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Burman MD, Bag S, Ghosal S, Bhowmik S. Glycation of Proteins and Its End Products: From Initiation to Natural Product-Based Therapeutic Preventions. ACS Pharmacol Transl Sci 2025; 8:636-653. [PMID: 40109756 PMCID: PMC11915047 DOI: 10.1021/acsptsci.4c00684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/13/2025] [Accepted: 02/19/2025] [Indexed: 03/22/2025]
Abstract
Diabetes is a chronic metabolic disorder characterized by elevated blood glucose levels, which lead to the glycation of proteins and the formation of advanced glycation end products (AGEs). These AGEs contribute to oxidative stress, inflammation, and the development of complications such as cardiovascular disease, nephropathy, and anemia, significantly increasing mortality rates among diabetic patients. This Review focuses on the role of glycation inhibitors as a potential strategy to prevent AGE-related pathologies. While synthetic glycation inhibitors have shown promise, their adverse effects highlight the need for safer alternatives. We specifically explore a range of natural compounds-flavonoids, curcuminoids, terpenes, stilbenes, lignans, and coumarins-that have demonstrated significant antiglycating properties. The mechanisms through which these natural products inhibit glycation, including antioxidant activity, metal ion chelation, and direct interference with the glycation process, are discussed in detail. This review underscores the potential of natural products as effective and safer glycation inhibitors, offering a promising avenue for the development of therapeutic strategies against diabetes and AGE-related disorders.
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Affiliation(s)
- Mangal Deep Burman
- Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, 92 A.P.C. Road, Kolkata 700009, India
| | - Sagar Bag
- Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, 92 A.P.C. Road, Kolkata 700009, India
| | - Souvik Ghosal
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to be University), Pondy-Cuddalore Main Road, Pillaiyarkuppam, Pondicherry 607402, India
| | - Sudipta Bhowmik
- Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, 92 A.P.C. Road, Kolkata 700009, India
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to be University), Pondy-Cuddalore Main Road, Pillaiyarkuppam, Pondicherry 607402, India
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Ramírez-Guerrero G, Reis T, Segovia-Hernández B, Aranda F, Verdugo C, Pedreros-Rosales C, Marcello M, León J, Rojas A, Galli F, Ronco C. Efficacy of HA130 Hemoadsorption in Removing Advanced Glycation End Products in Maintenance Hemodialysis Patients. Artif Organs 2025. [PMID: 39835591 DOI: 10.1111/aor.14954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/05/2025] [Accepted: 01/10/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND Patients on maintenance hemodialysis (HD) face complications due to the accumulation of protein-bound uremic toxins, such as advanced glycation end products (AGEs), which contribute to inflammation, oxidative stress, and cardiovascular disease. Conventional HD techniques inadequately remove AGEs. This study evaluates the efficacy of the HA130 hemoadsorption cartridge combined with high-flux HD (HF-HD) in enhancing AGE removal. METHODS This prospective, single-center study included 20 maintenance HD patients randomized into two groups: HF-HD alone (n = 10) and HF-HD plus hemoadsorption (n = 10). Blood samples were collected before and after a single session to measure carboxymethyllysine (CML), soluble RAGE (sRAGE), prolactin, and parathyroid hormone (PTH) levels. Reduction ratios (RR) were calculated, including corrected for hemoconcentration (RRc), to ensure accuracy. Statistical analyses included Mann-Whitney U and Chi-square tests. RESULTS The HF-HD plus hemoadsorption group showed significantly enhanced removal of CML compared to HF-HD alone, with RRc of 64.7% [52.6-74.9] versus 39.3% [33.8-49.4], respectively (p = 0.045). Similarly, uncorrected reduction ratios demonstrated a trend favoring hemoadsorption, with values of 57.5% [45.1-70.7] versus 30.3% [19.1-44.5] (p = 0.053). Importantly, sRAGE levels were preserved in both groups (RRc: 23.4% (15.1-30.4) vs. 21.8% (16.6-31.7), p = 0.791), highlighting the safety of hemoadsorption. Other biochemical parameters, including prolactin, PTH, albumin, and electrolytes, showed no significant differences between groups. All sessions were completed without adverse events. CONCLUSION Combining hemoadsorption with HF-HD significantly enhances CML removal, as evidenced by corrected RR, without compromising protective sRAGE levels. This innovative approach offers a promising adjunctive therapy for reducing AGEs-related complications in end-stage renal disease patients. Further longitudinal studies are needed to confirm these findings and evaluate long-term outcomes.
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Affiliation(s)
- Gonzalo Ramírez-Guerrero
- Nephrology and Dialysis Unit, Carlos Van Buren Hospital, Valparaíso, Chile
- International Renal Research Institute of Vicenza, Vicenza, Italy
| | - Thiago Reis
- Laboratory of Molecular Pharmacology, Faculty of Health Sciences, University of Brasília, Brasília, Brazil
- Division of Nephrology, University of São Paulo Medical School, São Paulo, Brazil
- CPQuali Pesquisa Clínica, Clinical Research Center, São Paulo, Brazil
| | | | - Francisca Aranda
- Nephrology and Dialysis Unit, Carlos Van Buren Hospital, Valparaíso, Chile
| | - Constanza Verdugo
- Nephrology and Dialysis Unit, Carlos Van Buren Hospital, Valparaíso, Chile
| | - Cristian Pedreros-Rosales
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
- Nephrology Service, Hospital Las Higueras, Talcahuano, Chile
| | - Matteo Marcello
- International Renal Research Institute of Vicenza, Vicenza, Italy
- Department of Nephrology, Dialysis and Transplantation, St. Bortolo Hospital Vicenza, Vicenza, Italy
| | - Janina León
- Nephrology and Dialysis Unit, Carlos Van Buren Hospital, Valparaíso, Chile
| | - Armando Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca, Chile
| | - Francesco Galli
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Claudio Ronco
- International Renal Research Institute of Vicenza, Vicenza, Italy
- Department of Nephrology, Dialysis and Transplantation, St. Bortolo Hospital Vicenza, Vicenza, Italy
- Department of Medicine (DIMED), Università Degli Studi di Padova, Padova, Italy
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Rojas A, Lindner C, Schneider I, Gonzalez I, Uribarri J. The RAGE Axis: A Relevant Inflammatory Hub in Human Diseases. Biomolecules 2024; 14:412. [PMID: 38672429 PMCID: PMC11048448 DOI: 10.3390/biom14040412] [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: 03/04/2024] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile; (A.R.); (I.G.)
| | - Cristian Lindner
- Department of Radiology, Faculty of Medicine, University of Concepción, Concepción 4030000, Chile;
| | - Ivan Schneider
- Centre of Primary Attention, South Metropolitan Health Service, Santiago 3830000, Chile;
| | - Ileana Gonzalez
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile; (A.R.); (I.G.)
| | - Jaime Uribarri
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10021, USA
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González I, Lindner C, Schneider I, Diaz E, Morales MA, Rojas A. Emerging and multifaceted potential contributions of polyphenols in the management of type 2 diabetes mellitus. World J Diabetes 2024; 15:154-169. [PMID: 38464365 PMCID: PMC10921170 DOI: 10.4239/wjd.v15.i2.154] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/16/2023] [Accepted: 01/19/2024] [Indexed: 02/04/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with a considerable impact on human life, long-term health expenditures, and substantial health losses. In this context, the use of dietary polyphenols to prevent and manage T2DM is widely documented. These dietary compounds exert their beneficial effects through several actions, including the protection of pancreatic islet β-cell, the antioxidant capacities of these molecules, their effects on insulin secretion and actions, the regulation of intestinal microbiota, and their contribution to ameliorate diabetic complications, particularly those of vascular origin. In the present review, we intend to highlight these multifaceted actions and the molecular mechanisms by which these plant-derived secondary metabolites exert their beneficial effects on type 2 diabetes patients.
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Affiliation(s)
- Ileana González
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile
| | - Cristian Lindner
- Department of Radiology, Faculty of Medicine, University of Concepción, Concepción 4030000, Chile
| | - Ivan Schneider
- Centre of Primary Attention, South Metropolitan Health Service, Santiago 3830000, Chile
| | - Erik Diaz
- Faculty of Medicine, Catholic University of Maule, Talca 3460000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
| | - Armando Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile
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Chen X, Li X, Cao B, Chen X, Zhang K, Han F, Kan C, Zhang J, Sun X, Guo Z. Mechanisms and efficacy of traditional Chinese herb monomers in diabetic kidney disease. Int Urol Nephrol 2024; 56:571-582. [PMID: 37552392 DOI: 10.1007/s11255-023-03703-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 07/04/2023] [Indexed: 08/09/2023]
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes and is the primary cause of end-stage renal disease. Current treatment strategies primarily focus on the inhibition of the renin-angiotensin-aldosterone system and the attainment of blood glucose control. Although current medical therapies for DKD have been shown to delay disease progression and improve long-term outcomes, their efficacy is limited and they may be restricted in certain cases, particularly when hyperkalemia is present. Traditional Chinese medicine (TCM) treatment has emerged as a significant complementary approach for DKD. TCM monomers, derived from various Chinese herbs, have been found to modulate multiple therapeutic targets and exhibit a broad range of therapeutic effects in patients with DKD. This review aims to summarize the mechanisms of action of TCM monomers in the treatment of DKD, based on findings from clinical trials, as well as cell and animal studies. The results of these investigations demonstrate the potential effective use of TCM monomers in treating or preventing DKD, offering a promising new direction for future research in the field. By providing a comprehensive overview of the mechanisms and efficacy of TCM monomers in DKD, this review highlights the potential of these natural compounds as alternative therapeutic options for improving outcomes in patients with DKD.
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Affiliation(s)
- Xuexun Chen
- Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Xuan Li
- Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Bo Cao
- Department of Emergency, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Xinping Chen
- Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Kexin Zhang
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Chengxia Kan
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
| | - Jingwen Zhang
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
| | - Xiaodong Sun
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China.
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
| | - Zhentao Guo
- Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China.
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Sadeghi M, Miroliaei M, Kamyabiamineh A, Taslimi P, Ghanadian M. The impact of AGEs on human health and the development of their inhibitors based on natural compounds. ARAB J CHEM 2023; 16:105143. [DOI: 10.1016/j.arabjc.2023.105143] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
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Rojas A, Lindner C, Schneider I, González I, Morales MA. Contributions of the receptor for advanced glycation end products axis activation in gastric cancer. World J Gastroenterol 2023; 29:997-1010. [PMID: 36844144 PMCID: PMC9950863 DOI: 10.3748/wjg.v29.i6.997] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/26/2022] [Accepted: 01/12/2023] [Indexed: 02/10/2023] Open
Abstract
Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products (RAGE) axis activation in the development of neoplasms, including gastric cancer (GC). This new actor in tumor biology plays an important role in the onset of a crucial and long-lasting inflammatory milieu, not only by supporting phenotypic changes favoring growth and dissemination of tumor cells, but also by functioning as a pattern-recognition receptor in the inflammatory response to Helicobacter pylori infection. In the present review, we aim to highlight how the overexpression and activation of the RAGE axis contributes to the proliferation and survival of GC cells as and their acquisition of more invasive phenotypes that promote dissemination and metastasis. Finally, the contribution of some single nucleotide polymorphisms in the RAGE gene as susceptibility or poor prognosis factors is also discussed.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Cristian Lindner
- Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Iván Schneider
- Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Ileana González
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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Bigagli E, D’Ambrosio M, Cinci L, Fiorindi C, Agostiniani S, Bruscoli E, Nannoni A, Lodovici M, Scaringi S, Giudici F, Luceri C. Impact of Preoperative Immunonutrition on Oxidative Stress and Gut Barrier Function in Surgical Patients with Crohn's Disease. Nutrients 2023; 15:nu15040882. [PMID: 36839239 PMCID: PMC9960923 DOI: 10.3390/nu15040882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/02/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Several international guidelines recommend a peri-operative immunonutrition (IN) support for patients care in elective colorectal surgery, to reduce postoperative complications, particularly infections. In Crohn's patients, is also used to mitigate the severity of the disease. We performed a pilot study on 16 Crohn's patients undergoing intestinal surgery for active disease, not responsive to pharmacological treatment; half of them received an oral nutritional supplement enriched with immunonutrients (IN patients) for 7 days prior to surgery, in addition to normal food intake. Markers of oxidative stress (Advanced Glycated End-products (AGEs) and Advanced Oxidation Protein Products (AOPPs) were measured both in plasma and tissue samples wherein the Receptor for Advanced Glycation End products (RAGE) and Tight Junction Protein 1 (TJP1) gene expression were also determined. Plasma AGEs were significantly and positively correlated with tissue levels of AGEs (p = 0.0354) and AOPPs (p = 0.0043) while they were negatively correlated with TJP1 expression (p = 0.0159). The expression of RAGE was also negatively correlated with that of TJP1 gene (p = 0.0146). IN patients exhibited significantly lower AGEs plasma levels (p = 0.0321) and a higher mucosal TJP1 expression (p = 0.0182). No patient had postoperative complications and the length of hospital stay was similar in the two groups, but IN patients, showed a significantly shorter time to resume fluid and solid diet. These preliminary data suggest that IN might support patient's recovery by improving intestinal mucosa barrier function through the regulation of AGEs/RAGE signaling.
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Affiliation(s)
- Elisabetta Bigagli
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Mario D’Ambrosio
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Lorenzo Cinci
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Camilla Fiorindi
- Department of Health Science, University of Firenze, 50134 Firenze, Italy
| | - Sara Agostiniani
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Elisa Bruscoli
- Department of Health Science, University of Firenze, 50134 Firenze, Italy
| | - Anita Nannoni
- Department of Health Science, University of Firenze, 50134 Firenze, Italy
| | - Maura Lodovici
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Stefano Scaringi
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy
| | - Francesco Giudici
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy
- Correspondence: (F.G.); (C.L.)
| | - Cristina Luceri
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
- Correspondence: (F.G.); (C.L.)
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Rojas A, Lindner C, Schneider I, Gonzàlez I, Morales MA. Receptor of advanced glycation end-products axis and gallbladder cancer: A forgotten connection that we should reconsider. World J Gastroenterol 2022; 28:5679-5690. [PMID: 36338887 PMCID: PMC9627425 DOI: 10.3748/wjg.v28.i39.5679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/05/2022] [Accepted: 09/09/2022] [Indexed: 02/06/2023] Open
Abstract
Compelling evidence derived from clinical and experimental research has demonstrated the crucial contribution of chronic inflammation in the development of neoplasms, including gallbladder cancer. In this regard, data derived from clinical and experimental studies have demonstrated that the receptor of advanced glycation end-products (RAGE)/AGEs axis plays an important role in the onset of a crucial and long-lasting inflammatory milieu, thus supporting tumor growth and development. AGEs are formed in biological systems or foods, and food-derived AGEs, also known as dietary AGEs are known to contribute to the systemic pool of AGEs. Once they bind to RAGE, the activation of multiple and crucial signaling pathways are triggered, thus favoring the secretion of several proinflammatory cytokines also involved in the promotion of gallbladder cancer invasion and migration. In the present review, we aimed to highlight the relevance of the association between high dietary AGEs intakes and high risk for gallbladder cancer, and emerging data supporting that dietary intervention to reduce gallbladder cancer risk is a very attractive approach that deserves much more research efforts.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Catholic University of Maule, Talca 34600000, Maule, Chile
| | - Cristian Lindner
- Medicine Faculty, Catholic University of Maule, Talca 34600000, Maule, Chile
| | - Iván Schneider
- Medicine Faculty, Catholic University of Maule, Talca 34600000, Maule, Chile
| | - Ileana Gonzàlez
- Biomedical Research Laboratories, Catholic University of Maule, Talca 34600000, Maule, Chile
| | - Miguel Angel Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Santiago, Chile
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Rojas A, Schneider I, Lindner C, Gonzalez I, Morales M. The RAGE/multiligand axis: a new actor in tumor biology. Biosci Rep 2022; 42:BSR20220395. [PMID: 35727208 PMCID: PMC9251583 DOI: 10.1042/bsr20220395] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/02/2022] [Accepted: 06/21/2022] [Indexed: 01/06/2023] Open
Abstract
The receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein which actively participates in several chronic inflammation-related diseases. RAGE, in addition to AGEs, has a wide repertoire of ligands, including several damage-associated molecular pattern molecules or alarmins such as HMGB1 and members of the S100 family proteins. Over the last years, a large and compelling body of evidence has revealed the active participation of the RAGE axis in tumor biology based on its active involvement in several crucial mechanisms involved in tumor growth, immune evasion, dissemination, as well as by sculpturing of the tumor microenvironment as a tumor-supportive niche. In the present review, we will detail the consequences of the RAGE axis activation to fuel essential mechanisms to guarantee tumor growth and spreading.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Ivan Schneider
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Cristian Lindner
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Ileana Gonzalez
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Miguel A. Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Universidad de Chile, Santiago 8320000, Chile, Santiago, Chile
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Giudice A, Aliberti SM, Barbieri A, Pentangelo P, Bisogno I, D'Arena G, Cianciola E, Caraglia M, Capunzo M. Potential Mechanisms by which Glucocorticoids Induce Breast Carcinogenesis through Nrf2 Inhibition. FRONT BIOSCI-LANDMRK 2022; 27:223. [PMID: 35866405 DOI: 10.31083/j.fbl2707223] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/20/2022] [Accepted: 06/30/2022] [Indexed: 01/03/2025]
Abstract
Breast cancer is the most common malignancy among women worldwide. Several studies indicate that, in addition to established risk factors for breast cancer, other factors such as cortisol release related to psychological stress and drug treatment with high levels of glucocorticoids may also contribute significantly to the initiation of breast cancer. There are several possible mechanisms by which glucocorticoids might promote neoplastic transformation of breast tissue. Among these, the least known and studied is the inhibition of the nuclear erythroid factor 2-related (Nrf2)-antioxidant/electrophile response element (ARE/EpRE) pathway by high levels of glucocorticoids. Specifically, Nrf2 is a potent transcriptional activator that plays a central role in the basal and inducible expression of many cytoprotective genes that effectively protect mammalian cells from various forms of stress and reduce the propensity of tissues and organisms to develop disease or malignancy including breast cancer. Consequently, a loss of Nrf2 in response to high levels of gluco-corticoids may lead to a decrease in cellular defense against oxidative stress, which plays an important role in the initiation of human mammary carcinogenesis. In the present review, we provide a comprehensive overview of the current state of knowledge of the cellular mechanisms by which both glucocorticoid pharmacotherapy and endogenous GCs (cortisol in humans and corticosterone in rodents) may contribute to breast cancer development through inhibition of the Nrf2-ARE/EpRE pathway and the protective role of melatonin against glucocorticoid-induced apoptosis in the immune system.
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Affiliation(s)
- Aldo Giudice
- Animal Facility, Istituto Nazionale Tumori - "Fondazione G. Pascale" - IRCCS, 80131 Naples, Italy
| | - Silvana Mirella Aliberti
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
| | - Antonio Barbieri
- Animal Facility, Istituto Nazionale Tumori - "Fondazione G. Pascale" - IRCCS, 80131 Naples, Italy
| | - Paola Pentangelo
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
| | - Ilaria Bisogno
- Department of Radiological, Oncological and Anatomo-Pathological Science, University of Rome "Sapienza", 00161 Rome, Italy
| | - Giovanni D'Arena
- Hematology Service, San Luca Hospital, ASL Salerno, 84124 Salerno, Italy
| | - Emidio Cianciola
- Anesthesia and Intensive Care Unit, "Immacolata di Sapri" Hospital- ASL Salerno, 84073 Salerno, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Mario Capunzo
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
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Fang J, Ouyang M, Qu Y, Wang M, Huang X, Lan J, Lai W, Xu Q. Advanced glycation end products promote melanogenesis via activating NLRP3 inflammasome in human dermal fibroblasts. J Invest Dermatol 2022; 142:2591-2602.e8. [PMID: 35421403 DOI: 10.1016/j.jid.2022.03.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 11/29/2022]
Abstract
Advanced glycation end products (AGEs) accumulation is significantly increased in the dermis of photoaged skin and plays crucial roles in photoaging. Although AGEs have been found to contribute to the yellowish discoloration of photoaged skin, their roles in photoaging-associated hyperpigmentation disorders have not been extensively studied. In this study, we observed that AGEs, NLRP3 and IL-18 were increased in the dermis of sun-exposed skin and lesions of melasma and solar lentigo and that dermal deposition of AGEs was positively correlated with epidermal melanin levels. Additionally, we found AGEs-BSA potently activated NLRP3 inflammasome and promoted IL-18 production and secretion in cultured fibroblasts, which was mediated by RAGE/NF-κB pathway. Moreover, AGEs-BSA significantly promoted melanogenesis through increasing tyrosinase activity and expression of microphthalmia-associated transcription factor and tyrosinase, which was dependent on NLRP3 inflammasome activation and IL-18 secretion in fibroblasts. Notably, AGEs-collagen could activate NLRP3 inflammasome in fibroblasts and enhance melanogenesis. Further, we found IL-18 enhanced melanogenesis through binding to its receptor and activating p38 MAPK and ERK1/2 signaling pathways in melanocytes. Importantly, the pro-melanogenesis of AGEs-BSA was verified in ex vivo cultured skin and mice models. These findings suggest that dermal AGEs stimulate melanogenesis and contribute to the development of photoaging-associated hyperpigmentation disorders.
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Affiliation(s)
- Jiaqi Fang
- Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Mengting Ouyang
- Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Yingying Qu
- Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Mengyao Wang
- Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Xianyin Huang
- Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Jingjing Lan
- Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Wei Lai
- Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China
| | - Qingfang Xu
- Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China.
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13
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Revisiting Methodologies for In Vitro Preparations of Advanced Glycation End Products. Appl Biochem Biotechnol 2022; 194:2831-2855. [PMID: 35257316 DOI: 10.1007/s12010-022-03860-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 02/24/2022] [Indexed: 11/02/2022]
Abstract
Chronic elevation of sugar and oxidative stress generally results in development of advanced glycation end products (AGEs) in diabetic individuals. Accumulation of AGEs in an individual can give rise to the activation of several pathways that will ultimately lead to various complications. Such AGEs can also be prepared in an in vitro environment. For an in vitro preparation of advanced glycation end products (AGEs), proteins, lipids, or nucleic acids are generally required to be incubated with reducing sugars at a physiological temperature or higher depending upon the protocol optimized for its preparation. Certain other factors are also optimized and added to the buffer to hasten its preparation or alter the properties of prepared AGEs. Through this review, we intend to highlight the various studies related to the experimental procedures for the preparation of different types of AGEs. In addition, we present the comparative study of methodologies optimized for the preparation of AGEs.
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14
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Gonzalez I, Araya P, Schneider I, Lindner C, Rojas A. Pattern recognition receptors and their roles in the host response to Helicobacter pylori infection. Future Microbiol 2021; 16:1229-1238. [PMID: 34615380 DOI: 10.2217/fmb-2021-0106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is highly prevalent, affecting 4.4 billion people globally. This pathogen is a risk factor in the pathogenesis of more than 75% of worldwide cases of gastric cancer. Pattern recognition receptors are essential in the innate immune response to H. pylori infection. They recognize conserved pathogen structures and myriad alarmins released by host cells in response to microbial components, cytokines or cellular stress, thus triggering a robust proinflammatory response, which is crucial in H. pylori-induced gastric carcinogenesis. In this review, we intend to highlight the main pattern recognition receptors involved in the recognition and host response to H. pylori, as well as the main structures recognized and the subsequent inflammatory response.
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Affiliation(s)
- Ileana Gonzalez
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
| | - Paulina Araya
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
| | - Ivan Schneider
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
| | - Cristian Lindner
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
| | - Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
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15
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Role of Advanced Glycation End-Products and Other Ligands for AGE Receptors in Thyroid Cancer Progression. J Clin Med 2021; 10:jcm10184084. [PMID: 34575195 PMCID: PMC8470575 DOI: 10.3390/jcm10184084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/30/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
To date, thyroid cancers (TCs) remain a clinical challenge owing to their heterogeneous nature. The etiopathology of TCs is associated not only with genetic mutations or chromosomal rearrangements, but also non-genetic factors, such as oxidative-, nitrosative-, and carbonyl stress-related alterations in tumor environment. These factors, through leading to the activation of intracellular signaling pathways, induce tumor tissue proliferation. Interestingly, the incidence of TCs is often coexistent with various simultaneous mutations. Advanced glycation end-products (AGEs), their precursors and receptors (RAGEs), and other ligands for RAGEs are reported to have significant influence on carcinogenesis and TCs progression, inducing gene mutations, disturbances in histone methylation, and disorders in important carcinogenesis-related pathways, such as PI3K/AKT/NF-kB, p21/MEK/MPAK, or JAK/STAT, RAS/ERK/p53, which induce synthesis of interleukins, growth factors, and cytokines, thus influencing metastasis, angiogenesis, and cancer proliferation. Precursors of AGE (such as methylglyoxal (MG)) and selected ligands for RAGEs: AS1004, AS1008, and HMGB1 may, in the future, become potential targets for TCs treatment, as low MG concentration is associated with less aggressive anaplastic thyroid cancer, whereas the administration of anti-RAGE antibodies inhibits the progression of papillary thyroid cancer and anaplastic thyroid cancer. This review is aimed at collecting the information on the role of compounds, engaged in glycation process, in the pathogenesis of TCs. Moreover, the utility of these compounds in the diagnosis and treatment of TCs is thoroughly discussed. Understanding the mechanism of action of these compounds on TCs pathogenesis and progression may potentially be the grounds for the development of new treatment strategies, aiming at quality-of-life improvements.
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16
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Wu Q, Zhao K, Chen Y, Ouyang Y, Feng Y, Li S, Zhang L, Feng N. Effect of lotus seedpod oligomeric procyanidins on AGEs formation in simulated gastrointestinal tract and cytotoxicity in Caco-2 cells. Food Funct 2021; 12:3527-3538. [PMID: 33900335 DOI: 10.1039/d0fo03152f] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
This study explored the effects of lotus seedpod oligomeric procyanidins (LSOPC) and their main monomer catechin (CC) on the formation of advanced glycation end products (AGEs) and Caco-2 cytotoxicity during gastrointestinal digestion. Studies have found that LSOPC and CC inhibited the AGEs formation effectively in simulated gastrointestinal digestion and protected Caco-2 cells from AGEs attack. The effect of CC on the inhibition of AGEs formation was significantly better than that of LSOPC. Further, they could effectively inhibit the digestive enzyme activity, reactive oxygen species, RAGE-p38MAPK-NF-κB signaling pathway, inflammatory factors (tumor necrosis factor alpha, interleukin 6), and adhesion factors (intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1) to protect Caco-2 cells.
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Affiliation(s)
- Qian Wu
- Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratoy of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei Research Center of Food Fermentation Engineering and Technology, Hubei University of Technology, Wuhan, Hubei 430068, China. and State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, 130 Changjiang West Road, Hefei, 230036, Anhui, P.R. China
| | - Kuoquan Zhao
- Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratoy of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei Research Center of Food Fermentation Engineering and Technology, Hubei University of Technology, Wuhan, Hubei 430068, China.
| | - Yuanyuan Chen
- College of Food Science, Southwest University, Chongqing, 400715, China
| | - Yu Ouyang
- Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratoy of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei Research Center of Food Fermentation Engineering and Technology, Hubei University of Technology, Wuhan, Hubei 430068, China.
| | - Yingna Feng
- Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratoy of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei Research Center of Food Fermentation Engineering and Technology, Hubei University of Technology, Wuhan, Hubei 430068, China.
| | - Shuyi Li
- College of Food Science and Engineering, Wuhan Polytechnic University, Wuhan, Hubei 430023, China
| | - Liang Zhang
- State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, 130 Changjiang West Road, Hefei, 230036, Anhui, P.R. China
| | - Nianjie Feng
- Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratoy of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei Research Center of Food Fermentation Engineering and Technology, Hubei University of Technology, Wuhan, Hubei 430068, China. and School of Materials and Chemical Engineering, Hubei University of Technology, Wuhan, Hubei 430068, China
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17
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Rojas A, Schneider I, Lindner C, Gonzàlez I, Morales MA. Receptor for advanced glycation end-products axis and coronavirus disease 2019 in inflammatory bowel diseases: A dangerous liaison? World J Gastroenterol 2021; 27:2270-2280. [PMID: 34040321 PMCID: PMC8130044 DOI: 10.3748/wjg.v27.i19.2270] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/22/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Compelling evidence supports the crucial role of the receptor for advanced glycation end-products (RAGE) axis activation in many clinical entities. Since the beginning of the coronavirus disease 2019 pandemic, there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in inflammatory gastrointestinal disorders, such as inflammatory bowel diseases (IBD). However, clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of infection. In the present review, we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients, the RAGE axis activation as well as the cross-talk with the renin-angiotensin system, are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme (ACE) 2. The soluble form of RAGE functions as a decoy for its ligands, and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation, particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3634000, Chile
| | - Iván Schneider
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3634000, Chile
| | - Cristian Lindner
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3634000, Chile
| | - Ileana Gonzàlez
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3634000, Chile
| | - Miguel Angel Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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18
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Rojas A, Lindner C, Gonzàlez I, Morales MA. Advanced-glycation end-products axis: A contributor to the risk of severe illness from COVID-19 in diabetes patients. World J Diabetes 2021; 12:590-602. [PMID: 33995847 PMCID: PMC8107984 DOI: 10.4239/wjd.v12.i5.590] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/29/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products (RAGE) in orchestrating a plethora of proinflammatory cellular responses leading to many of the complications and end-organ damages reported in patients with diabetes mellitus (DM). During the coronavirus disease 2019 (COVID-19) pandemic, many clinical reports have pointed out that DM increases the risk of COVID-19 complications, hospitalization requirements, as well as the overall severe acute respiratory syndrome coronavirus 2 case-fatality rate. In the present review, we intend to focus on how the basal activation state of the RAGE axis in common preexisting conditions in DM patients such as endothelial dysfunction and hyperglycemia-related prothrombotic phenotype, as well as the contribution of RAGE signaling in lung inflammation, may then lead to the increased mortality risk of COVID-19 in these patients. Additionally, the cross-talk between the RAGE axis with either another severe acute respiratory syndrome coronavirus 2 receptor molecule different of angiotensin-converting enzyme 2 or the renin-angiotensin system imbalance produced by viral infection, as well as the role of this multi-ligand receptor on the obesity-associated low-grade inflammation in the higher risk for severe illness reported in diabetes patients with COVID-19, are also discussed.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Cristian Lindner
- Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Ileana Gonzàlez
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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19
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Garay-Sevilla ME, Gomez-Ojeda A, González I, Luévano-Contreras C, Rojas A. Contribution of RAGE axis activation to the association between metabolic syndrome and cancer. Mol Cell Biochem 2021; 476:1555-1573. [PMID: 33398664 DOI: 10.1007/s11010-020-04022-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023]
Abstract
Far beyond the compelling proofs supporting that the metabolic syndrome represents a risk factor for diabetes and cardiovascular diseases, a growing body of evidence suggests that it is also a risk factor for different types of cancer. However, the involved molecular mechanisms underlying this association are not fully understood, and they have been mainly focused on the individual contributions of each component of the metabolic syndrome such as obesity, hyperglycemia, and high blood pressure to the development of cancer. The Receptor for Advanced Glycation End-products (RAGE) axis activation has emerged as an important contributor to the pathophysiology of many clinical entities, by fueling a chronic inflammatory milieu, and thus supporting an optimal microenvironment to promote tumor growth and progression. In the present review, we intend to highlight that RAGE axis activation is a crosswise element on the potential mechanistic contributions of some relevant components of metabolic syndrome into the association with cancer.
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Affiliation(s)
- Ma Eugenia Garay-Sevilla
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Armando Gomez-Ojeda
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Ileana González
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Claudia Luévano-Contreras
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile.
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20
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Bobkova NV. The Balance between Two Branches of RAS Can Protect from Severe COVID-19 Course. BIOCHEMISTRY (MOSCOW) SUPPLEMENT. SERIES A, MEMBRANE AND CELL BIOLOGY 2021; 15:36-51. [PMID: 33643542 PMCID: PMC7897458 DOI: 10.1134/s1990747821010037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/09/2020] [Accepted: 09/22/2020] [Indexed: 12/23/2022]
Abstract
The COVID-19 pandemic has swept the world and required the mobilization of scientists and clinicians around the world to combat this serious disease. Along with SARS-CoV-2 virology research, understanding of the fundamental physiological processes, molecular and cellular mechanisms and intracellular signaling pathways underlying the clinical manifestations of COVID-19 is important for effective therapy of this disease. The review describes in detail the interaction of the components of the renin-angiotensin system (RAS) and receptors of end-glycosylated products (RAGE), which plays a special role in normal lung physiology and in pathological conditions in COVID-19, including the development of acute respiratory distress syndrome and "cytokine storm". A separate section is devoted to the latest developments aimed at correcting the dysfunction of the RAS caused by the binding of the virus to angiotensin converting enzyme 2 (ACE2)- the central element of this system. Analysis of published theoretical, clinical, and experimental data indicates the need for a complex treatment to prevent a severe course of COVID-19 using MasR agonists, blockers of the AT1R and NF-κB signaling pathway, as well as compounds with neuroprotective and neuroregenerative effects.
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Affiliation(s)
- N. V. Bobkova
- Institute of Cell Biophysics, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, 142290 Pushchino, Moscow oblast Russia
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21
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Jin Q, Zhu Q, Wang K, Chen M, Li X. Allisartan isoproxil attenuates oxidative stress and inflammation through the SIRT1/Nrf2/NF‑κB signalling pathway in diabetic cardiomyopathy rats. Mol Med Rep 2021; 23:215. [PMID: 33495841 PMCID: PMC7845586 DOI: 10.3892/mmr.2021.11854] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023] Open
Abstract
Allisartan isoproxil is a new nonpeptide angiotensin II receptor blocker (ARB) precursor drug that is used to treat hypertension and reduce the risk of heart disease. The present study explored the effects of allisartan isoproxil on diabetic cardiomyopathy (DCM) and revealed the roles of hyperglycaemia-induced oxidative stress and inflammation. A rat DCM model was established by high-fat diet feeding in combination with intraperitoneal injection of streptozocin. Echocardiographs showed that diabetic rats exhibited significantly decreased cardiac function. Troponin T (cTnT) and B-type natriuretic peptide (BNP) were significantly increased in DCM rats as obtained by ELISA. Allisartan isoproxil significantly improved the EF% and E™/A™ ratio. Histopathologic staining showed that allisartan isoproxil prevented histological alterations, attenuated the accumulation of collagen, and ameliorated cTnT and BNP levels. Western blot and immunohistochemical results indicated that the expression levels of silent information regulator 2 homologue 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (Nrf2) were decreased in the hearts of diabetic rats, and antioxidant defences were also decreased. In addition, allisartan isoproxil decreased the expression of NF-κB p65 and the inflammatory cytokines TNF-α and IL-1β which were determined by reverse transcription-quantitative PCR in the diabetic heart. Western blotting and TUNEL staining results also showed that cardiac Bax and cleaved caspase-3 and the number of apoptotic myocardial cells were increased in the diabetic heart and decreased following treatment with allisartan isoproxil. In conclusion, the present results indicated that allisartan isoproxil alleviated DCM by attenuating diabetes-induced oxidative stress and inflammation through the SIRT1/Nrf2/NF-κB signalling pathway.
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Affiliation(s)
- Qinyang Jin
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Qin Zhu
- Department of Nephrology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, P.R. China
| | - Kai Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Mengli Chen
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xinli Li
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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22
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Elia E, Ministrini S, Carbone F, Montecucco F. Diabetic cardiomyopathy and inflammation: development of hostile microenvironment resulting in cardiac damage. Minerva Cardiol Angiol 2021; 70:357-369. [PMID: 33427423 DOI: 10.23736/s2724-5683.20.05454-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Diabetes mellitus is emerging as a major risk factor for heart failure. Diabetic cardiomyopathy is defined as a myocardial dysfunction that is not caused by underlying hypertension or coronary artery disease. Studies about clinical features, natural history and outcomes of the disease are few and often conflicting, because a universally accepted operative definition of diabetic cardiomyopathy is still lacking. Hyperglycemia and related metabolic and endocrine disorders are the triggering factors of myocardial damage in diabetic cardiomyopathy through multiple mechanisms. Among these mechanisms, inflammation has a relevant role, similar to other chronic myocardial disease, such as hypertensive or ischemic heart disease. A balance between inflammatory damage and healing processes is fundamental for homeostasis of myocardial tissue, whereas diabetes mellitus produces an imbalance, promoting inflammation and delaying healing. Therefore, diabetes-related chronic inflammatory state can produce a progressive qualitative deterioration of myocardial tissue, which reflects on progressive left ventricular functional impairment, which can be either diastolic, with prevalent myocardial hypertrophy, or systolic, with prevalent myocardial fibrosis. The aim of this narrative review is to summarize the existing evidence about the role of inflammation in diabetic cardiomyopathy onset and development. Ultimately, potential pharmacological strategies targeting inflammatory response will be reviewed and discussed.
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Affiliation(s)
- Edoardo Elia
- Division of Cardiology, Department of Internal Medicine, Città della Salute e della Scienza, Turin, Italy
| | - Stefano Ministrini
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa - Italian Cardiovascular Network, Genoa, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy - .,IRCCS Ospedale Policlinico San Martino, Genoa - Italian Cardiovascular Network, Genoa, Italy
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23
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Kerby A, Shingleton D, Batra G, Sharps MC, Baker BC, Heazell AEP. Placental Morphology and Cellular Characteristics in Stillbirths in Women With Diabetes and Unexplained Stillbirths. Arch Pathol Lab Med 2021; 145:82-89. [PMID: 33367657 DOI: 10.5858/arpa.2019-0524-oa] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Women with diabetes have increased stillbirth risk. Although the underlying pathophysiological processes are poorly understood, stillbirth is frequently related to abnormal placental structure and function. OBJECTIVE.— To investigate placental morphology and cellular characteristics in the placentas of women with diabetes who had stillbirths and stillbirths of unexplained cause. DESIGN.— Placentas from women with uncomplicated live births, live births in women with diabetes, unexplained stillbirths, and stillbirths related to diabetes (n = 10/group) underwent clinical histopathologic assessment and were also investigated using immunohistochemical staining to quantify syncytial nuclear aggregates, proliferation, trophoblast area, vascularization, T cells, placental macrophages (Hofbauer cells), and the receptor for advanced glycation end products. RESULTS.— Ki67+ cells were decreased in unexplained stillbirths compared with live births in women with diabetes. Both stillbirth groups had increased cytokeratin 7+/nuclear area compared with controls. Blood vessels/villi were decreased in unexplained stillbirth compared with live births from women with diabetes. Compared with uncomplicated controls, CD163+ macrophages were increased in live births in women with diabetes and unexplained stillbirths, and further increased in stillbirths related to diabetes. There was no change in CD3+ T cells or syncytial nuclear aggregates. Receptor for advanced glycation end products-positive cells were decreased in both stillbirth groups compared with diabetes-related live births. Co-localization of receptor for advanced glycation end products in macrophages was increased in both stillbirth groups compared with live birth groups. CONCLUSIONS.— Stillbirths related to diabetes exhibit placental phenotypic differences compared with live births. Further investigation of these parameters may provide understanding of the pathologic mechanisms of stillbirth and aid the development of stillbirth prevention strategies.
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Affiliation(s)
- Alan Kerby
- From Tommy's Maternal and Fetal Health Research Centre, St. Mary's Hospital, Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom (Kerby, Baker, Heazell, Sharps)
| | | | - Gauri Batra
- The Department of Paediatric and Perinatal Pathology, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom (Batra)
| | - Megan C Sharps
- From Tommy's Maternal and Fetal Health Research Centre, St. Mary's Hospital, Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom (Kerby, Baker, Heazell, Sharps)
| | - Bernadette C Baker
- From Tommy's Maternal and Fetal Health Research Centre, St. Mary's Hospital, Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom (Kerby, Baker, Heazell, Sharps)
| | - Alexander E P Heazell
- From Tommy's Maternal and Fetal Health Research Centre, St. Mary's Hospital, Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom (Kerby, Baker, Heazell, Sharps).,The Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester, United Kingdom (Heazell)
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24
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Zellers JA, Eekhoff JD, Tang SY, Hastings MK, Lake SP. Clinical complications of tendon tissue mechanics due to collagen cross-linking in diabetes. THE SCIENCE, ETIOLOGY AND MECHANOBIOLOGY OF DIABETES AND ITS COMPLICATIONS 2021:201-226. [DOI: 10.1016/b978-0-12-821070-3.00009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Garay-Sevilla ME, Beeri MS, de la Maza MP, Rojas A, Salazar-Villanea S, Uribarri J. The potential role of dietary advanced glycation endproducts in the development of chronic non-infectious diseases: a narrative review. Nutr Res Rev 2020; 33:298-311. [PMID: 32238213 DOI: 10.1017/s0954422420000104] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Increasing clinical and experimental evidence accumulated during the past few decades supports an important role for dietary advanced glycation endproducts (AGE) in the pathogenesis of many chronic non-infectious diseases, such as type 2 diabetes, CVD and others, that are reaching epidemic proportions in the Western world. Although AGE are compounds widely recognised as generated in excess in the body in diabetic patients, the potential importance of exogenous AGE, mostly of dietary origin, has been largely ignored in the general nutrition audience. In the present review we aim to describe dietary AGE, their mechanisms of formation and absorption into the body as well as their main mechanisms of action. We will present in detail current evidence of their potential role in the development of several chronic non-infectious clinical conditions, some general suggestions on how to restrict them in the diet and evidence regarding the potential benefits of lowering their consumption.
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Affiliation(s)
- M E Garay-Sevilla
- Medical Science Department, University of Guanajuato, Guanajuato, Mexico
| | - M S Beeri
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat Gan, Israel
| | - M P de la Maza
- Institute of Nutrition and Food Technology Dr. Fernando Monckeberg Barros, University of Chile, Santiago, Chile
| | - A Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca, Chile
| | - S Salazar-Villanea
- Department of Animal Science, Universidad de Costa Rica, San Pedro Montes de Oca, San José, Costa Rica
| | - J Uribarri
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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26
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Yao H, Sun J, Wei J, Zhang X, Chen B, Lin Y. Kaempferol Protects Blood Vessels From Damage Induced by Oxidative Stress and Inflammation in Association With the Nrf2/HO-1 Signaling Pathway. Front Pharmacol 2020; 11:1118. [PMID: 32792954 PMCID: PMC7387620 DOI: 10.3389/fphar.2020.01118] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/09/2020] [Indexed: 12/12/2022] Open
Abstract
Over recent years, an increasing number of studies have confirmed that the occurrence and development of vascular pathological changes are closely related to oxidative stress and the inflammatory response of the vascular endothelium. Kaempferol is the most common flavonoid compound found in fruits and vegetables. Our present research identified that kaempferol had the capability to protect the vascular endothelium in a mouse model of vascular injury and explored the specific mechanisms underlying these effects by investigating oxidative stress, the extent of cardiovascular injury, and inflammatory markers such as NF-κB, TNF-α, IL-6, and the Nrf2/HO-1 signaling pathway. Analysis showed that kaempferol reduced oxidative stress and inflammation mediated by H2O2 and paraquat, respectively, both in vitro and in vivo. Furthermore, kaempferol suppressed the levels of TNF-α and IL-6, and the activation of NF-κB, in aortic tissues and human umbilical vein endothelial cells (HUVECs). Finally, we observed that kaempferol corrected the levels of antioxidants and elevated the protein levels of Nrf2 and HO-1 in aortic tissues and HUVECs. Collectively, our findings prove that kaempferol protects blood vessels from damage induced by oxidative stress and inflammation and that the Nrf2/HO-1 signaling pathway plays a key role in mediating these effects.
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Affiliation(s)
- He Yao
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Jingyu Sun
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Jie Wei
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Xin Zhang
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Bing Chen
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yajun Lin
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China.,The Key Laboratory of Geriatrics, Peking University Fifth School of Clinical Medicine, Beijing, China
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27
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Rojas A, Gonzalez I, Morales MA. SARS-CoV-2-mediated inflammatory response in lungs: should we look at RAGE? Inflamm Res 2020; 69:641-643. [PMID: 32372149 PMCID: PMC7200049 DOI: 10.1007/s00011-020-01353-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 04/21/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile.
| | - Ileana Gonzalez
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Miguel A Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
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28
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Six I, Flissi N, Lenglet G, Louvet L, Kamel S, Gallet M, Massy ZA, Liabeuf S. Uremic Toxins and Vascular Dysfunction. Toxins (Basel) 2020; 12:toxins12060404. [PMID: 32570781 PMCID: PMC7354618 DOI: 10.3390/toxins12060404] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/15/2020] [Accepted: 06/17/2020] [Indexed: 02/07/2023] Open
Abstract
Vascular dysfunction is an essential element found in many cardiovascular pathologies and in pathologies that have a cardiovascular impact such as chronic kidney disease (CKD). Alteration of vasomotricity is due to an imbalance between the production of relaxing and contracting factors. In addition to becoming a determining factor in pathophysiological alterations, vascular dysfunction constitutes the first step in the development of atherosclerosis plaques or vascular calcifications. In patients with CKD, alteration of vasomotricity tends to emerge as being a new, less conventional, risk factor. CKD is characterized by the accumulation of uremic toxins (UTs) such as phosphate, para-cresyl sulfate, indoxyl sulfate, and FGF23 and, consequently, the deleterious role of UTs on vascular dysfunction has been explored. This accumulation of UTs is associated with systemic alterations including inflammation, oxidative stress, and the decrease of nitric oxide production. The present review proposes to summarize our current knowledge of the mechanisms by which UTs induce vascular dysfunction.
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Affiliation(s)
- Isabelle Six
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
- Correspondence: ; Tel./Fax: +03-22-82-54-25
| | - Nadia Flissi
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
| | - Gaëlle Lenglet
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
| | - Loïc Louvet
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
| | - Said Kamel
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
- Amiens-Picardie University Hospital, Human Biology Center, 80054 Amiens, France
| | - Marlène Gallet
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
| | - Ziad A. Massy
- Service de Néphrologie et Dialyse, Assistance Publique—Hôpitaux de Paris (APHP), Hôpital Universitaire Ambroise Paré, 92100 Boulogne Billancourt, France;
- INSERM U1018, Equipe 5, CESP (Centre de Recherche en Épidémiologie et Santé des Populations), Université Paris Saclay et Université Versailles Saint Quentin en Yvelines, 94800 Villejuif, France
| | - Sophie Liabeuf
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
- Pharmacology Department, Amiens University Hospital, 80025 Amiens, France
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29
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Torres-Gomez A, Cabañas C, Lafuente EM. Phagocytic Integrins: Activation and Signaling. Front Immunol 2020; 11:738. [PMID: 32425937 PMCID: PMC7203660 DOI: 10.3389/fimmu.2020.00738] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 03/31/2020] [Indexed: 01/06/2023] Open
Abstract
Phagocytic integrins are endowed with the ability to engulf and dispose of particles of different natures. Evolutionarily conserved from worms to humans, they are involved in pathogen elimination and apoptotic and tumoral cell clearance. Research in the field of integrin-mediated phagocytosis has shed light on the molecular events controlling integrin activation and their effector functions. However, there are still some aspects of the regulation of the phagocytic process that need to be clarified. Here, we have revised the molecular events controlling phagocytic integrin activation and the downstream signaling driving particle engulfment, and we have focused particularly on αMβ2/CR3, αXβ2/CR4, and a brief mention of αVβ5/αVβ3integrins.
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Affiliation(s)
- Alvaro Torres-Gomez
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.,Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Carlos Cabañas
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.,Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain.,Severo Ochoa Center for Molecular Biology (CSIC-UAM), Madrid, Spain
| | - Esther M Lafuente
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.,Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain
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30
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González I, Morales MA, Rojas A. Polyphenols and AGEs/RAGE axis. Trends and challenges. Food Res Int 2020; 129:108843. [PMID: 32036875 DOI: 10.1016/j.foodres.2019.108843] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 11/07/2019] [Accepted: 11/18/2019] [Indexed: 02/07/2023]
Abstract
The formation of advanced glycation end-products (AGEs) is a key pathophysiological event linked not only to the onset and progression of diabetic complications, but also to neurodegeneration, cardiovascular diseases, cancer, and others important human diseases. AGEs contributions to pathophysiology are mainly through the formation of cross-links and by engaging the receptor for advanced glycation end-products (RAGE). Polyphenols are secondary metabolites found largely in fruits, vegetables, cereals, and beverages, and during many years, important efforts have been made to elucidate their beneficial effects on human health, mainly ascribed to their antioxidant activities. In the present review, we highlighted the beneficial actions of polyphenols aimed to diminish the harmful consequences of advanced glycation, mainly by the inhibition of ROS formation during glycation, the inhibition of Schiff base, Amadori products, and subsequent dicarbonyls group formation, the activation of the glyoxalase system, as well as by blocking either AGEs-RAGE interaction or cell signaling.
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Affiliation(s)
- Ileana González
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Miguel A Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chil
| | - Armando Rojas
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile.
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31
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Leonova T, Popova V, Tsarev A, Henning C, Antonova K, Rogovskaya N, Vikhnina M, Baldensperger T, Soboleva A, Dinastia E, Dorn M, Shiroglasova O, Grishina T, Balcke GU, Ihling C, Smolikova G, Medvedev S, Zhukov VA, Babakov V, Tikhonovich IA, Glomb MA, Bilova T, Frolov A. Does Protein Glycation Impact on the Drought-Related Changes in Metabolism and Nutritional Properties of Mature Pea ( Pisum sativum L.) Seeds? Int J Mol Sci 2020; 21:E567. [PMID: 31952342 PMCID: PMC7013545 DOI: 10.3390/ijms21020567] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 01/01/2020] [Accepted: 01/03/2020] [Indexed: 12/24/2022] Open
Abstract
Protein glycation is usually referred to as an array of non-enzymatic post-translational modifications formed by reducing sugars and carbonyl products of their degradation. The resulting advanced glycation end products (AGEs) represent a heterogeneous group of covalent adducts, known for their pro-inflammatory effects in mammals, and impacting on pathogenesis of metabolic diseases and ageing. In plants, AGEs are the markers of tissue ageing and response to environmental stressors, the most prominent of which is drought. Although water deficit enhances protein glycation in leaves, its effect on seed glycation profiles is still unknown. Moreover, the effect of drought on biological activities of seed protein in mammalian systems is still unstudied with respect to glycation. Therefore, here we address the effects of a short-term drought on the patterns of seed protein-bound AGEs and accompanying alterations in pro-inflammatory properties of seed protein in the context of seed metabolome dynamics. A short-term drought, simulated as polyethylene glycol-induced osmotic stress and applied at the stage of seed filling, resulted in the dramatic suppression of primary seed metabolism, although the secondary metabolome was minimally affected. This was accompanied with significant suppression of NF-kB activation in human SH-SY5Y neuroblastoma cells after a treatment with protein hydrolyzates, isolated from the mature seeds of drought-treated plants. This effect could not be attributed to formation of known AGEs. Most likely, the prospective anti-inflammatory effect of short-term drought is related to antioxidant effect of unknown secondary metabolite protein adducts, or down-regulation of unknown plant-specific AGEs due to suppression of energy metabolism during seed filling.
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Affiliation(s)
- Tatiana Leonova
- Department of Biochemistry, St. Petersburg State University, 199004 St. Petersburg, Russia
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
| | - Veronika Popova
- Department of Biochemistry, St. Petersburg State University, 199004 St. Petersburg, Russia
- Department of Plant Physiology and Biochemistry, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Alexander Tsarev
- Department of Biochemistry, St. Petersburg State University, 199004 St. Petersburg, Russia
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
| | - Christian Henning
- Institute of Chemistry - Food Chemistry, Martin-Luther University Halle-Wittenberg, 06120 Halle, Germany
| | - Kristina Antonova
- Department of Biochemistry, St. Petersburg State University, 199004 St. Petersburg, Russia
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
| | - Nadezhda Rogovskaya
- Research Institute of Hygiene, Occupational Pathology and Human Ecology, 188663 Leningrad Oblast, Russia
| | - Maria Vikhnina
- Department of Biochemistry, St. Petersburg State University, 199004 St. Petersburg, Russia
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
| | - Tim Baldensperger
- Institute of Chemistry - Food Chemistry, Martin-Luther University Halle-Wittenberg, 06120 Halle, Germany
| | - Alena Soboleva
- Department of Biochemistry, St. Petersburg State University, 199004 St. Petersburg, Russia
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
| | - Ekaterina Dinastia
- Department of Biochemistry, St. Petersburg State University, 199004 St. Petersburg, Russia
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
- Postovsky Institute of Organic Synthesis of Ural Division of Russian Academy of Sciences, 620137 Yekaterinburg, Russia
| | - Mandy Dorn
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
| | - Olga Shiroglasova
- Department of Plant Physiology and Biochemistry, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Tatiana Grishina
- Department of Biochemistry, St. Petersburg State University, 199004 St. Petersburg, Russia
| | - Gerd U Balcke
- Department of Metabolic and Cell Biology, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
| | - Christian Ihling
- Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, 06120 Halle, Germany
| | - Galina Smolikova
- Department of Plant Physiology and Biochemistry, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Sergei Medvedev
- Department of Plant Physiology and Biochemistry, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Vladimir A Zhukov
- All-Russia Research Institute for Agricultural Microbiology, 196608 St. Petersburg, Russia
| | - Vladimir Babakov
- Research Institute of Hygiene, Occupational Pathology and Human Ecology, 188663 Leningrad Oblast, Russia
| | - Igor A Tikhonovich
- All-Russia Research Institute for Agricultural Microbiology, 196608 St. Petersburg, Russia
- Department of Genetics and Biotechnology, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Marcus A Glomb
- Institute of Chemistry - Food Chemistry, Martin-Luther University Halle-Wittenberg, 06120 Halle, Germany
| | - Tatiana Bilova
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
- Department of Plant Physiology and Biochemistry, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Andrej Frolov
- Department of Biochemistry, St. Petersburg State University, 199004 St. Petersburg, Russia
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
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32
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Schröter D, Höhn A. Role of Advanced Glycation End Products in Carcinogenesis and their Therapeutic Implications. Curr Pharm Des 2019; 24:5245-5251. [PMID: 30706806 PMCID: PMC6635609 DOI: 10.2174/1381612825666190130145549] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/24/2019] [Indexed: 01/09/2023]
Abstract
Aging is one of the biggest risk factors for the major prevalent diseases such as cardiovascular diseases, neurodegeneration and cancer, but due to the complex and multifactorial nature of the aging process, the molecular mechanisms underlying age-related diseases are not yet fully understood. Research has been intensive in the last years aiming to characterize the pathophysiology of aging and develop therapies to fight age-related diseases. In this context advanced glycation end products (AGEs) have received attention. AGEs, when accumulated in tissues, significantly increase the level of inflammation in the body which has long been associated with the development of cancer. Here we discuss the classical settings promoting AGE formation, as well as reduction strategies, occurrence and relevance of AGEs in cancer tissues and the role of AGE-interaction with the receptor for advanced glycation end products (RAGE) in cancer initiation and progression.
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Affiliation(s)
- David Schröter
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany.,Leibniz Institute of Vegetable and Ornamental Crops Grossbeeren e.V. (IGZ), 14979 Grossbeeren.,Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, 20146 Hamburg, Germany
| | - Annika Höhn
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany.,German Center for Diabetes Research (DZD), 85764 Muenchen-Neuherberg, German
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Hajizadeh-Sharafabad F, Sahebkar A, Zabetian-Targhi F, Maleki V. The impact of resveratrol on toxicity and related complications of advanced glycation end products: A systematic review. Biofactors 2019; 45:651-665. [PMID: 31185146 DOI: 10.1002/biof.1531] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 05/17/2019] [Indexed: 12/12/2022]
Abstract
Accumulation of advanced glycation end products (AGEs) promotes the generation of free radicals, which leads to chronic oxidative stress predisposing to chronic oxidative stress, inflammation, and related diseases. This systematic review aimed to determine the effect of resveratrol (RSV) on AGE-induced toxicity and its deleterious consequences. A comprehensive search was performed through literature were published until December 2018 using relevant keywords. The databases that were used for the search were PubMed, Scopus, Embase, ProQuest, and Google Scholar. A total of 29 eligible studies were found and included in the review for the analysis. Except one, all studies showed suppressing effects for RSV on the production of AGEs or receptor for advanced glycation end products (RAGE) and its detrimental consequences including oxidative stress, inflammatory response, cellular immune reactions, insulin response, and atherosclerosis. RSV exerts its effects through influencing RAGE, nuclear factor kappa B (NF-κB), peroxisome proliferator-activated receptor (PPAR) γ, and transforming growth factor (TGF)-β activities. This review suggests that RSV has got potential to decrease AGEs toxicity and inhibit the AGE-induced complications. More clinical trials are suggested to evaluate the beneficial effect of RSV on AGEs in chronic metabolic diseases.
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MESH Headings
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/metabolism
- Antioxidants/pharmacology
- Atherosclerosis/drug therapy
- Atherosclerosis/genetics
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Gene Expression Regulation
- Glycation End Products, Advanced/antagonists & inhibitors
- Glycation End Products, Advanced/genetics
- Glycation End Products, Advanced/metabolism
- Glycation End Products, Advanced/toxicity
- Humans
- Inflammation
- Mitogen-Activated Protein Kinases/genetics
- Mitogen-Activated Protein Kinases/metabolism
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Oxidative Stress
- PPAR gamma/genetics
- PPAR gamma/metabolism
- Pyruvaldehyde/metabolism
- Resveratrol/pharmacology
- Signal Transduction
- Transforming Growth Factor beta1/genetics
- Transforming Growth Factor beta1/metabolism
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Affiliation(s)
- Fatemeh Hajizadeh-Sharafabad
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fateme Zabetian-Targhi
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - Vahid Maleki
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
- Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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34
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Eichhorst A, Daniel C, Rzepka R, Sehnert B, Nimmerjahn F, Voll RE, Chevalier N. Relevance of Receptor for Advanced Glycation end Products (RAGE) in Murine Antibody-Mediated Autoimmune Diseases. Int J Mol Sci 2019; 20:ijms20133234. [PMID: 31266174 PMCID: PMC6651235 DOI: 10.3390/ijms20133234] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/24/2022] Open
Abstract
It is incompletely understood how self-antigens become targets of humoral immunity in antibody-mediated autoimmune diseases. In this context, alarmins are discussed as an important level of regulation. Alarmins are recognized by various receptors, such as receptor for advanced glycation end products (RAGE). As RAGE is upregulated under inflammatory conditions, strongly binds nucleic acids and mediates pro-inflammatory responses upon alarmin recognition, our aim was to examine its contribution to immune complex-mediated autoimmune diseases. This question was addressed employing RAGE−/− animals in murine models of pristane-induced lupus, collagen-induced, and serum-transfer arthritis. Autoantibodies were assessed by enzyme-linked immunosorbent assay, renal disease by quantification of proteinuria and histology, arthritis by scoring joint inflammation. The associated immune status was determined by flow cytometry. In both disease entities, we detected tendentiously decreased autoantibody levels in RAGE−/− mice, however no differences in clinical outcome. In accordance with autoantibody levels, a subgroup of the RAGE−/− animals showed a decrease in plasma cells, and germinal center B cells and an increase in follicular B cells. Based on our results, we suggest that RAGE deficiency alone does not significantly affect antibody-mediated autoimmunity. RAGE may rather exert its effects along with other receptors linking environmental factors to auto-reactive immune responses.
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Affiliation(s)
- Alexandra Eichhorst
- Department of Rheumatology and Clinical Immunology, Medical Centre-University of Freiburg, Faculty of Medicine, 79106 Freiburg, Baden-Wuerttemberg, Germany
| | - Christoph Daniel
- Department of Nephropathology, Friedrich-Alexander University (FAU) of Erlangen-Nuremberg, 91054 Erlangen, Bavaria, Germany
| | - Rita Rzepka
- Department of Rheumatology and Clinical Immunology, Medical Centre-University of Freiburg, Faculty of Medicine, 79106 Freiburg, Baden-Wuerttemberg, Germany
| | - Bettina Sehnert
- Department of Rheumatology and Clinical Immunology, Medical Centre-University of Freiburg, Faculty of Medicine, 79106 Freiburg, Baden-Wuerttemberg, Germany
| | - Falk Nimmerjahn
- Department of Biology, Friedrich-Alexander University (FAU) of Erlangen-Nuremberg, 91058 Erlangen, Bavaria, Germany
| | - Reinhard E Voll
- Department of Rheumatology and Clinical Immunology, Medical Centre-University of Freiburg, Faculty of Medicine, 79106 Freiburg, Baden-Wuerttemberg, Germany
| | - Nina Chevalier
- Department of Rheumatology and Clinical Immunology, Medical Centre-University of Freiburg, Faculty of Medicine, 79106 Freiburg, Baden-Wuerttemberg, Germany.
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35
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Zhang W, Zhao T, Zhao Y, Gui D, Xu Y. Advanced Glycation End Products in Chinese Medicine Mediated Aging Diseases: A Review. Curr Vasc Pharmacol 2019; 18:322-333. [PMID: 31060489 DOI: 10.2174/1570161117666190507112157] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 04/11/2019] [Accepted: 04/12/2019] [Indexed: 12/25/2022]
Abstract
Aging has become a worldwide problem. During this process, the incidence of related diseases such as diabetes and atherosclerosis increases dramatically. Studies within the most recent two decades suggest a pivotal role of Advanced Glycation End Products (AGEs) in the aging process. This review aims to systemically summarize the effects and potential mechanism of Chinese Medicines on inhibiting AGEs-related aging diseases.
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Affiliation(s)
- Wenqian Zhang
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao SAR, China
| | - Tingting Zhao
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao SAR, China
| | - Yonghua Zhao
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao SAR, China.,Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, Macao SAR, China
| | - Dingkun Gui
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Youhua Xu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao SAR, China
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36
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Rojas A, Morales M, Gonzalez I, Araya P. Inhibition of RAGE Axis Signaling: A Pharmacological Challenge. Curr Drug Targets 2019; 20:340-346. [PMID: 30124149 DOI: 10.2174/1389450119666180820105956] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 06/18/2018] [Accepted: 08/16/2018] [Indexed: 02/07/2023]
Abstract
The Receptor for Advanced Glycation End Products (RAGE) is an important cell surface receptor, which belongs to the IgG super family and is now considered as a pattern recognition receptor. Because of its relevance in many human clinical settings, it is now pursued as a very attractive therapeutic target. However, particular features of this receptor such as a wide repertoire of ligands with different binding domains, the existence of many RAGE variants as well as the presence of cytoplasmatic adaptors leading a diverse signaling, are important limitations in the search for successful pharmacological approaches to inhibit RAGE signaling. Therefore, the present review aimed to display the most promising approaches to inhibit RAGE signaling, and provide an up to date review of progress in this area.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Miguel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
| | - Ileana Gonzalez
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Paulina Araya
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca, Chile
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37
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Yadav SK, Kambis TN, Mishra PK. Regulating Inflammatory Cytokines in the Diabetic Heart. OXIDATIVE STRESS IN HEART DISEASES 2019:427-436. [DOI: 10.1007/978-981-13-8273-4_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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38
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Vorup-Jensen T, Jensen RK. Structural Immunology of Complement Receptors 3 and 4. Front Immunol 2018; 9:2716. [PMID: 30534123 PMCID: PMC6275225 DOI: 10.3389/fimmu.2018.02716] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 11/05/2018] [Indexed: 01/10/2023] Open
Abstract
Complement receptors (CR) 3 and 4 belong to the family of beta-2 (CD18) integrins. CR3 and CR4 are often co-expressed in the myeloid subsets of leukocytes, but they are also found in NK cells and activated T and B lymphocytes. The heterodimeric ectodomain undergoes considerable conformational change in order to switch the receptor from a structurally bent, ligand-binding in-active state into an extended, ligand-binding active state. CR3 binds the C3d fragment of C3 in a way permitting CR2 also to bind concomitantly. This enables a hand-over of complement-opsonized antigens from the cell surface of CR3-expressing macrophages to the CR2-expressing B lymphocytes, in consequence acting as an antigen presentation mechanism. As a more enigmatic part of their functions, both CR3 and CR4 bind several structurally unrelated proteins, engineered peptides, and glycosaminoglycans. No consensus motif in the proteinaceous ligands has been established. Yet, the experimental evidence clearly suggest that the ligands are primarily, if not entirely, recognized by a single site within the receptors, namely the metal-ion dependent adhesion site (MIDAS). Comparison of some recent identified ligands points to CR3 as inclined to bind positively charged species, while CR4, by contrast, binds strongly negative-charged species, in both cases with the critical involvement of deprotonated, acidic groups as ligands for the Mg2+ ion in the MIDAS. These properties place CR3 and CR4 firmly within the realm of modern molecular medicine in several ways. The expression of CR3 and CR4 in NK cells was recently demonstrated to enable complement-dependent cell cytotoxicity toward antibody-coated cancer cells as part of biological therapy, constituting a significant part of the efficacy of such treatment. With the flexible principles of ligand recognition, it is also possible to propose a response of CR3 and CR4 to existing medicines thereby opening a possibility of drug repurposing to influence the function of these receptors. Here, from advances in the structural and cellular immunology of CR3 and CR4, we review insights on their biochemistry and functions in the immune system.
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Affiliation(s)
- Thomas Vorup-Jensen
- Biophysical Immunology Laboratory, Department of Biomedicine, Aarhus University, Aarhus, Denmark.,Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark
| | - Rasmus Kjeldsen Jensen
- Department of Molecular Biology and Genetics-Structural Biology, Aarhus University, Aarhus, Denmark
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ROJAS A, GONZÁLEZ I, ARAYA P. RAGE in Cancer Lung: the End of a Long and Winding Road is in Sight. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2018; 21:655-657. [PMID: 30201062 PMCID: PMC6136999 DOI: 10.3779/j.issn.1009-3419.2018.09.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Armando ROJAS
- Armando Rojas, E-mail:
| | - Ileana GONZÁLEZ
| | - Paulina ARAYA
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40
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Wu Y, Su SA, Xie Y, Shen J, Zhu W, Xiang M. Murine models of vascular endothelial injury: Techniques and pathophysiology. Thromb Res 2018; 169:64-72. [PMID: 30015230 DOI: 10.1016/j.thromres.2018.07.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 06/08/2018] [Accepted: 07/08/2018] [Indexed: 12/13/2022]
Abstract
Vascular endothelial injury (VEI) triggers pathological processes in various cardiovascular diseases, such as coronary heart disease and hypertension. To further elucidate the in vivo pathological mechanisms of VEI, many animal models have been established. For the easiness of genetic manipulation and feeding, murine models become most commonly applied for investigating VEI. Subsequently, countless valuable information concerning pathogenesis has been obtained and therapeutic strategies for VEI have been developed. This review will highlight some typical murine VEI models from the perspectives of pharmacological intervention, surgery and genetic manipulation. The techniques, pathophysiology, advantages, disadvantages and the experimental purpose of each model will also be discussed.
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Affiliation(s)
- Yue Wu
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China
| | - Sheng-An Su
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China
| | - Yao Xie
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China
| | - Jian Shen
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China
| | - Wei Zhu
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China.
| | - Meixiang Xiang
- Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou 310009, Zhejiang Province, China.
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41
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Rojas A, Añazco C, González I, Araya P. Extracellular matrix glycation and receptor for advanced glycation end-products activation: a missing piece in the puzzle of the association between diabetes and cancer. Carcinogenesis 2018; 39:515-521. [PMID: 29373651 DOI: 10.1093/carcin/bgy012] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 01/22/2018] [Indexed: 02/07/2023] Open
Abstract
A growing body of epidemiologic evidence suggests that people with diabetes are at a significantly higher risk of many forms of cancer. However, the molecular mechanisms underlying this association are not fully understood. Cancer cells are surrounded by a complex milieu, also known as tumor microenvironment, which contributes to the development and metastasis of tumors. Of note, one of the major components of this niche is the extracellular matrix (ECM), which becomes highly disorganized during neoplastic progression, thereby stimulating cancer cell transformation, growth and spread. One of the consequences of chronic hyperglycemia, the most frequently observed sign of diabetes and the etiological source of diabetes complications, is the irreversible glycation and oxidation of proteins and lipids leading to the formation of the advanced glycation end-products (AGEs). These compounds may covalently crosslink and biochemically modify structure and functions of many proteins, and AGEs accumulation is particularly high in long-living proteins with low biological turnover, features that are shared by most, if not all, ECM proteins. AGEs-modified proteins are recognized by AGE-binding proteins, and thus glycated ECM components have the potential to trigger Receptor for advanced glycation end-products-dependent mechanisms. The biological consequence of receptor for advanced glycation end-products activation mechanisms seems to be connected, in different ways, to drive some hallmarks of cancer onset and tumor growth. The present review intends to highlight the potential impact of ECM glycation on tumor progression by triggering receptor for advanced glycation end-products-mediated mechanisms.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Preclinical Sciences Department, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Carolina Añazco
- Biomedical Research Laboratories, Preclinical Sciences Department, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Ileana González
- Biomedical Research Laboratories, Preclinical Sciences Department, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Paulina Araya
- Biomedical Research Laboratories, Preclinical Sciences Department, Medicine Faculty, Catholic University of Maule, Talca, Chile
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42
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Chen X, Qian J, Wang L, Li J, Zhao Y, Han J, Khan Z, Chen X, Wang J, Liang G. Kaempferol attenuates hyperglycemia-induced cardiac injuries by inhibiting inflammatory responses and oxidative stress. Endocrine 2018; 60:83-94. [PMID: 29392616 DOI: 10.1007/s12020-018-1525-4] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 01/09/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE Suppression of inflammation and oxidative stress is an attractive strategy to against diabetic cardiomyopathy (DCM). Kaempferol (KPF) exerts both anti-inflammatory and antioxidant pharmacological properties. However, little is known about the effect of KPF on protecting myocardial injury in diabetes. The present study aimed to investigate the effect of KPF on DCM and underlying mechanism. METHODS Anti-inflammation and anti-oxidative stress activities of KPF were evaluated in H9c2 cells or primary cardiomyocytes by real-time quantitate PCR, immunoblotting, immunofluorescence, ELISA, and FACS. Streptozotocin (STZ)-induced type 1 diabetes mellitus mice were constructed. Corresponding to experiments in vitro, the therapeutic effect of KPF was also assessed using heart tissues from mice. RESULTS KPF significantly inhibited high glocose (HG) induced expression of inflammatory cytokines and generation of ROS, leading to reduced fibrotic responses and cell apoptosis in vitro. KPF mediated DCM protective effects through inhibiting nuclear factor-κB (NF-κB) nucleus translocation and activating nuclear factor-erythroid 2 p45-related factor-2 (Nrf-2). In STZ-induced type 1 diabetic mouse model, KPF prevented diabetes-induced cardiac fibrosis and apoptosis. These changes were also accompanied by reducing inflammation and oxidative stress in diabetic mice hearts. CONCLUSION KPF is a potential therapeutic agent for the treatment of DCM, mechanically linked to inhibition of NF-κB and Nrf-2 activation.
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Affiliation(s)
- Xuemei Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China
| | - Jianchang Qian
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China
| | - Lintao Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China
| | - Jieli Li
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China
| | - Yunjie Zhao
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China
| | - Jibo Han
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China
- Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China
| | - Zia Khan
- Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A5C1, Canada
| | - Xiaojun Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China
| | - Jingying Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China.
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China.
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Espinosa-Zurutuza M, González-Villalva A, Albarrán-Alonso JC, Colín-Barenque L, Bizarro-Nevares P, Rojas-Lemus M, López-Valdéz N, Fortoul TI. Oxidative Stress as a Mechanism Involved in Kidney Damage After Subchronic Exposure to Vanadium Inhalation and Oral Sweetened Beverages in a Mouse Model. Int J Toxicol 2017; 37:45-52. [PMID: 29254395 DOI: 10.1177/1091581817745504] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Kidney diseases have notably increased in the last few years. This is partially explained by the increase in metabolic syndrome, diabetes, and systemic blood hypertension. However, there is a segment of the population that has neither of the previous risk factors, yet suffers kidney damage. Exposure to atmospheric pollutants has been suggested as a possible risk factor. Air-suspended particles carry on their surface a variety of fuel combustion-related residues such as metals, and vanadium is one of these. Vanadium might produce oxidative stress resulting in the damage of some organs such as the kidney. Additionally, in countries like Mexico, the ingestion of sweetened beverages is a major issue; whether these beverages alone are responsible for direct kidney damage or whether their ingestion promotes the progression of an existing renal damage generates controversy. In this study, we report the combined effect of vanadium inhalation and sweetened beverages ingestion in a mouse model. Forty CD-1 male mice were distributed in 4 groups: control, vanadium inhalation, 30% sucrose in drinking water, and vanadium inhalation plus sucrose 30% in drinking water. Our results support that vanadium inhalation and the ingestion of 30% sucrose induce functional and histological kidney damage and an increase in oxidative stress biomarkers, which were higher in the combined effect of vanadium plus 30% sucrose. The results also support that the ingestion of 30% sucrose alone without hyperglycemia also produces kidney damage.
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Affiliation(s)
- Maribel Espinosa-Zurutuza
- 1 Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico
| | - Adriana González-Villalva
- 1 Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico
| | - Juan Carlos Albarrán-Alonso
- 1 Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico
| | | | - Patricia Bizarro-Nevares
- 1 Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico
| | - Marcela Rojas-Lemus
- 1 Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico
| | - Nelly López-Valdéz
- 1 Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico
| | - Teresa I Fortoul
- 1 Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico
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Frati G, Schirone L, Chimenti I, Yee D, Biondi-Zoccai G, Volpe M, Sciarretta S. An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy. Cardiovasc Res 2017; 113:378-388. [PMID: 28395009 DOI: 10.1093/cvr/cvx011] [Citation(s) in RCA: 176] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 01/20/2017] [Indexed: 02/05/2023] Open
Abstract
Heart failure is a highly morbid and mortal clinical condition that represents the last stage of most cardiovascular disorders. Diabetes is strongly associated with an increased incidence of heart failure and directly promotes cardiac hypertrophy, fibrosis, and apoptosis. These changes, in turn, contribute to the development of ventricular dysfunction. The clinical condition associated with the spectrum of cardiac abnormalities induced by diabetes is termed diabetic cardiomyopathy. Myocardial inflammation has recently emerged as a pathophysiological process contributing to cardiac hypertrophy, fibrosis, and dysfunction in cardiac diseases. Myocardial inflammation is also implicated in the development of diabetic cardiomyopathy. Several molecular mechanisms link diabetes to myocardial inflammation. The NF-κB signalling pathway and the renin-angiotensin-aldosterone system are strongly activated in the diabetic heart, thereby promoting myocardial inflammation. Advanced glycation end-products and damage-associated molecular pattern molecules also represent strong triggers for inflammation. The mediators resulting from this inflammatory process modulate specific intracellular signalling mechanisms in cardiac cells that promote the development of diabetic cardiomyopathy. This review article will provide an overview of the signalling molecular mechanisms linking diabetic cardiomyopathy to myocardial inflammation.
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Affiliation(s)
- Giacomo Frati
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy.,Department of AngioCardioNeurology, IRCCS Neuromed, 86077 Pozzilli (IS), Italy
| | - Leonardo Schirone
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy
| | - Isotta Chimenti
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy
| | - Derek Yee
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Giuseppe Biondi-Zoccai
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy.,Department of AngioCardioNeurology, IRCCS Neuromed, 86077 Pozzilli (IS), Italy
| | - Massimo Volpe
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy.,Department of AngioCardioNeurology, IRCCS Neuromed, 86077 Pozzilli (IS), Italy
| | - Sebastiano Sciarretta
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy.,Department of AngioCardioNeurology, IRCCS Neuromed, 86077 Pozzilli (IS), Italy
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Sharma I, Tupe RS, Wallner AK, Kanwar YS. Contribution of myo-inositol oxygenase in AGE:RAGE-mediated renal tubulointerstitial injury in the context of diabetic nephropathy. Am J Physiol Renal Physiol 2017; 314:F107-F121. [PMID: 28931523 DOI: 10.1152/ajprenal.00434.2017] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Advanced glycation end products (AGEs) play a role in pathogenesis of diabetic nephropathy (DN). Myo-inositol oxygenase (MIOX) has been implicated in tubulointerstitial injury in the context of DN. We investigated the effect of AGEs on MIOX expression and delineated mechanisms that lead to tubulointerstitial injury. The status of MIOX, RAGE, and relevant cellular signaling pathways activated following AGE:RAGE interaction was examined in tubular cells and kidneys of AGE-BSA-treated mice. A solid-phase assay revealed an enhanced binding of RAGE with AGE-BSA, AGE-laminin, and AGE-collagen IV. The cells treated with AGE-BSA had increased MIOX activity/expression and promoter activity. This was associated with activation of various signaling kinases of phosphatidylinositol 3-kinase (PI3K)-AKT pathway and increased expression of NF-κB, transforming growth factor (TGF)-β, and fibronectin, which was negated with the treatment of MIOX/RAGE- small interfering (si) RNA. Concomitant with MIOX upregulation, there was an increased generation of reactive oxygen species (ROS), which could be abrogated with MIOX/RAGE- siRNA treatment. The kidneys of mice treated with AGE-BSA had significantly high urinary A/C ratio, upregulation of MIOX, RAGE and NF-κB, along with influx of monocytes into the tubulointerstitium, increased the expression of MCP-1, IL-6, and fibronectin and increased the generation of ROS. Such perturbations were abrogated with the concomitant treatment of inhibitors MIOX or RAGE (d-glucarate and FPS-ZM1). These studies support a role of AGE:RAGE interaction in the activation of PI3K-AKT pathway and upregulation of MIOX, with excessive generation of ROS, increased expression of NF-κB, inflammatory cytokines, TGF-β, and fibronectin. Collectively, these observations highlight the relevance of the biology of MIOX in the contribution toward tubulointerstitial injury in DN.
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Affiliation(s)
- Isha Sharma
- Departments of Pathology and Medicine, Northwestern University , Chicago, Illinois
| | - Rashmi S Tupe
- Biochemical Sciences Division, Rajiv Gandhi Institute of IT and Biotechnology, Bharati Vidyapeeth University , Pune , India
| | - Aryana K Wallner
- Departments of Pathology and Medicine, Northwestern University , Chicago, Illinois
| | - Yashpal S Kanwar
- Departments of Pathology and Medicine, Northwestern University , Chicago, Illinois
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Kulp JL, Cloudsdale IS, Kulp JL, Guarnieri F. Hot-spot identification on a broad class of proteins and RNA suggest unifying principles of molecular recognition. PLoS One 2017; 12:e0183327. [PMID: 28837642 PMCID: PMC5570288 DOI: 10.1371/journal.pone.0183327] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 08/02/2017] [Indexed: 01/03/2023] Open
Abstract
Chemically diverse fragments tend to collectively bind at localized sites on proteins, which is a cornerstone of fragment-based techniques. A central question is how general are these strategies for predicting a wide variety of molecular interactions such as small molecule-protein, protein-protein and protein-nucleic acid for both experimental and computational methods. To address this issue, we recently proposed three governing principles, (1) accurate prediction of fragment-macromolecule binding free energy, (2) accurate prediction of water-macromolecule binding free energy, and (3) locating sites on a macromolecule that have high affinity for a diversity of fragments and low affinity for water. To test the generality of these concepts we used the computational technique of Simulated Annealing of Chemical Potential to design one small fragment to break the RecA-RecA protein-protein interaction and three fragments that inhibit peptide-deformylase via water-mediated multi-body interactions. Experiments confirm the predictions that 6-hydroxydopamine potently inhibits RecA and that PDF inhibition quantitatively tracks the water-mediated binding predictions. Additionally, the principles correctly predict the essential bound waters in HIV Protease, the surprisingly extensive binding site of elastase, the pinpoint location of electron transfer in dihydrofolate reductase, the HIV TAT-TAR protein-RNA interactions, and the MDM2-MDM4 differential binding to p53. The experimental confirmations of highly non-obvious predictions combined with the precise characterization of a broad range of known phenomena lend strong support to the generality of fragment-based methods for characterizing molecular recognition.
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Affiliation(s)
- John L. Kulp
- Conifer Point Pharmaceuticals, Doylestown, Pennsylvania, United States of America
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, Pennsylvania, United States of America
| | - Ian S. Cloudsdale
- Conifer Point Pharmaceuticals, Doylestown, Pennsylvania, United States of America
| | - John L. Kulp
- Conifer Point Pharmaceuticals, Doylestown, Pennsylvania, United States of America
| | - Frank Guarnieri
- PAKA Pulmonary Pharmaceuticals, Acton, Massachusetts, United States of America
- * E-mail:
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47
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Luévano-Contreras C, Gómez-Ojeda A, Macías-Cervantes MH, Garay-Sevilla ME. Dietary Advanced Glycation End Products and Cardiometabolic Risk. Curr Diab Rep 2017; 17:63. [PMID: 28695383 DOI: 10.1007/s11892-017-0891-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW This report analyzes emerging evidence about the role of dietary advanced glycation end products (AGEs) as a cardiometabolic risk factor. Two important aspects are discussed: First, the modulation of AGE load by dietary AGEs; second, if the evidence of clinical and observational studies is enough to make dietary recommendations towards lowering AGE intake. RECENT FINDINGS Clinical studies in subjects with diabetes mellitus have shown that high intake of dietary AGEs increases inflammation markers, oxidative stress, and could impair endothelial function. In subjects at risk for cardiometabolic diseases (with overweight, obesity, or prediabetes), dietary AGE restriction decreases some inflammatory molecules and improves insulin sensitivity. However, studies in healthy subjects are limited, and not all of the studies have shown a decrease in circulating AGEs. Therefore, it is still unclear if dietary AGEs represent a health concern for people potentially at risk for cardiometabolic diseases. The evidence shows that dietary AGEs are bioavailable and absorbed, and the rate of excretion depends on dietary intake. The metabolic fate of most dietary AGEs remains unknown. Regardless, most studies have shown that by diminishing AGE intake, circulating levels will also decrease. Thus, dietary AGEs can modulate the AGE load at least in patients with DM, overweight, or obesity. Studies with specific clinical outcomes and large-scale observational studies are needed for a better risk assessment of dietary AGEs and to establish dietary recommendations accordingly.
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Affiliation(s)
- Claudia Luévano-Contreras
- Department of Medical Sciences, University of Guanajuato, 20 de Enero 929, León, Guanajuato, Mexico.
| | - Armando Gómez-Ojeda
- Department of Medical Sciences, University of Guanajuato, 20 de Enero 929, León, Guanajuato, Mexico
| | | | - Ma Eugenia Garay-Sevilla
- Department of Medical Sciences, University of Guanajuato, 20 de Enero 929, León, Guanajuato, Mexico
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A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:3920195. [PMID: 28751931 PMCID: PMC5511646 DOI: 10.1155/2017/3920195] [Citation(s) in RCA: 276] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 05/30/2017] [Indexed: 02/07/2023]
Abstract
Pathological molecular mechanisms involved in myocardial remodeling contribute to alter the existing structure of the heart, leading to cardiac dysfunction. Among the complex signaling network that characterizes myocardial remodeling, the distinct processes are myocyte loss, cardiac hypertrophy, alteration of extracellular matrix homeostasis, fibrosis, defective autophagy, metabolic abnormalities, and mitochondrial dysfunction. Several pathophysiological stimuli, such as pressure and volume overload, trigger the remodeling cascade, a process that initially confers protection to the heart as a compensatory mechanism. Yet chronic inflammation after myocardial infarction also leads to cardiac remodeling that, when prolonged, leads to heart failure progression. Here, we review the molecular pathways involved in cardiac remodeling, with particular emphasis on those associated with myocardial infarction. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. We will also discuss data derived from gene therapy approaches for modulating key mediators of cardiac remodeling.
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Lopez-Moreno J, Quintana-Navarro GM, Camargo A, Jimenez-Lucena R, Delgado-Lista J, Marin C, Tinahones FJ, Striker GE, Roche HM, Perez-Martinez P, Lopez-Miranda J, Yubero-Serrano EM. Dietary fat quantity and quality modifies advanced glycation end products metabolism in patients with metabolic syndrome. Mol Nutr Food Res 2017; 61. [PMID: 28233454 DOI: 10.1002/mnfr.201601029] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 01/07/2017] [Accepted: 02/15/2017] [Indexed: 12/17/2022]
Abstract
SCOPE Advanced glycation end products (AGEs) increase in dysmetabolic conditions. Lifestyle, including diet, has shown be effective in preventing the development of metabolic syndrome (MetS). We investigated whether AGE metabolism is affected by diets with different fat quantity and quality in MetS patients. METHODS AND RESULTS A randomized, controlled trial assigned 75 MetS patients to one of four diets: high SFA (HSFA), high MUFA (HMUFA), and two low-fat, high-complex carbohydrate diets (LFHCC) supplemented with long-chain n-3 PUFA or placebo for 12-weeks each. Dietary and serum AGE [methylglyoxal (MG: lysine-MG-H1) and N-carboxymethyllysine] levels and gene expression related to AGE metabolism in peripheral blood mononuclear cells (AGER1, RAGE, GloxI, and Sirt1 mRNA) were determined. HMUFA diet reduced serum AGE (sAGE) and RAGE mRNA, increased AGER1 and GloxI mRNA levels compared to the other diets. LFHCC n-3 diet reduced sAGE levels and increased AGER1 mRNA levels compared to LFHCC and HSFA diets. Multiple regression analyses showed that sMG and AGER1 mRNA appeared as significant predictors of oxidative stress/inflammation-related parameters. CONCLUSIONS Low AGE content in HMUFA diet reduces sAGEs and modulates the gene expression related to AGE metabolism in MetS patients, which may be used as a therapeutic approach to reduce the incidence of MetS and related chronic diseases.
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Affiliation(s)
- Javier Lopez-Moreno
- Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain.,CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Gracia M Quintana-Navarro
- Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain.,CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Antonio Camargo
- Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain.,CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Rosa Jimenez-Lucena
- Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain.,CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Javier Delgado-Lista
- Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain.,CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Carmen Marin
- Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain.,CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Francisco J Tinahones
- CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain.,Biomedical Research Institute of Malaga (IBIMA), Virgen de la Victoria Hospital, University of Malaga, Malaga, Spain
| | - Gary E Striker
- Division of Experimental Diabetes and Aging, Department of Geriatrics, Divisions of Icahn School of Medicine at Mount Sinai, New York, USA
| | - Helen M Roche
- Nutrigenomics Research Group, UCD Conway Institute/UCD Institute of Food and Health, School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland
| | - Pablo Perez-Martinez
- Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain.,CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Jose Lopez-Miranda
- Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain.,CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Elena M Yubero-Serrano
- Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain.,CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
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50
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Song Y, Wang Y, Zhang Y, Geng W, Liu W, Gao Y, Li S, Wang K, Wu X, Kang L, Yang C. Advanced glycation end products regulate anabolic and catabolic activities via NLRP3-inflammasome activation in human nucleus pulposus cells. J Cell Mol Med 2017; 21:1373-1387. [PMID: 28224704 PMCID: PMC5487914 DOI: 10.1111/jcmm.13067] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 11/21/2016] [Indexed: 12/30/2022] Open
Abstract
Intervertebral disc degeneration is widely recognized as a cause of lower back pain, neurological dysfunction and other musculoskeletal disorders. The major inflammatory cytokine IL‐1β is associated with intervertebral disc degeneration; however, the molecular mechanisms that drive IL‐1β production in the intervertebral disc, especially in nucleus pulposus (NP) cells, are unknown. In some tissues, advanced glycation end products (AGEs), which accumulate in NP tissues and promote its degeneration, increase oxidative stress and IL‐1β secretion, resulting in disorders, such as obesity, diabetes mellitus and ageing. It remains unclear whether AGEs exhibit similar effects in NP cells. In this study, we observed significant activation of the NLRP3 inflammasome in NP tissues obtained from patients with degenerative disc disease compared to that with idiopathic scoliosis according to results detected by Western blot and immunofluorescence. Using NP cells established from healthy tissues, our in vitro study revealed that AGEs induced an inflammatory response in NP cells and a degenerative phenotype in a NLRP3‐inflammasome‐dependent manner related to the receptor for AGEs (RAGE)/NF‐κB pathway and mitochondrial damage induced by mitochondrial reactive oxygen species (mtROS) generation, mitochondrial permeability transition pore (mPTP) activation and calcium mobilization. Among these signals, both RAGE and mitochondrial damage primed NLRP3 and pro‐IL‐1β activation as upstream signals of NF‐κB activity, whereas mitochondrial damage was critical for the assembly of inflammasome components. These results revealed that accumulation of AGEs in NP tissue may initiate inflammation‐related degeneration of the intervertebral disc via activation of the NLRP3 inflammasome.
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Affiliation(s)
- Yu Song
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Wang
- Department of Physical Education, China University of Geosciences, Wuhan, China
| | - Yukun Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wen Geng
- China Medical University, Shenyang, China
| | - Wei Liu
- Department of Orthopedics, First Hospital of Wuhan, Wuhan, China
| | - Yong Gao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Li
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Wang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinghuo Wu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liang Kang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cao Yang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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