by MS. Retention efficiency of the identified ALEs-HSA by VC1 was determined. Elucidation of structural requirements making an ALE a RAGE binder was obtained by computational studies. The mechanism here proposed for ALEs can be considered as a general mechanism of protein-protein interaction.
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Affiliation(s)
- Marco Mol
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Genny Degani
- Department of Biosciences, Via Celoria 26, Università degli Studi di Milano, 20133 Milano, Italy
| | - Crescenzo Coppa
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Giovanna Baron
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Laura Popolo
- Department of Biosciences, Via Celoria 26, Università degli Studi di Milano, 20133 Milano, Italy
| | - Marina Carini
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy.
| | - Giulio Vistoli
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
| | - Alessandra Altomare
- Department of Pharmaceutical Sciences, Via Mangiagalli 25, Università degli Studi di Milano, 20133 Milano, Italy
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Abdulmahdi W, Rabadi MM, Jules E, Marghani Y, Marji N, Leung J, Zhang F, Siani A, Siskind T, Vedovino K, Chowdhury N, Sekulic M, Ratliff BB. Kidney dysfunction in the low-birth weight murine adult: implications of oxidative stress. Am J Physiol Renal Physiol 2018; 315:F583-F594. [DOI: 10.1152/ajprenal.00164.2018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Maternal undernutrition (MUN) during pregnancy leads to low-birth weight (LBW) neonates that have a reduced kidney nephron endowment and higher morbidity as adults. Using a severe combined caloric and protein-restricted mouse model of MUN to generate LBW mice, we examined the progression of renal insufficiency in LBW adults. Through 6 mo of age, LBW males experienced greater albuminuria (ELISA analysis), a more rapid onset of glomerular hypertrophy, and a worse survival rate than LBW females. In contrast, both sexes experienced a comparable progressive decline in renal vascular density (immunofluorescence analysis), renal blood flow (Laser-Doppler flowmetry analysis), glomerular filtration rate (FITC-sinistrin clearance analysis), and a progressive increase in systemic blood pressure (measured via tail-cuff method). Isolated aortas from both LBW sexes demonstrated reduced vasodilation in response to ACh, indicative of reduced nitric oxide bioavailability and endothelial dysfunction. ELISA and immunofluorescence analysis revealed a significant increase of circulating reactive oxygen species and NADPH oxidase type 4 (NOX4) expression in both LBW sexes, although these increases were more pronounced in males. Although more effective in males, chronic tempol treatment did improve all observed pathologies in both sexes of LBW mice. Chronic NOX4 inhibition with GKT137831 was more effective than tempol in preventing pathologies in LBW males. In conclusion, despite some minor differences, LBW female and male adults have a reduced nephron endowment comparable with progressive renal and vascular dysfunction, which is associated with increased oxidative stress and subsequent endothelial dysfunction. Tempol treatment and/or NOX4 inhibition attenuates renal and vascular dysfunction in LBW adults.
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Affiliation(s)
- Wasan Abdulmahdi
- Department of Physiology, Renal Research Institute, New York Medical College, Valhalla, New York
| | - May M. Rabadi
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
| | - Edson Jules
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
| | - Yara Marghani
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
| | - Noor Marji
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
| | - Jessica Leung
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
| | - Frank Zhang
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Avi Siani
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
| | - Tamar Siskind
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
| | - Kiara Vedovino
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
| | - Nazrul Chowdhury
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
| | - Miroslav Sekulic
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Brian B. Ratliff
- Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York
- Department of Physiology, Renal Research Institute, New York Medical College, Valhalla, New York
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15
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Unsaturated aldehyde, 4-hydroxynonenal (HNE) alters the structural integrity of HSA with consequences in the immuno-pathology of rheumatoid arthritis. Int J Biol Macromol 2018; 112:306-314. [DOI: 10.1016/j.ijbiomac.2018.01.188] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 01/27/2018] [Accepted: 01/29/2018] [Indexed: 12/18/2022]
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16
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Usende IL, Olopade JO, Emikpe BO, Oyagbemi AA, Adedapo AA. Oxidative stress changes observed in selected organs of African giant rats ( Cricetomys gambianus) exposed to sodium metavanadate. Int J Vet Sci Med 2018; 6:80-89. [PMID: 30255083 PMCID: PMC6147385 DOI: 10.1016/j.ijvsm.2018.03.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 02/28/2018] [Accepted: 03/14/2018] [Indexed: 12/11/2022] Open
Abstract
Vanadium is a contaminant of crude oil that released into the atmosphere through burning of fossil fuels. The mechanism by which it exerts toxic influences had not been fully elucidated in African giant rat (AGR). This study investigates the mechanisms of sodium metavanadate (SMV) induced oxidative stress in AGR. A total of 24 adult male AGR weighing 600-850 g were used. Animals were randomly divided into six groups. Groups 1, 3 and 5 served as control while groups 2, 4 and 6 were treated with intraperitoneal 3 mg/kg body weight of SMV for 3, 7 and 14 days, respectively. Serum, brain, liver, testes, kidneys, spleen and lungs were harvested for biochemical assays. SMV induced significant increase in malondialdehyde, hydrogen peroxide, sulfhydryl (total thiol) and protein carbonyl levels but decreased non-protein thiol levels in tissues accessed. A significant decrease was observed in glutathione-S-transferase (GST), superoxide dismutase (SOD), reduced glutathione (GSH) and glutathione peroxidase (GPx) levels in SMV treated rats compared to controls. Serum myeloperoxidase, xanthine oxidase and Advanced Oxidative Protein Products (AOPP) were markedly increased while nitrous oxide levels were significantly decreased in all treated groups. SMV exposure to AGR induced oxidative stress through generation of reactive oxygen species (ROS) and depletion of the antioxidant defence system. These conditions could become severe with prolonged exposure.
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Affiliation(s)
- Ifukibot L. Usende
- Department of Veterinary Anatomy, University of Abuja, Nigeria
- Department of Veterinary Anatomy, University of Ibadan, Nigeria
| | | | | | - Ademola A. Oyagbemi
- Department of Veterinary Physiology and Biochemistry, University of Ibadan, Nigeria
| | - Adeolu A. Adedapo
- Department of Veterinary Pharmacology and Toxicology, University of Ibadan, Nigeria
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The Role of Galectins as Modulators of Metabolism and Inflammation. Mediators Inflamm 2018; 2018:9186940. [PMID: 29950926 PMCID: PMC5987346 DOI: 10.1155/2018/9186940] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 04/19/2018] [Accepted: 05/09/2018] [Indexed: 12/15/2022] Open
Abstract
Galectins are β-galcotosid-binding lectins. The function of galectins varies with their tissue-specific and subcellular location, and their binding to carbohydrates makes them key players in several intra- and extracellular processes where they bind to glycosylated proteins and lipids. In humans, there are 12 identified galectins, some with tissue-specific distribution. Galectins are found inside cells and in the nucleus, cytosol, and organelles, as well as extracellularly. Galectin-1, -2, -3, -4, -7, -8, -9, and -12 can all induce T-cell apoptosis and modulate inflammation. In the context of metabolic control and loss of the same in, for example, diabetes, galectin-1, -2, -3, -9, and -12 are especially interesting. This review presents information on galectins relevant to the control of inflammation and metabolism and the potential to target galectins for therapeutic purposes.
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18
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Ahmad S, Khan H, Siddiqui Z, Khan MY, Rehman S, Shahab U, Godovikova T, Silnikov V, Moinuddin. AGEs, RAGEs and s-RAGE; friend or foe for cancer. Semin Cancer Biol 2018; 49:44-55. [DOI: 10.1016/j.semcancer.2017.07.001] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 06/22/2017] [Accepted: 07/05/2017] [Indexed: 12/22/2022]
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19
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Renal fibrosis: Recent translational aspects. Matrix Biol 2017; 68-69:318-332. [PMID: 29292218 DOI: 10.1016/j.matbio.2017.12.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 12/15/2017] [Accepted: 12/21/2017] [Indexed: 01/14/2023]
Abstract
Renal fibrogenesis is the common final pathway to all renal injuries that consequently leads to Chronic Kidney Disease (CKD). Renal fibrogenesis corresponds to the replacement of renal functional tissue by extra-cellular matrix proteins, mainly collagens, that ultimately impairs kidney function. Blockade of the renin angiotensin system by Angiotensin Converting Enzyme inhibitors (ACEi) or Angiotensin Receptor Blockers (ARBs) was the first strategy that proved efficient to blunt the development of renal fibrogenesis independently of its systemic action on blood pressure. Although this strategy has been published 20years ago, there is to date no novel therapeutic targets that are both safe and efficient in hindering renal fibrogenesis and CKD in humans, nor there is any new biomarker to precisely quantify this process. In our review, we will focus on the most recent pathways leading to fibrogenesis which have a high therapeutic potential in humans and on the most promising biomarkers of renal fibrosis.
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20
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Iacobini C, Menini S, Blasetti Fantauzzi C, Pesce CM, Giaccari A, Salomone E, Lapolla A, Orioli M, Aldini G, Pugliese G. FL-926-16, a novel bioavailable carnosinase-resistant carnosine derivative, prevents onset and stops progression of diabetic nephropathy in db/db mice. Br J Pharmacol 2017; 175:53-66. [PMID: 29053168 DOI: 10.1111/bph.14070] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 10/06/2017] [Accepted: 10/09/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND PURPOSE The advanced glycation end products (AGEs) participate in the pathogenesis of diabetic nephropathy (DN) by promoting renal inflammation and injury. L-carnosine acts as a quencher of the AGE precursors reactive carbonyl species (RCS), but is rapidly inactivated by carnosinase. In this study, we evaluated the effect of FL-926-16, a carnosinase-resistant and bioavailable carnosine derivative, on the onset and progression of DN in db/db mice. EXPERIMENTAL APPROACH Adult male db/db mice and coeval db/m controls were left untreated or treated with FL-926-16 (30 mg·kg-1 body weight) from weeks 6 to 20 (prevention protocol) or from weeks 20 to 34 (regression protocol). KEY RESULTS In the prevention protocol, FL-926-16 significantly attenuated increases in creatinine (-80%), albuminuria (-77%), proteinuria (-75%), mean glomerular area (-34%), fractional (-40%) and mean (-42%) mesangial area in db/db mice. This protective effect was associated with a reduction in glomerular matrix protein expression and cell apoptosis, circulating and tissue oxidative and carbonyl stress, and renal inflammatory markers, including the NLRP3 inflammasome. In the regression protocol, the progression of DN was completely blocked, although not reversed, by FL-926-16. In cultured mesangial cells, FL-926-16 prevented NLRP3 expression induced by RCS but not by the AGE Nε -carboxymethyllysine. CONCLUSION AND IMPLICATIONS FL-926-16 is effective at preventing the onset of DN and halting its progression in db/db mice by quenching RCS, thereby reducing the accumulation of their protein adducts and the consequent inflammatory response. In a future perspective, this novel compound may represent a promising AGE-reducing approach for DN therapy.
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Affiliation(s)
- Carla Iacobini
- Department of Clinical Molecular Medicine, 'La Sapienza' University, Rome, Italy
| | - Stefano Menini
- Department of Clinical Molecular Medicine, 'La Sapienza' University, Rome, Italy
| | | | | | - Andrea Giaccari
- Endo-Metabolic Diseases Unit, Catholic University, Rome, Italy
| | - Enrica Salomone
- Endo-Metabolic Diseases Unit, Catholic University, Rome, Italy
| | | | - Marica Orioli
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical Molecular Medicine, 'La Sapienza' University, Rome, Italy
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21
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Agnello L, Bivona G, Lo Sasso B, Scazzone C, Bazan V, Bellia C, Ciaccio M. Galectin-3 in acute coronary syndrome. Clin Biochem 2017; 50:797-803. [PMID: 28456545 DOI: 10.1016/j.clinbiochem.2017.04.018] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 04/20/2017] [Accepted: 04/25/2017] [Indexed: 11/18/2022]
Abstract
Acute coronary syndrome (ACS) is a very common cause of hospitalizations worldwide each year. In the past decades biomarkers have become an indispensable tool for diagnosis, risk stratification and prognosis of cardiovascular disease, including ACS. Despite Troponin is considered the gold standard in diagnosis of ACS, several molecules have been investigated to identify predictive biomarkers of prognosis. Among these, Gal-3 has emerged as a promising prognostic marker. It has a pivotal role in inflammation and fibrosis. Both experimental and clinical studies have shown Gal-3 is an independent predictor of all-cause mortality, cardiovascular death and occurrence of HF following ACS. This article reviews the literature data regarding the role of Galectin-3 in ACS setting.
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Affiliation(s)
- Luisa Agnello
- Sezione Biochimica Clinica e Medicina Molecolare Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche, Università degli Studi di Palermo, Italy
| | - Giulia Bivona
- Sezione Biochimica Clinica e Medicina Molecolare Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche, Università degli Studi di Palermo, Italy
| | - Bruna Lo Sasso
- Sezione Biochimica Clinica e Medicina Molecolare Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche, Università degli Studi di Palermo, Italy
| | - Concetta Scazzone
- Sezione Biochimica Clinica e Medicina Molecolare Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche, Università degli Studi di Palermo, Italy
| | - Viviana Bazan
- Dipartimento di Discipline Chirurgiche, Oncologiche e Stomatologiche, Università degli Studi di Palermo, Italy
| | - Chiara Bellia
- Sezione Biochimica Clinica e Medicina Molecolare Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche, Università degli Studi di Palermo, Italy
| | - Marcello Ciaccio
- Sezione Biochimica Clinica e Medicina Molecolare Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche, Università degli Studi di Palermo, Italy; UOC Medicina di Laboratorio - CoreLab, AOUP "P. Giaccone", Palermo, Italy.
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22
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Oyagbemi AA, Omobowale TO, Asenuga ER, Adejumobi AO, Ajibade TO, Ige TM, Ogunpolu BS, Adedapo AA, Yakubu MA. Sodium fluoride induces hypertension and cardiac complications through generation of reactive oxygen species and activation of nuclear factor kappa beta. ENVIRONMENTAL TOXICOLOGY 2017; 32:1089-1101. [PMID: 27378751 DOI: 10.1002/tox.22306] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 06/06/2016] [Accepted: 06/11/2016] [Indexed: 06/06/2023]
Abstract
Human exposure to sodium fluoride through its daily usage is almost inevitable. Cardiovascular and renal dysfunction has been associated with fluoride toxicity. Therefore, this study investigated the mechanism of action of sodium fluoride (NaF) induced hypertension and cardiovascular complications Forty male albino rats of an average of 10 rats per group were used. Group A received clean tap water. Toxicity was induced in Group B to D by administering graded doses of NaF through drinking water ad libitum for 10 days at 150 ppm, 300 ppm, and 600 ppm concentration respectively. Following administration of NaF, there was significant increase in systolic pressure, diastolic pressure and mean arterial pressure. Markers of oxidative stress; malondialdehyde, hydrogen peroxide, advance oxidation protein products, and protein carbonyl were significantly increased in dose-dependent pattern in the cardiac and renal tissues of rats together with significant decrease in the GST activity in NaF-treated rats compared to the control. Also serum markers of inflammation, cardiac, and renal damage including myeloperoxidase, xanthine oxidase, blood urea nitrogen, creatinine, Lactate dehydrogenase (LDH), and Creatinine kinase myocardial band (CK-MB) significantly increased indicating induction of oxidative stress, renal, and cardiac damage after exposure. Histopathology of the kidney and heart revealed aberrations in the histological architecture in NaF-treated rats. Also, immunohistochemistry showed higher expression of nuclear factor kappa beta (NF-kB) in the cardiac and renal tissues of rats administered NaF. Combining all, these results indicate NaF-induced hypertension through generation of reactive oxygen species and activation of renal and cardiac NF-kB expressions. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1089-1101, 2017.
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Affiliation(s)
- Ademola Adetokunbo Oyagbemi
- Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | | | | | | | - Temitayo Olabisi Ajibade
- Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Temitope Moses Ige
- Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Blessing Seun Ogunpolu
- Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Adeolu Alex Adedapo
- Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria
| | - Momoh Audu Yakubu
- Department of Environmental and Interdisciplinary Sciences, College of Science, Technology and Engineering, Texas Southern University, 3100 Cleburne Avenue, Houston, TX, 77004, USA
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23
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Cannizzaro L, Rossoni G, Savi F, Altomare A, Marinello C, Saethang T, Carini M, Payne DM, Pisitkun T, Aldini G, Leelahavanichkul A. Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome. Nutr Metab (Lond) 2017; 14:5. [PMID: 28101123 PMCID: PMC5237238 DOI: 10.1186/s12986-016-0149-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 11/29/2016] [Indexed: 12/26/2022] Open
Abstract
Background The AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). PPARγ activation is known to modulate metabolic syndrome; however a systems-level investigation looking at the protective effects of PPARγ activation as related to the AROS axis has not been performed. The aim of this work is to simultaneously characterize multiple molecular parameters within the AROS axis, using samples taken from different body fluids and tissues of a rat model of HFD-induced metabolic syndrome, in the presence or absence of a PPARγ agonist, Rosiglitazone (RGZ). Methods Rats were fed with 60% HFD for the first half of the treatment duration (21 days) then continued with either HFD alone or HFD plus RGZ for the second half. Results Rats receiving HFD alone showed metabolic syndrome manifestations including hypertension, dyslipidemia, increased glucose levels and insulin resistance, as well as abnormal kidney and inflammatory parameters. Systolic blood pressure, plasma triglyceride and glucose levels, plasma creatinine, and albuminuria were significantly improved in the presence of RGZ. The following molecular parameters of the AROS axis were significantly upregulated in our rat model: carboxymethyl lysine (CML) in urine and liver; carboxyethyl lysine (CEL) in urine; advanced glycation end products (AGEs) in plasma; receptor for advanced glycation end products (RAGE) in liver and kidney; advanced oxidation protein products (AOPP) in plasma; and 4-hydroxynonenal (HNE) in plasma, liver, and kidney. Conversely, with RGZ administration, the upregulation of AOPP and AGEs in plasma, CML and CEL in urine, RAGE in liver as well as HNE in plasma and liver was significantly counteracted/prevented. Conclusions Our data demonstrate (i) the systems-level regulatory landscape of HFD-induced metabolic syndrome involving multiple molecular parameters, including HNE, AGEs and their receptor RAGE, and (ii) attenuation of metabolic syndrome by PPARγ modulation. Electronic supplementary material The online version of this article (doi:10.1186/s12986-016-0149-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Luca Cannizzaro
- Systems Biology Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand ; Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
| | - Giuseppe Rossoni
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milan, Italy
| | - Federica Savi
- Pathological Anatomy Unit (U.O.C. Anatomia Patologica), ASST Santi Paolo e Carlo, Via di Rudinì 8, 20142 Milan, Italy
| | - Alessandra Altomare
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
| | - Cristina Marinello
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
| | - Thammakorn Saethang
- Systems Biology Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand
| | - Marina Carini
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
| | - D Michael Payne
- Systems Biology Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand
| | - Trairak Pisitkun
- Systems Biology Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
| | - Asada Leelahavanichkul
- Center of Excellence in Immunology and Immune-mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand
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24
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Saccon F, Gatto M, Ghirardello A, Iaccarino L, Punzi L, Doria A. Role of galectin-3 in autoimmune and non-autoimmune nephropathies. Autoimmun Rev 2016; 16:34-47. [PMID: 27666815 DOI: 10.1016/j.autrev.2016.09.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023]
Abstract
Galectins are evolutionary conserved β-galactoside binding proteins with a carbohydrate-recognition domain (CRD) of approximately 130 amino acids. In mammals, 15 members of the galectin family have been identified and classified into three subtypes according to CRD organization: prototype, tandem repeat-type and chimera-type galectins. Galectin-3 (gal-3) is the only chimera type galectin in vertebrates containing one CRD linked to an unusual long N-terminal domain which displays non-lectin dependent activities. Although recent studies revealed unique, pleiotropic and context-dependent functions of gal-3 in both extracellular and intracellular space, gal-3 specific pathways and its ligands have not been clearly defined yet. In the kidney gal-3 is involved in later stages of nephrogenesis as well as in renal cell cancer. However, gal-3 has recently been associated with lupus glomerulonephritis, with Familial Mediterranean Fever-induced proteinuria and renal amyloidosis. Gal-3 has been studied in experimental acute kidney damage and in the subsequent regeneration phase as well as in several models of chronic kidney disease, including nephropathies induced by aging, ischemia, hypertension, diabetes, hyperlipidemia, unilateral ureteral obstruction and chronic allograft injury. Because of the pivotal role of gal-3 in the modulation of immune system, wound repair, fibrosis and tumorigenesis, it is not surprising that gal-3 can be an intriguing prognostic biomarker as well as a promising therapeutic target in a great variety of diseases, including chronic kidney disease, chronic heart failure and cardio-renal syndrome. This review summarizes the functions of gal-3 in kidney pathophysiology focusing on the reported role of gal-3 in autoimmune diseases.
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Affiliation(s)
- Francesca Saccon
- Division of Rheumatology, Department of Medicine (DIMED), University of Padova, Italy
| | - Mariele Gatto
- Division of Rheumatology, Department of Medicine (DIMED), University of Padova, Italy
| | - Anna Ghirardello
- Division of Rheumatology, Department of Medicine (DIMED), University of Padova, Italy
| | - Luca Iaccarino
- Division of Rheumatology, Department of Medicine (DIMED), University of Padova, Italy
| | - Leonardo Punzi
- Division of Rheumatology, Department of Medicine (DIMED), University of Padova, Italy
| | - Andrea Doria
- Division of Rheumatology, Department of Medicine (DIMED), University of Padova, Italy.
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Abstract
SIGNIFICANCE A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. RECENT ADVANCES Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. CRITICAL ISSUES The review summarizes the critical sources of oxidative stress in the kidney during injury/disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. FUTURE DIRECTIONS Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones. Antioxid. Redox Signal. 25, 119-146.
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Affiliation(s)
- Brian B Ratliff
- 1 Department of Medicine, Renal Research Institute , New York Medical College, Valhalla, New York.,2 Department of Physiology, Renal Research Institute , New York Medical College, Valhalla, New York
| | - Wasan Abdulmahdi
- 2 Department of Physiology, Renal Research Institute , New York Medical College, Valhalla, New York
| | - Rahul Pawar
- 1 Department of Medicine, Renal Research Institute , New York Medical College, Valhalla, New York
| | - Michael S Wolin
- 2 Department of Physiology, Renal Research Institute , New York Medical College, Valhalla, New York
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Musso G, Cassader M, Gambino R. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov 2016; 15:249-74. [PMID: 26794269 DOI: 10.1038/nrd.2015.3] [Citation(s) in RCA: 337] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease - the most common chronic liver disease - encompasses a histological spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Over the next decade, NASH is projected to be the most common indication for liver transplantation. The absence of an effective pharmacological therapy for NASH is a major incentive for research into novel therapeutic approaches for this condition. The current focus areas for research include the modulation of nuclear transcription factors; agents that target lipotoxicity and oxidative stress; and the modulation of cellular energy homeostasis, metabolism and the inflammatory response. Strategies to enhance resolution of inflammation and fibrosis also show promise to reverse the advanced stages of liver disease.
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Affiliation(s)
- Giovanni Musso
- Gradenigo Hospital, Corso Regina Margherita 8, 10132 Turin, Italy
| | - Maurizio Cassader
- Department of Medical Sciences, University of Turin, Corso A.M. Dogliotti 14, 10126, Turin, Italy
| | - Roberto Gambino
- Department of Medical Sciences, University of Turin, Corso A.M. Dogliotti 14, 10126, Turin, Italy
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Kong SY, Takeuchi M, Hyogo H, McKeown-Eyssen G, Yamagishi SI, Chayama K, O'Brien PJ, Ferrari P, Overvad K, Olsen A, Tjønneland A, Boutron-Ruault MC, Bastide N, Carbonnel F, Kühn T, Kaaks R, Boeing H, Aleksandrova K, Trichopoulou A, Lagiou P, Vasilopoulou E, Masala G, Pala V, Santucci De Magistris M, Tumino R, Naccarati A, Bueno-de-Mesquita HB, Peeters PH, Weiderpass E, Quirós JR, Jakszyn P, Sánchez MJ, Dorronsoro M, Gavrila D, Ardanaz E, Rutegård M, Nyström H, Wareham NJ, Khaw KT, Bradbury KE, Romieu I, Freisling H, Stavropoulou F, Gunter MJ, Cross AJ, Riboli E, Jenab M, Bruce WR. The Association between Glyceraldehyde-Derived Advanced Glycation End-Products and Colorectal Cancer Risk. Cancer Epidemiol Biomarkers Prev 2015; 24:1855-63. [PMID: 26404963 PMCID: PMC6284787 DOI: 10.1158/1055-9965.epi-15-0422] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 07/28/2015] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND A large proportion of colorectal cancers are thought to be associated with unhealthy dietary and lifestyle exposures, particularly energy excess, obesity, hyperinsulinemia, and hyperglycemia. It has been suggested that these processes stimulate the production of toxic reactive carbonyls from sugars such as glyceraldehyde. Glyceraldehyde contributes to the production of a group of compounds known as glyceraldehyde-derived advanced glycation end-products (glycer-AGEs), which may promote colorectal cancer through their proinflammatory and pro-oxidative properties. The objective of this study nested within a prospective cohort was to explore the association of circulating glycer-AGEs with risk of colorectal cancer. METHODS A total of 1,055 colorectal cancer cases (colon n = 659; rectal n = 396) were matchced (1:1) to control subjects. Circulating glycer-AGEs were measured by a competitive ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (95% CI), adjusting for potential confounding factors, including smoking, alcohol, physical activity, body mass index, and diabetes status. RESULTS Elevated glycer-AGEs levels were not associated with colorectal cancer risk (highest vs. lowest quartile, 1.10; 95% CI, 0.82-1.49). Subgroup analyses showed possible divergence by anatomical subsites (OR for colon cancer, 0.83; 95% CI, 0.57-1.22; OR for rectal cancer, 1.90; 95% CI, 1.14-3.19; Pheterogeneity = 0.14). CONCLUSIONS In this prospective study, circulating glycer-AGEs were not associated with risk of colon cancer, but showed a positive association with the risk of rectal cancer. IMPACT Further research is needed to clarify the role of toxic products of carbohydrate metabolism and energy excess in colorectal cancer development.
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Affiliation(s)
- So Yeon Kong
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Kanazawa, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | | | - Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - Peter J O'Brien
- Department of Pharmacology, University of Toronto, Toronto, Canada
| | - Pietro Ferrari
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Kim Overvad
- Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Anja Olsen
- Diet, Genes, and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Anne Tjønneland
- Diet, Genes, and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Marie-Christine Boutron-Ruault
- Lifestyle, Genes, and Health: Trans-generational Integrated Epidemiology, EMT, Institute Gustave Roussy, Villejuif, France
| | - Nadia Bastide
- Lifestyle, Genes, and Health: Trans-generational Integrated Epidemiology, EMT, Institute Gustave Roussy, Villejuif, France
| | - Franck Carbonnel
- Lifestyle, Genes, and Health: Trans-generational Integrated Epidemiology, EMT, Institute Gustave Roussy, Villejuif, France. Service d'hépato-gastroentérologie, Hôpital Bicetre, Le Kremlin-Bicêtre Cedex, France
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Heiner Boeing
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Krasimira Aleksandrova
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece. Department of Hygiene, Epidemiology, and Medical Statistics, University of Athens Medical School, Athens, Greece. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece
| | - Pagona Lagiou
- Department of Hygiene, Epidemiology, and Medical Statistics, University of Athens Medical School, Athens, Greece. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - Effie Vasilopoulou
- Department of Hygiene, Epidemiology, and Medical Statistics, University of Athens Medical School, Athens, Greece
| | - Giovanna Masala
- Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy
| | - Valeria Pala
- Epidemiology and Prevention Unit, IRCCS Foundation, National Cancer Institute, Milan, Italy
| | | | - Rosario Tumino
- Cancer Registry and Histopathology Unit, "Civic - MP Arezzo" Hospital, Ragusa, Italy
| | - Alessio Naccarati
- Human Genetics Foundation, Torino Molecular and Genetic Epidemiology Unit, Torino, Italy
| | - H B Bueno-de-Mesquita
- Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and Environment (RIVM), Bilthoven, the Netherlands. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands. Department of Epidemiology and Biostatistics, The School of Public Health, Imperil College London, London, United Kingdom. Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Petra H Peeters
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatics, School of Public Health, Imperial College, London, United Kingdom
| | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway. Cancer Registry of Norway, Oslo, Norway. Department of Medical Epidemiology and Biostatistics, Karolinska Instituet, Stockholm, Sweden. Department of Genetic Epidemiology, Folkhälsan Research Center, Helsinki, Finland
| | | | - Paula Jakszyn
- Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain
| | - María-José Sánchez
- CIBER Epidemiology and Public Health (CIBERESP), Spain. Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs. GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
| | - Miren Dorronsoro
- Public Health Direction and CIBERESP-Biodonostia Research Institute, Basque Regional Health Department, San Sebastian, Spain
| | - Diana Gavrila
- CIBER Epidemiology and Public Health (CIBERESP), Spain. Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
| | - Eva Ardanaz
- CIBER Epidemiology and Public Health (CIBERESP), Spain. Navarre Public Health Institute, Pamplona, Spain
| | - Martin Rutegård
- Department of Surgery, Department of Surgical and Perioperative Sciences, Umeå University, Sweden
| | - Hanna Nyström
- Department of Surgery, Department of Surgical and Perioperative Sciences, Umeå University, Sweden
| | - Nicholas J Wareham
- MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Kay-Tee Khaw
- Clinical Gerontology Unit, Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, United Kingdom
| | - Kathryn E Bradbury
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Isabelle Romieu
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Heinz Freisling
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Faidra Stavropoulou
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Marc J Gunter
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Mazda Jenab
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
| | - W Robert Bruce
- Department of Nutritional Sciences, University of Toronto, Toronto, Canada.
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Kim CS, Park S, Chun Y, Song W, Kim HJ, Kim J. Treadmill Exercise Attenuates Retinal Oxidative Stress in Naturally-Aged Mice: An Immunohistochemical Study. Int J Mol Sci 2015; 16:21008-20. [PMID: 26404251 PMCID: PMC4613238 DOI: 10.3390/ijms160921008] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 08/21/2015] [Accepted: 08/26/2015] [Indexed: 01/30/2023] Open
Abstract
In the retina, a number of degenerative diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration, may occur as a result of aging. Oxidative damage is believed to contribute to the pathogenesis of aging as well as to age-related retinal disease. Although physiological exercise has been shown to reduce oxidative stress in rats and mice, it is not known whether it has a similar effect in retinal tissues. The aim of this study was to evaluate retinal oxidative stress in naturally-aged mice. In addition, we evaluated the effects of aerobic training on retinal oxidative stress by immunohistochemically evaluating oxidative stress markers. A group of twelve-week-old male mice were not exercised (young control). Two groups of twenty-two-month-old male mice were created: an old control group and a treadmill exercise group. The old control group mice were not exercised. The treadmill exercise group mice ran on a treadmill (5 to 12 m/min, 30 to 60 min/day, 3 days/week for 12 weeks). The retinal thickness and number of cells in the ganglion cell layer of the naturally-aged mice were reduced compared to those in the young control mice. However, treadmill exercise reversed these morphological changes in the retinas. We evaluated retinal expression of carboxymethyllysine (CML), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine. The retinas from the aged mice showed increased CML, 8-OHdG, and nitrotyrosine immunostaining intensities compared to young control mice. The exercise group exhibited significantly lower CML levels and nitro-oxidative stress than the old control group. These results suggest that regular exercise can reduce retinal oxidative stress and that physiological exercise may be distinctly advantageous in reducing retinal oxidative stress.
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Affiliation(s)
- Chan-Sik Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Sok Park
- Department of Sports and Health Management, Mokwon University, Daejeon 35349, Korea.
| | - Yoonseok Chun
- Sports Wellness Center, Yong In University, Gyeonggi-do 17092, Korea.
| | - Wook Song
- Health and Exercise Science Laboratory, Seoul National University, Seoul 08826, Korea.
| | - Hee-Jae Kim
- Health and Exercise Science Laboratory, Seoul National University, Seoul 08826, Korea.
| | - Junghyun Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
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Penno G, Solini A, Zoppini G, Fondelli C, Trevisan R, Vedovato M, Gruden G, Lamacchia O, Pontiroli AE, Arosio M, Orsi E, Pugliese G. Hypertriglyceridemia Is Independently Associated with Renal, but Not Retinal Complications in Subjects with Type 2 Diabetes: A Cross-Sectional Analysis of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study. PLoS One 2015; 10:e0125512. [PMID: 25942403 PMCID: PMC4420503 DOI: 10.1371/journal.pone.0125512] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 02/19/2015] [Indexed: 11/30/2022] Open
Abstract
Objective Atherogenic dyslipidemia seems to play a major role in microvascular complications and in residual microvascular risk after statin therapy, which reduces triglycerides up to 40%. We assessed whether raised TG levels are associated with an increased burden from microvascular complications in patients with type 2 diabetes. Methods Subjects from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study (n=15,773) were divided in 4 groups depending on whether they had plasma triglycerides below (NTG, 67.8%) or above (HTG, 32.2%) 1.7 mmol/L and were (42.4%) or not on (57.6%) statin therapy. Estimated GFR (eGFR) was calculated from serum creatinine, albuminuria was measured by immunonephelometry or immunoturbidimetry, and retinopathy was evaluated by fundus examination. Results HTG subjects, either with or without statin, had higher prevalence of albuminuria, reduced eGFR and chronic kidney disease (CKD), especially the albuminuric forms, but not of retinopathy, than NTG subjects. In contrast, cardiovascular disease and advanced DR were more prevalent in subjects on statin than in those not, independently of triglyceride levels. Logistic regression analysis confirmed that HTG, without or with statin, was independently associated with micro and macroalbuminuria, mildly to severely reduced eGFR, and all CKD phenotypes, but not with retinopathy. The adjusted odd ratios for CKD increased linearly for every 0.26 mmol/L increase (approximately one decile) in triglyceride levels. The increase was higher with increasing severity of albuminuria, eGFR loss and CKD phenotype as well as in subjects receiving than in those not receiving statin treatment. Conclusions Triglycerides are associated with CKD, but not retinopathy in subjects with type 2 diabetes, independently of statin treatment. These data point to a possible role of hypertriglyceridemia in the development of CKD, though it remains to be demonstrated that diabetic individuals might benefit from triglyceride reduction with statins and eventually with combination therapy with fibrates. Trial Registration www.ClinicalTrials.gov NCT00715481
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Affiliation(s)
- Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Anna Solini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giacomo Zoppini
- Division of Endocrinology and Metabolic Diseases, University of Verona, Verona, Italy
| | | | - Roberto Trevisan
- Endocrinology and Diabetes Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Monica Vedovato
- Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
| | - Gabriella Gruden
- Department of Internal Medicine, University of Turin, Turin, Italy
| | - Olga Lamacchia
- Department of Medical Sciences, University of Foggia, Foggia, Italy
| | - Antonio E. Pontiroli
- Department of Medicine, Surgery and Odontoiatrics, San Paolo Hospital, University of Milan, Milan, Italy
| | - Maura Arosio
- Endocrinology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy
| | - Emanuela Orsi
- Diabetes Unit, IRCCS “Cà Granda—Ospedale Maggiore Policlinico” Foundation, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, “La Sapienza” University, Rome, Italy
- * E-mail:
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Pugliese G, Iacobini C, Pesce CM, Menini S. Galectin-3: an emerging all-out player in metabolic disorders and their complications. Glycobiology 2014; 25:136-50. [PMID: 25303959 DOI: 10.1093/glycob/cwu111] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Galectin-3 has been increasingly recognized as an important modulator of several biological functions, by interacting with several molecules inside and outside the cell, and an emerging player in numerous disease conditions. Galectin-3 exerts various and sometimes contrasting effects according to its location, type of injury or site of damage. Strong evidence indicates that galectin-3 participates in the pathogenesis of diabetic complications via its receptor function for advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs). AGEs/ALEs are produced to an increased extent in target organs of complications, such as kidney and vessels; here, lack of galectin-3 impairs their removal, leading to accelerated damage. In contrast, in the liver, AGE/ALE tissue content and injury are decreased, because lack of galectin-3 results in reduced uptake and tissue accumulation of these by-products. Some of these effects can be explained by changes in the expression of receptor for AGEs (RAGE), associated with galectin-3 deletion and consequent changes in AGE/ALE tissue levels. Furthermore, galectin-3 might exert AGE/ALE- and RAGE-independent effects, favoring resolution of inflammation and modulating fibrogenesis and ectopic osteogenesis. These effects are mediated by intracellular and extracellular galectin-3, the latter via interaction with N-glycans at the cell surface to form lattice structures. Recently, galectin-3 has been implicated in the development of metabolic disorders because it favors glucose homeostasis and prevents the deleterious activation of adaptive and innate immune response to obesogenic/diabetogenic stimuli. In conclusion, galectin-3 is an emerging all-out player in metabolic disorders and their complications that deserves further investigation as the potential target of therapeutic intervention.
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Affiliation(s)
- Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, Rome 00189, Italy
| | - Carla Iacobini
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, Rome 00189, Italy
| | - Carlo M Pesce
- DINOGMI, University of Genoa Medical School, Genoa 16132, Italy
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, Rome 00189, Italy
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Savic J, Zeljkovic A, Bogavac-Stanojevic N, Simic-Ogrizovic S, Kravljaca M, Stosovic M, Vekic J, Spasojevic-Kalimanovska V, Jelic-Ivanovic Z, Gojkovic T, Spasic S. Association of small, dense low-density lipoprotein cholesterol and galectin-3 in patients with chronic kidney disease. Scandinavian Journal of Clinical and Laboratory Investigation 2014; 74:637-43. [DOI: 10.3109/00365513.2014.928944] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Jasna Savic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade,
Belgrade, Serbia
| | - Aleksandra Zeljkovic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade,
Belgrade, Serbia
| | | | - Sanja Simic-Ogrizovic
- Nephrology Clinic, Clinical Centre of Serbia,
Belgrade, Serbia
- School of Medicine, University of Belgrade,
Belgrade, Serbia
| | | | - Milan Stosovic
- Nephrology Clinic, Clinical Centre of Serbia,
Belgrade, Serbia
| | - Jelena Vekic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade,
Belgrade, Serbia
| | | | - Zorana Jelic-Ivanovic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade,
Belgrade, Serbia
| | - Tamara Gojkovic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade,
Belgrade, Serbia
| | - Slavica Spasic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade,
Belgrade, Serbia
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Betaine supplementation protects against high-fructose-induced renal injury in rats. J Nutr Biochem 2014; 25:353-62. [DOI: 10.1016/j.jnutbio.2013.11.010] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 11/18/2013] [Accepted: 11/18/2013] [Indexed: 01/26/2023]
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Bertoletti L, Regazzoni L, Altomare A, Colombo R, Colzani M, Vistoli G, Marchese L, Carini M, De Lorenzi E, Aldini G. Advanced glycation end products of beta2-microglobulin in uremic patients as determined by high resolution mass spectrometry. J Pharm Biomed Anal 2013; 91:193-201. [PMID: 24469019 DOI: 10.1016/j.jpba.2013.12.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Revised: 12/16/2013] [Accepted: 12/19/2013] [Indexed: 11/25/2022]
Abstract
By using a high resolution top-down and bottom-up approach we identified and characterized the AGEs of beta2-microglobulin (β2-m) formed by incubating the protein in the presence of glucose and of the main reactive carbonyl species. Glucose induced glycation on the N-terminal residue, while glyoxal (GO) and methylglyoxal (MGO) covalently reacted with Arg3. Carboxymethyl (CM-R) and imidazolinone (R-GO) derivatives were identified in the case of GO and carboxyethyl arginine (CE-R) and methyl-imidazolinone (R-MGO) for MGO. Interestingly, α,β-unsaturated aldehydes [4-hydroxy-2-nonenal (HNE); 4-oxo-2-nonenal (ONE); acrolein (ACR)] did not induce any covalent modifications up to 100μM. The different reactivity of β2-m towards the different RCS was then rationalized by molecular modeling studies. The MS method was then applied to fully characterize the AGEs of β2-m isolated from the urine of uremic subjects. CM-R, CE-R and R-MGO were easily identified on Arg3 and their relative abundance in respect to the native protein determined by a semi-quantitative approach. Overall, the AGEs content of urinary β2-m ranged from 0.2 to 1% in uremic subjects. The results here reported offer novel insights and technical achievements for a potential biological role of AGEs-β2-m in pathological conditions.
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Affiliation(s)
- Laura Bertoletti
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
| | - Luca Regazzoni
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
| | - Alessandra Altomare
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
| | - Raffaella Colombo
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
| | - Mara Colzani
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
| | - Giulio Vistoli
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
| | - Loredana Marchese
- Department of Molecular Medicine, University of Pavia, Via Forlanini 6, 27100 Pavia, Italy.
| | - Marina Carini
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
| | - Ersilia De Lorenzi
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
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Vistoli G, De Maddis D, Cipak A, Zarkovic N, Carini M, Aldini G. Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation. Free Radic Res 2013; 47 Suppl 1:3-27. [PMID: 23767955 DOI: 10.3109/10715762.2013.815348] [Citation(s) in RCA: 579] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs) have a pathogenetic role in the development and progression of different oxidative-based diseases including diabetes, atherosclerosis, and neurological disorders. AGEs and ALEs represent a quite complex class of compounds that are formed by different mechanisms, by heterogeneous precursors and that can be formed either exogenously or endogenously. There is a wide interest in AGEs and ALEs involving different aspects of research which are essentially focused on set-up and application of analytical strategies (1) to identify, characterize, and quantify AGEs and ALEs in different pathophysiological conditions; (2) to elucidate the molecular basis of their biological effects; and (3) to discover compounds able to inhibit AGEs/ALEs damaging effects not only as biological tools aimed at validating AGEs/ALEs as drug target, but also as promising drugs. All the above-mentioned research stages require a clear picture of the chemical formation of AGEs/ALEs but this is not simple, due to the complex and heterogeneous pathways, involving different precursors and mechanisms. In view of this intricate scenario, the aim of the present review is to group the main AGEs and ALEs and to describe, for each of them, the precursors and mechanisms of formation.
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Affiliation(s)
- G Vistoli
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, Milan, Italy
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Declèves AE, Rychak JJ, Smith DJ, Sharma K. Effects of high-fat diet and losartan on renal cortical blood flow using contrast ultrasound imaging. Am J Physiol Renal Physiol 2013; 305:F1343-51. [PMID: 24049144 DOI: 10.1152/ajprenal.00326.2013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Obesity-related kidney disease occurs as a result of complex interactions between metabolic and hemodynamic effects. Changes in microvascular perfusion may play a major role in kidney disease; however, these changes are difficult to assess in vivo. Here, we used perfusion ultrasound imaging to evaluate cortical blood flow in a mouse model of high-fat diet-induced kidney disease. C57BL/6J mice were randomized to a standard diet (STD) or a high-fat diet (HFD) for 30 wk and then treated either with losartan or a placebo for an additional 6 wk. Noninvasive ultrasound perfusion imaging of the kidney was performed during infusion of a microbubble contrast agent. Blood flow within the microvasculature of the renal cortex and medulla was derived from imaging data. An increase in the time required to achieve full cortical perfusion was observed for HFD mice relative to STD. This was reversed following treatment with losartan. These data were concurrent with an increased glomerular filtration rate in HFD mice compared with STD- or HFD-losartan-treated mice. Losartan treatment also abrogated fibro-inflammatory disease, assessed by markers at the protein and messenger level. Finally, a reduction in capillary density was found in HFD mice, and this was reversed upon losartan treatment. This suggests that alterations in vascular density may be responsible for the elevated perfusion time observed by imaging. These data demonstrate that ultrasound contrast imaging is a robust and sensitive method for evaluating changes in renal microvascular perfusion and that cortical perfusion time may be a useful parameter for evaluating obesity-related renal disease.
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Affiliation(s)
- Anne-Emilie Declèves
- Center for Renal Translational Medicine, Division of Nephrology-Hypertension, 405 Stein Clinical Research Bldg., MC 0711, Univ. of California San Diego, La Jolla, CA, 92093.
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Solini A, Menini S, Rossi C, Ricci C, Santini E, Blasetti Fantauzzi C, Iacobini C, Pugliese G. The purinergic 2X7 receptor participates in renal inflammation and injury induced by high-fat diet: possible role of NLRP3 inflammasome activation. J Pathol 2013; 231:342-53. [PMID: 23843215 DOI: 10.1002/path.4237] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 07/04/2013] [Accepted: 07/05/2013] [Indexed: 01/05/2023]
Abstract
Renal disease associated with type 2 diabetes and the metabolic syndrome is characterized by a distinct inflammatory phenotype. The purinergic 2X7 receptor (P2X7 R) and the nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasome have been separately shown to play a role in two models of non-metabolic chronic kidney disease. Moreover, the NLRP3 inflammasome has been implicated in chronic low-grade sterile inflammation characterizing metabolic disorders, though the mechanism(s) involved in inflammasome activation under these conditions are still unknown. We investigated the role of P2X7 R (through activation of the NLRP3 inflammasome) in renal inflammation and injury induced by a high-fat diet, an established model of the metabolic syndrome. On a high-fat diet, mice lacking P2X7 R developed attenuated renal functional and structural alterations as well as reduced inflammation, fibrosis, and oxidative/carbonyl stress, as compared with wild-type animals, in the absence of significant differences in metabolic parameters. This was associated with blunted up-regulation of the NLRP3 inflammasome components NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), pro-caspase 1, pro-interleukin (IL)-1β, and pro-IL-18, as well as reduced inflammasome activation, as evidenced by decreased formation of mature caspase 1, whereas mature IL-1β and IL-18 were not detected. Up-regulated expression of NLRP3 and pro-caspase 1, post-translational processing of pro-caspase-1, and release of IL-18 in response to lipopolysaccharide + 2'(3')-O-(4-benzoylbenzoyl)ATP were attenuated by P2X7 R silencing in cultured mouse podocytes. Protein and mRNA expression of P2X7 R, NLRP3, and ASC were also increased in kidneys from subjects with type 2 diabetes and the metabolic syndrome, showing histologically documented renal disease. These data provide evidence of a major role for the purinergic system, at least in part through activation of the NLRP3 inflammasome, in the process driving 'metabolic' renal inflammation and injury and identify P2X7 R and NLRP3 as novel therapeutic targets.
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Affiliation(s)
- Anna Solini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Park S, Kim CS, Lee J, Suk Kim J, Kim J. Effect of Regular Exercise on the Histochemical Changes of d-Galactose-Induced Oxidative Renal Injury in High-Fat Diet-Fed Rats. Acta Histochem Cytochem 2013; 46:111-9. [PMID: 24023395 PMCID: PMC3766828 DOI: 10.1267/ahc.13012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 06/26/2013] [Indexed: 01/01/2023] Open
Abstract
Renal lipid accumulation exhibits slowly developing chronic kidney disease and is associated with increased oxidative stress. The impact of exercise on the obese- and oxidative stress-related renal disease is not well understood. The purpose of this study was to investigate whether a high-fat diet (HFD) would accelerate d-galactose-induced aging process in rat kidney and to examine the preventive effect of regular exercise on the obese- and oxidative stress-related renal disease. Oxidative stress was induced by an administration of d-galactose (100 mg/kg intraperitoneally injected) for 9 weeks, and d-galactose-treated rats were also fed with a high-fat diet (60% kcal as fat) for 9 weeks to induce obesity. We investigated the efficacy of regular exercise in reducing renal injury by analyzing Nε-carboxymethyllysine (CML), 8-hydroxygluanine (8-OHdG) and apoptosis. When rats were fed with a HFD for 9 weeks in d-galactose-treated rats, an increased CML accumulation, oxidative DNA damage and renal podocyte loss were observed in renal glomerular cells and tubular epithelial cells. However, the regular exercise restored all these renal changes in HFD plus d-galactose-treated rats. Our data suggested that long-term HFD may accelerate the deposition of lipoxidation adducts and oxidative renal injury in d-galactose-treated rats. The regular exercise protects against obese- and oxidative stress-related renal injury by inhibiting this lipoxidation burden.
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Affiliation(s)
- Sok Park
- Division of Sports industry & Science, Mokwon University
| | - Chan-Sik Kim
- Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine
- Department of Physiology, Ajou University School of Medicine
| | - Jin Lee
- Department of Anatomy and Cell Biology, Collage of Medicine, Hanyang University
| | - Jung Suk Kim
- Department of Judo, College of Martial Arts, Yongin University
| | - Junghyun Kim
- Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine
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Menini S, Iacobini C, Ricci C, Blasetti Fantauzzi C, Salvi L, Pesce CM, Relucenti M, Familiari G, Taurino M, Pugliese G. The galectin-3/RAGE dyad modulates vascular osteogenesis in atherosclerosis. Cardiovasc Res 2013; 100:472-80. [DOI: 10.1093/cvr/cvt206] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Aldini G, Vistoli G, Stefek M, Chondrogianni N, Grune T, Sereikaite J, Sadowska-Bartosz I, Bartosz G. Molecular strategies to prevent, inhibit, and degrade advanced glycoxidation and advanced lipoxidation end products. Free Radic Res 2013; 47 Suppl 1:93-137. [PMID: 23560617 DOI: 10.3109/10715762.2013.792926] [Citation(s) in RCA: 111] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The advanced glycoxidation end products (AGEs) and lipoxidation end products (ALEs) contribute to the development of diabetic complications and of other pathologies. The review discusses the possibilities of counteracting the formation and stimulating the degradation of these species by pharmaceuticals and natural compounds. The review discusses inhibitors of ALE and AGE formation, cross-link breakers, ALE/AGE elimination by enzymes and proteolytic systems, receptors for advanced glycation end products (RAGEs) and blockade of the ligand-RAGE axis.
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Affiliation(s)
- Giancarlo Aldini
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
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New pathways to control inflammatory responses in adipose tissue. Curr Opin Pharmacol 2013; 13:613-7. [PMID: 23648270 DOI: 10.1016/j.coph.2013.04.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 04/12/2013] [Indexed: 12/24/2022]
Abstract
Obesity is characterized by the presence of chronic inflammation in adipose tissue, particularly in the visceral compartment, that has been causally linked to development of obesity-associated comorbidities. This link can be either direct or indirect, through induction of insulin resistance. This review summarizes recent evidence on potential pharmacological targets of adipose tissue inflammation, with emphasis on mediators that are being studied for intervention in chronic inflammatory diseases and are therefore viable therapeutical candidates. Specifically, we discuss evidence on the role of the inflammasome and its downstream products as a potential target for anti-inflammatory strategies as well as T regulatory (Treg) cells and mediators involved in the resolution phase of inflammation such as resolvins, protectins, annexin A1 (ANXA1) and galectins as potential targets for novel agonist therapies.
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Fisher-Wellman KH, Mattox TA, Thayne K, Katunga LA, La Favor JD, Neufer PD, Hickner RC, Wingard CJ, Anderson EJ. Novel role for thioredoxin reductase-2 in mitochondrial redox adaptations to obesogenic diet and exercise in heart and skeletal muscle. J Physiol 2013; 591:3471-86. [PMID: 23613536 DOI: 10.1113/jphysiol.2013.254193] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Increased fatty acid availability and oxidative stress are physiological consequences of exercise (Ex) and a high-fat, high-sugar (HFHS) diet. Despite these similarities, the global effects of Ex are beneficial, whereas HFHS diets are largely deleterious to the cardiovascular system. The reasons for this disparity are multifactorial and incompletely understood. We hypothesized that differences in redox adaptations following HFHS diet in comparison to exercise may underlie this disparity, particularly in mitochondria. Our objective in this study was to determine mechanisms by which heart and skeletal muscle (red gastrocnemius, RG) mitochondria experience differential redox adaptations to 12 weeks of HFHS diet and/or exercise training (Ex) in rats. Surprisingly, both HFHS feeding and Ex led to contrasting effects in heart and RG, in that mitochondrial H2O2 decreased in heart but increased in RG following both HFHS diet and Ex, in comparison to sedentary animals fed a control diet. These differences were determined to be due largely to increased antioxidant/anti-inflammatory enzymes in the heart following the HFHS diet, which did not occur in RG. Specifically, upregulation of mitochondrial thioredoxin reductase-2 occurred with both HFHS and Ex in the heart, but only with Ex in RG, and systematic evaluation of this enzyme revealed that it is critical for suppressing mitochondrial H2O2 during fatty acid oxidation. These findings are novel and important in that they illustrate the unique ability of the heart to adapt to oxidative stress imposed by HFHS diet, in part through upregulation of thioredoxin reductase-2. Furthermore, upregulation of thioredoxin reductase-2 plays a critical role in preserving the mitochondrial redox status in the heart and skeletal muscle with exercise.
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Wan X, Chen X, Liu L, Zhao Y, Huang WJ, Zhang Q, Miao GG, Chen W, Xie HG, Cao CC. Berberine ameliorates chronic kidney injury caused by atherosclerotic renovascular disease through the suppression of NFκB signaling pathway in rats. PLoS One 2013; 8:e59794. [PMID: 23555784 PMCID: PMC3608549 DOI: 10.1371/journal.pone.0059794] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 02/19/2013] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Impaired renal function in atherosclerotic renovascular disease (ARD) may be the result of crosstalk between atherosclerotic renovascular stenosis and amplified oxidative stress, inflammation and fibrosis. Berberine (BBR) regulates cholesterol metabolism and exerts antioxidant effects. Accordingly, we hypothesized that BBR treatment may ameliorate ARD-induced kidney injury through its cholesterol-lowering effect and also suppression of the pathways involved in oxidative stress, inflammation and NFκB activation. METHODS Male rats were subjected to unilateral renal artery stenosis with silver-irritant coil, and then fed with 12-week hypercholesterolemic diet. Rats with renal artery stenosis were randomly assigned to two groups (n = 6 each) - ARD, or ARD+BBR - according to diet alone or in combination with BBR. Similarly, age-matched rats underwent sham operation and were also fed with hypercholesterolemic diet alone or in combination with BBR as two corresponding controls. Single-kidney hemodynamic metrics were measured in vivo with Doppler ultrasound to determine renal artery flow. The metrics reflecting hyperlipidemia, oxidative stress, renal structure and function, inflammation and NFκB activation were measured, respectively. RESULTS Compared with control rats, ARD rats had a significant increase in urinary albumin, plasma cholesterol, LDL and thiobarbituric acid reactive substances (TBARS) and a significant decrease in SOD activity. When exposed to 12-week BBR, ARD rats had significantly lower levels in blood pressure, LDL, urinary albumin, and TBARS. In addition, there were significantly lower expression levels of iNOS and TGF-β in the ARD+BBR group than in the ARD group, with attenuated NFκB-DNA binding activity and down-regulated protein levels of subunits p65 and p50 as well as IKKβ. CONCLUSIONS We conclude that BBR can improve hypercholesterolemia and redox status in the kidney, eventually ameliorating chronic renal injury in rats with ARD, and that BBR can act against proinflammatory and profibrotic responses through suppression of the NFκB signaling pathway.
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Affiliation(s)
- Xin Wan
- Division of Nephrology, Department of Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xin Chen
- Division of Cardiothoracic Surgery, Department of Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Lin Liu
- Division of Nephrology, Department of Medicine, Xuzhou Medical College, Xuzhou, China
| | - Ye Zhao
- Division of Nephrology, Department of Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wen-Juan Huang
- Division of Nephrology, Department of Medicine, Xuzhou Medical College, Xuzhou, China
| | - Qian Zhang
- Division of Nephrology, Department of Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Gang-Gang Miao
- Division of Cardiothoracic Surgery, Department of Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wen Chen
- Division of Cardiothoracic Surgery, Department of Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hong-Guang Xie
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Pharmacology, Nanjing Medical University School of Pharmacy, Nanjing, China
| | - Chang-Chun Cao
- Division of Nephrology, Department of Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Pang J, Rhodes DH, Pini M, Akasheh RT, Castellanos KJ, Cabay RJ, Cooper D, Perretti M, Fantuzzi G. Increased adiposity, dysregulated glucose metabolism and systemic inflammation in Galectin-3 KO mice. PLoS One 2013; 8:e57915. [PMID: 23451284 PMCID: PMC3579848 DOI: 10.1371/journal.pone.0057915] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 01/27/2013] [Indexed: 12/14/2022] Open
Abstract
Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO) WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acute-phase proteins, number of circulating pro-inflammatory Ly6Chigh monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARγ, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20-week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1α and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation.
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Affiliation(s)
- Jingbo Pang
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Davina H. Rhodes
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Maria Pini
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Rand T. Akasheh
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Karla J. Castellanos
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Robert J. Cabay
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Dianne Cooper
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Mauro Perretti
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Giamila Fantuzzi
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
- * E-mail:
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Rhodes DH, Pini M, Castellanos KJ, Montero-Melendez T, Cooper D, Perretti M, Fantuzzi G. Adipose tissue-specific modulation of galectin expression in lean and obese mice: evidence for regulatory function. Obesity (Silver Spring) 2013; 21:310-9. [PMID: 23401338 PMCID: PMC3610793 DOI: 10.1002/oby.20016] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 06/11/2012] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Galectins (Gal) exert many activities, including regulation of inflammation and adipogenesis. We evaluated modulation of Gal-1, -3, -9 and -12 in visceral (VAT) and subcutaneous (SAT) adipose tissue in mice. DESIGN AND METHODS We used two mouse models of obesity, high-fat diet induced obesity (DIO) and ob/ob mice. We also evaluated the response of Gal-1 KO mice to DIO. RESULTS Both age and diet modulated expression of galectins, with DIO mice having higher serum Gal-1 and Gal-3 versus lean mice after 13-17 weeks of high-fat diet. In DIO mice there was a progressive increase in expression of Gal-1 and Gal-9 in SAT, whereas Gal-3 increased in both VAT and SAT. Expression of Gal-12 declined over time in VAT of DIO mice, similar to adiponectin. Obesity lead to increased production of Gal-1 in adipocytes, whereas the increased Gal-3 and Gal-9 of obesity mostly derived from the stromovascular fraction. Expression of Gal-12 was restricted to adipocytes. There was increased production of Gal-3 and Gal-9, but not Gal-1, in CD11c(-) and CD11c(+) macrophages from VAT of DIO versus lean mice. Expression of Gal-1, -3 and -12 in VAT and SAT of ob/ob mice followed a trend comparable to DIO mice. Rosiglitazone reduced serum Gal-1, but not Gal-3 and modulated expression of Gal-3 in VAT and Gal-9 and Gal-12 in SAT of DIO mice. High-fat feeding lead to increased adiposity in Gal-1 KO versus WT mice, with loss of correlation between leptin and adiposity and no alterations in glucose and insulin levels. CONCLUSIONS Obesity leads to differential modulation of Gal-1, 3, 9 and 12 in VAT and SAT, with Gal-1 acting as a modulator of adiposity.
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Affiliation(s)
- Davina H. Rhodes
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA
| | - Maria Pini
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA
| | - Karla J. Castellanos
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA
| | - Trinidad Montero-Melendez
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Dianne Cooper
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Mauro Perretti
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Giamila Fantuzzi
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA
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Menini S, Iacobini C, Ricci C, Scipioni A, Blasetti Fantauzzi C, Giaccari A, Salomone E, Canevotti R, Lapolla A, Orioli M, Aldini G, Pugliese G. D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. Br J Pharmacol 2012; 166:1344-56. [PMID: 22229552 DOI: 10.1111/j.1476-5381.2012.01834.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE Lipoxidation-derived reactive carbonyl species (RCS) such as 4-hydroxy-2-nonenal (HNE) react with proteins to form advanced lipoxidation end products (ALEs), which have been implicated in both atherosclerosis and renal disease. L-carnosine acts as an endogenous HNE scavenger, but it is rapidly inactivated by carnosinase. This study aimed at assessing the effect of the carnosinase-resistant, D-carnosine, on HNE-induced cellular injury and of its bioavailable prodrug D-carnosine octylester on experimental atherosclerosis and renal disease. EXPERIMENTAL APPROACH Vascular smooth muscle cells (VSMCs) were exposed to HNE or H₂O₂ plus D-carnosine. ApoE null mice fed a Western, pro-atherogenic diet were treated with D-carnosine octylester for 12 weeks. KEY RESULTS In vitro, D-carnosine attenuated the effect of HNE, but not of H₂O₂, on VSMCs. In vivo, D-carnosine octylester-treated mice showed reduced lesion area and a more stable plaque phenotype compared with untreated animals, with reduced foam cell accumulation, inflammation and apoptosis and increased clearance of apoptotic bodies and collagen deposition, resulting in decreased necrotic core formation. Likewise, renal lesions were attenuated in D-carnosine octylester-treated versus untreated mice, with lower inflammation, apoptosis and fibrosis. This was associated with increased urinary levels of HNE-carnosine adducts and reduced protein carbonylation, circulating and tissue ALEs, expression of receptors for these products, and systemic and tissue oxidative stress. CONCLUSIONS AND IMPLICATIONS These data indicate RCS quenching with a D-carnosine ester was highly effective in attenuating experimental atherosclerosis and renal disease by reducing carbonyl stress and inflammation and that this may represent a promising therapeutic strategy in humans.
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Affiliation(s)
- Stefano Menini
- Department of Clinical and Molecular Medicine, La Sapienza University of Rome, Rome, Italy
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Abstract
Vascular endothelial dysfunction is determined by both genetic and environmental factors that cause decreased bioavailability of the vasodilator nitric oxide. This is a hallmark of atherosclerosis, hypertension, and coronary heart disease, which are major complications of metabolic disorders, including diabetes and obesity. Several therapeutic interventions, including changes in lifestyle as well as pharmacologic treatments, are useful for improving endothelial dysfunction in the face of lipotoxicity. This review discusses the current understanding of molecular and physiologic mechanisms underlying lipotoxicity-mediated endothelial dysfunction as well as relevant therapeutic approaches to ameliorate dyslipidemia and consequent endothelial dysfunction that have the potential to improve cardiovascular and metabolic outcomes.
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Affiliation(s)
- Jeong-a Kim
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, 1808 7th Avenue South, BDB 777, Birmingham, AL 35294-0012, USA
- Department of Cell Biology, University of Alabama at Birmingham, 1808 7th Avenue South, BDB 777, Birmingham, AL 35294, USA
| | - Monica Montagnani
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University “Aldo Moro” at Bari, Policlinico, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Sruti Chandrasekran
- Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland at Baltimore, 660 West Redwood Street, HH 495, Baltimore, MD 21201, USA
| | - Michael J. Quon
- Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland at Baltimore, 660 West Redwood Street, HH 495, Baltimore, MD 21201, USA
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Shevalye H, Lupachyk S, Watcho P, Stavniichuk R, Khazim K, Abboud HE, Obrosova IG. Prediabetic nephropathy as an early consequence of the high-calorie/high-fat diet: relation to oxidative stress. Endocrinology 2012; 153:1152-61. [PMID: 22234462 PMCID: PMC3281531 DOI: 10.1210/en.2011-1997] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
This study evaluated early renal functional, structural, and biochemical changes in high-calorie/high-fat diet fed mice, a model of prediabetes and alimentary obesity. Male C57BL6/J mice were fed normal (11 kcal% fat) or high-fat (58 kcal% fat) diets for 16 wk. Renal changes were evaluated by histochemistry and immunohistochemistry, Western blot analysis, ELISA, enzymatic assays, and chemiluminometry. High-fat diet consumption led to increased body and kidney weights, impaired glucose tolerance, hyperinsulinemia, polyuria, a 2.7-fold increase in 24-h urinary albumin excretion, 20% increase in renal glomerular volume, 18% increase in renal collagen deposition, and 8% drop of glomerular podocytes. It also resulted in a 5.3-fold increase in urinary 8-isoprostane excretion and a 38% increase in renal cortex 4-hydroxynonenal adduct accumulation. 4-hydroxynonenal adduct level and immunoreactivity or Sirtuin 1 expression in renal medulla were not affected. Studies of potential mechanisms of the high-fat diet induced renal cortex oxidative injury revealed that whereas nicotinamide adenine dinucleotide phosphate reduced form oxidase activity only tended to increase, 12/15-lipoxygenase was significantly up-regulated, with approximately 12% increase in the enzyme protein expression and approximately 2-fold accumulation of 12(S)-hydroxyeicosatetraenoic acid, a marker of 12/15-lipoxygenase activity. Accumulation of periodic acid-Schiff -positive material, concentrations of TGF-β, sorbitol pathway intermediates, and expression of nephrin, CAAT/enhancer-binding protein homologous protein, phosphoeukaryotic initiation factor-α, and total eukaryotic initiation factor-α in the renal cortex were indistinguishable between experimental groups. Vascular endothelial growth factor concentrations were reduced in high-fat diet fed mice. In conclusion, systemic and renal cortex oxidative stress associated with 12/15-lipoxygenase overexpression and activation is an early phenomenon caused by high-calorie/high-fat diet consumption and a likely contributor to kidney disease associated with prediabetes and alimentary obesity.
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Affiliation(s)
- Hanna Shevalye
- Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA
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49
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Deletion of scavenger receptor A protects mice from progressive nephropathy independent of lipid control during diet-induced hyperlipidemia. Kidney Int 2012; 81:1002-1014. [PMID: 22377830 PMCID: PMC3343314 DOI: 10.1038/ki.2011.457] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Scavenger receptor A (SR-A) is a key transmembrane receptor in the endocytosis of lipids and contributes to the pathogenesis of atherosclerosis. To assess its role in hyperlipidemic chronic kidney disease, wild-type and SR-A-deficient (knockout) mice underwent uninephrectomy followed by either normal or high-fat diet. After 16 weeks of diet intervention, hyperlipidemic wild-type mice presented characteristic features of progressive nephropathy: albuminuria, renal fibrosis, and overexpression of transforming growth factor (TGF)-β1/Smad. These changes were markedly diminished in hyperlipidemic knockout mice and attributed to reduced renal lipid retention, oxidative stress, and CD11c(+) cell infiltration. In vitro, overexpression of SR-A augmented monocyte chemoattractant protein-1 release and TGF-β1/Smad activation in HK-2 cells exposed to oxidized low-density lipoprotein. SR-A knockdown prevented lipid-induced cell injury. Moreover, wild-type to knockout bone marrow transplantation resulted in renal fibrosis in uninephrectomized mice following 16 weeks of the high-fat diet. In contrast, knockout to wild-type bone marrow transplantation led to markedly reduced albuminuria, CD11c(+) cell infiltration, and renal fibrosis compared to wild-type to SR-A knockout or wild-type to wild-type bone marrow transplanted mice, without difference in plasma lipid levels. Thus, SR-A on circulating leukocytes rather than resident renal cells predominantly mediates lipid-induced kidney injury.
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50
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Riazy M, Lougheed M, Adomat HH, Guns EST, Eigendorf GK, Duronio V, Steinbrecher UP. Fluorescent adducts formed by reaction of oxidized unsaturated fatty acids with amines increase macrophage viability. Free Radic Biol Med 2011; 51:1926-36. [PMID: 21930200 DOI: 10.1016/j.freeradbiomed.2011.08.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 08/22/2011] [Accepted: 08/24/2011] [Indexed: 10/17/2022]
Abstract
Macrophages are prominent components of human atherosclerotic lesions and they are believed to accelerate the progression and/or complications of both early and advanced atherosclerotic lesions. We and others have shown that oxidized low-density lipoprotein (oxLDL) induces growth and inhibits apoptosis in murine bone marrow-derived macrophages. In this study, we sought to characterize the oxidative modification of LDL that is responsible for this prosurvival effect. We found that both the modified lipid and the modified protein components of oxLDL can increase the viability of macrophages. The key modification appeared to involve derivatization of amino groups in apoB or in phosphatidylethanolamine by lipid peroxidation products. These reactive oxidation products were primarily unfragmented hydroperoxide- or endoperoxide-containing oxidation products of linoleic acid or arachidonic acid. LC-MS/MS studies showed that some of the arachidonic acid-derived lysine adducts were isolevuglandins that contain lactam and hydroxylactam rings. MS/MS analysis of linoleic acid autoxidation adducts was consistent with 5- or 6-membered nitrogen-containing heterocycles derived from unfragmented oxidation products. The amine modification by oxidation products generated a fluorescence pattern with an excitation maximum at 350nm and emission maximum at 430nm. This is very similar to the fluorescence spectrum of copper-oxidized LDL.
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Affiliation(s)
- Maziar Riazy
- Department of Medicine, University of British Columbia, and Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
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