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Wang R, Xu YX, Xu F, Wang CH, Zhao LH, Wang LH, Chen WG, Wang XQ, Duan CW, Su JB. Increased blood urea nitrogen levels and compromised peripheral nerve function in patients with type 2 diabetes. World J Diabetes 2025; 16:101966. [DOI: 10.4239/wjd.v16.i4.101966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 12/14/2024] [Accepted: 01/09/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Increased blood urea nitrogen (BUN) levels have been demonstrated to be associated with broader metabolic disturbances and the incidence of type 2 diabetes (T2D), potentially playing a role in the development of diabetic complications, including diabetic peripheral neuropathy.
AIM To examine the relationship between BUN levels and peripheral nerve function in patients with T2D.
METHODS This observational study involved the systematic recruitment of 585 patients with T2D for whom BUN levels and estimated glomerular filtration rate were measured. Electromyography was used to assess peripheral motor and sensory nerve function in all patients, and overall composite Z-scores were subsequently calculated for nerve latency, amplitude, and conduction velocity (NCV) across the median, ulnar, common peroneal, posterior tibial, superficial peroneal, and sural nerves.
RESULTS Across the quartiles of BUN levels, the overall composite Z-score for latency (F = 38.996, P for trend < 0.001) showed a significant increasing trend, whereas the overall composite Z-scores for amplitude (F = 50.972, P for trend < 0.001) and NCV (F = 30.636, P for trend < 0.001) exhibited a significant decreasing trend. Moreover, the BUN levels were closely correlated with the latency, amplitude, and NCV of each peripheral nerve. Furthermore, multivariate linear regression analysis revealed that elevated BUN levels were linked to a higher overall composite Z-score for latency (β = 0.166, t = 3.864, P < 0.001) and lower overall composite Z-scores for amplitude (β = -0.184, t = -4.577, P < 0.001) and NCV (β = -0.117, t = -2.787, P = 0.006) independent of the estimated glomerular filtration rate and other clinical covariates. Additionally, when the analysis was restricted to sensory or motor nerves, elevated BUN levels remained associated with sensory or motor peripheral nerve dysfunction.
CONCLUSION Increased BUN levels were independently associated with compromised peripheral nerve function in patients with T2D.
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Affiliation(s)
- Rui Wang
- Department of Endocrinology, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
| | - Yu-Xian Xu
- Department of Endocrinology, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
| | - Feng Xu
- Department of Endocrinology, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
| | - Chun-Hua Wang
- Department of Endocrinology, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
| | - Li-Hua Zhao
- Department of Endocrinology, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
| | - Li-Hua Wang
- Department of Nursing, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
| | - Wei-Guan Chen
- Department of Rehabilitation, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
| | - Xue-Qin Wang
- Department of Endocrinology, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
| | - Cheng-Wei Duan
- Medical Research Center, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
| | - Jian-Bin Su
- Department of Endocrinology, The Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong 226001, Jiangsu Province, China
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Schini-Kerth VB, Diouf I, Muzammel H, Said A, Auger C. Natural Products to Promote Vascular Health. Handb Exp Pharmacol 2025; 287:33-60. [PMID: 39317849 DOI: 10.1007/164_2024_721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
Maintaining good vascular health is a major component in healthy ageing as it reduces the risk of cardiovascular diseases. Endothelial dysfunction, in particular, is a key mechanism in the development of major cardiovascular diseases including hypertension, atherosclerosis and diabetes. Recently, endothelial senescence has emerged as a pivotal early event in age-related endothelial dysfunction. Endothelial function is characterized by an imbalance between the endothelial formation of vasoprotective mechanisms, including the formation of nitric oxide (NO) and endothelium-dependent hyperpolarization responses, and an increased level of oxidative stress involving several pro-oxidant enzymes such as NADPH oxidases and, often also, the appearance of cyclooxygenase-derived vasoconstrictors. Pre-clinical studies have indicated that natural products, in particular several polyphenol-rich foods, can trigger activating pathways in endothelial cells promoting an increased formation of NO and endothelium-dependent hyperpolarization. In addition, some can even exert beneficial effects on endothelial senescence. Moreover, some of these products have been associated with the prevention and/or improvement of established endothelial dysfunction in several experimental models of cardiovascular diseases and in humans with cardiovascular diseases. Therefore, intake of certain natural products, such as dietary and plant-derived polyphenol-rich products, appears to be an attractive approach for a healthy vascular system in ageing.
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Affiliation(s)
- Valérie B Schini-Kerth
- Translational Cardiovascular Medicine, UR 3074, CRBS, University of Strasbourg, Strasbourg, France.
| | - Ibrahima Diouf
- Translational Cardiovascular Medicine, UR 3074, CRBS, University of Strasbourg, Strasbourg, France
| | - Hira Muzammel
- Translational Cardiovascular Medicine, UR 3074, CRBS, University of Strasbourg, Strasbourg, France
| | - Amissi Said
- Translational Cardiovascular Medicine, UR 3074, CRBS, University of Strasbourg, Strasbourg, France
| | - Cyril Auger
- Regenerative Nanomedicine, INSERM UMR 1260, CRBS, University of Strasbourg, Strasbourg, France
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Indrio F, Pettoello-Mantovani M, Giardino I, Masciari E. The Role of Artificial Intelligence in Pediatrics from Treating Illnesses to Managing Children's Overall Well-Being. J Pediatr 2024; 275:114291. [PMID: 39242077 DOI: 10.1016/j.jpeds.2024.114291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 09/02/2024] [Indexed: 09/09/2024]
Affiliation(s)
- Flavia Indrio
- Department of Experimental Medicine, Pediatric Unit, University of Salento, Lecce, Italy; European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany
| | - Massimo Pettoello-Mantovani
- European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany; Department of Medical and Surgical Sciences, Pediatric Unit, University of Foggia, Foggia, Italy.
| | - Ida Giardino
- Department of Clinical and Experimental Medicine, Center of Laboratory Medicine, University of Foggia, Foggia, Italy
| | - Elio Masciari
- Department of Electrical Engineering and Information Technologies, University of Naples Federico II, Naples, Italy
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Levassort H, Boucquemont J, Lambert O, Liabeuf S, Laville SM, Teillet L, Tabcheh AH, Frimat L, Combe C, Fouque D, Laville M, Jacquelinet C, Helmer C, Alencar de Pinho N, Pépin M, Massy ZA. Urea Level and Depression in Patients with Chronic Kidney Disease. Toxins (Basel) 2024; 16:326. [PMID: 39057966 PMCID: PMC11281192 DOI: 10.3390/toxins16070326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/10/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Depression is common in patients with chronic kidney disease (CKD). Experimental studies suggest the role of urea toxicity in depression. We assessed both the incidence of antidepressant prescriptions and depressive symptoms (measured by CESD (Center for Epidemiologic Depression) scale) in 2505 patients with CKD (Stage 3-4) followed up over 5 years in the Chronic Kidney Disease Renal Epidemiology and Information Network (CKD-REIN) cohort. We used a joint model to assess the association between the serum urea level and incident antidepressant prescriptions, and mixed models for the association between the baseline serum urea level and CESD score over the 5-year follow-up. Among the 2505 patients, 2331 were not taking antidepressants at baseline. Of the latter, 87 started taking one during a median follow-up of 4.6 years. After adjustment for confounding factors, the hazard ratio for incident antidepressant prescription associated with the serum urea level (1.28 [95%CI, 0.94,1.73] per 5 mmol/L increment) was not significant. After adjustment, the serum urea level was associated with the mean change in the CESD score (β = 0.26, [95%CI, 0.11,0.41] per 5 mmol/L increment). Depressive symptoms burden was associated with serum urea level unlike depression events. Further studies are needed to draw firm conclusions and better understand the mechanisms of depression in CKD.
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Affiliation(s)
- Hélène Levassort
- Geriatrics, Hôpital Ambroise-Paré, Assistance Publique des Hôpitaux de Paris (APHP), UVSQ, 9 Avenue Charles de Gaulle, F-92100 Boulogne-Billancourt, France (M.P.)
- Centre for Research in Epidemiology and Population Health (CESP), Clinical Epidemiology Team, Inserm U1018, Paris-Saclay University, 12 Avenue Paul Vaillant Couturier, F-94800 Villejuif, France (O.L.); (A.-H.T.); (N.A.d.P.)
| | - Julie Boucquemont
- Centre for Research in Epidemiology and Population Health (CESP), Clinical Epidemiology Team, Inserm U1018, Paris-Saclay University, 12 Avenue Paul Vaillant Couturier, F-94800 Villejuif, France (O.L.); (A.-H.T.); (N.A.d.P.)
| | - Oriane Lambert
- Centre for Research in Epidemiology and Population Health (CESP), Clinical Epidemiology Team, Inserm U1018, Paris-Saclay University, 12 Avenue Paul Vaillant Couturier, F-94800 Villejuif, France (O.L.); (A.-H.T.); (N.A.d.P.)
| | - Sophie Liabeuf
- Pharmacoepidemiology Unit, Department of Clinical Pharmacology, Amiens-Picardie University Medical Center, F-80054 Amiens, France (S.M.L.)
- MP3CV Laboratory, Jules Verne University of Picardie, F-80054 Amiens, France
| | - Solene M. Laville
- Pharmacoepidemiology Unit, Department of Clinical Pharmacology, Amiens-Picardie University Medical Center, F-80054 Amiens, France (S.M.L.)
- MP3CV Laboratory, Jules Verne University of Picardie, F-80054 Amiens, France
| | - Laurent Teillet
- Geriatrics, Hôpital Ambroise-Paré, Assistance Publique des Hôpitaux de Paris (APHP), UVSQ, 9 Avenue Charles de Gaulle, F-92100 Boulogne-Billancourt, France (M.P.)
- Centre for Research in Epidemiology and Population Health (CESP), Clinical Epidemiology Team, Inserm U1018, Paris-Saclay University, 12 Avenue Paul Vaillant Couturier, F-94800 Villejuif, France (O.L.); (A.-H.T.); (N.A.d.P.)
| | - Abdel-Hay Tabcheh
- Centre for Research in Epidemiology and Population Health (CESP), Clinical Epidemiology Team, Inserm U1018, Paris-Saclay University, 12 Avenue Paul Vaillant Couturier, F-94800 Villejuif, France (O.L.); (A.-H.T.); (N.A.d.P.)
| | - Luc Frimat
- Service de Néphrologie, CHRU de Nancy, F-54000 Vandoeuvre-lès-Nancy, France;
- Université de Lorraine, APEMAC, F-54000 Nancy, France
| | - Christian Combe
- Service de Néphrologie Transplantation Dialyse Aphérèse, Centre Hospitalier Universitaire de Bordeaux, F-33076 Bordeaux, France;
- Inserm U1026, Université Bordeaux Segalen, F-33076 Bordeaux, France
| | - Denis Fouque
- Service de Néphrologie, Centre Hospitalier Lyon Sud, Université de Lyon, Carmen, F-69495 Pierre-Bénite, France;
| | - Maurice Laville
- Université Claude Bernard Lyon 1, Carmen INSERM U1060, F-69495 Pierre-Bénite, France
| | - Christian Jacquelinet
- Centre for Research in Epidemiology and Population Health (CESP), Clinical Epidemiology Team, Inserm U1018, Paris-Saclay University, 12 Avenue Paul Vaillant Couturier, F-94800 Villejuif, France (O.L.); (A.-H.T.); (N.A.d.P.)
- Agence de la Biomédecine, F-93212 Saint-Denis La Plaine, France
| | - Catherine Helmer
- Bordeaux Population Health Center, INSERM U1219, 146 rue Léo Saignat, F-33076 Bordeaux, France;
| | - Natalia Alencar de Pinho
- Centre for Research in Epidemiology and Population Health (CESP), Clinical Epidemiology Team, Inserm U1018, Paris-Saclay University, 12 Avenue Paul Vaillant Couturier, F-94800 Villejuif, France (O.L.); (A.-H.T.); (N.A.d.P.)
| | - Marion Pépin
- Geriatrics, Hôpital Ambroise-Paré, Assistance Publique des Hôpitaux de Paris (APHP), UVSQ, 9 Avenue Charles de Gaulle, F-92100 Boulogne-Billancourt, France (M.P.)
- Centre for Research in Epidemiology and Population Health (CESP), Clinical Epidemiology Team, Inserm U1018, Paris-Saclay University, 12 Avenue Paul Vaillant Couturier, F-94800 Villejuif, France (O.L.); (A.-H.T.); (N.A.d.P.)
| | - Ziad A. Massy
- Centre for Research in Epidemiology and Population Health (CESP), Clinical Epidemiology Team, Inserm U1018, Paris-Saclay University, 12 Avenue Paul Vaillant Couturier, F-94800 Villejuif, France (O.L.); (A.-H.T.); (N.A.d.P.)
- Association Pour L’Utilisation du Rein Artificiel dans la Région Parisienne (AURA), 185a rue Raymond Losserand, F-75014 Paris, France
- Ambroise Paré University Hospital, APHP, Department of Nephrology, 9 Avenue Charles de Gaulle, F-92100 Boulogne-Billancourt, France
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Fang YP, Zhao Y, Huang JY, Yang X, Liu Y, Zhang XL. The functional role of cellular senescence during vascular calcification in chronic kidney disease. Front Endocrinol (Lausanne) 2024; 15:1330942. [PMID: 38318291 PMCID: PMC10839002 DOI: 10.3389/fendo.2024.1330942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 01/03/2024] [Indexed: 02/07/2024] Open
Abstract
Vascular calcification (VC) has emerged as a key predictor of cardiovascular events in patients with chronic kidney disease (CKD). In recent years, an expanding body of research has put forth the concept of accelerated vascular aging among CKD patients, highlighting the significance of vascular cells senescence in the process of VC. Within the milieu of uremia, senescent vascular endothelial cells (VECs) release extracellular microvesicles (MV) that promote vascular smooth muscle cells (VSMCs) senescence, thereby triggering the subsequent osteogenic phenotypic switch and ultimately contributing to the VC process. In addition, senescent vascular progenitor or stem cells with diminished ability to differentiate into VECs and VSMCS, compromise the repair of vascular integrity, on the other hand, release a cascade of molecules associated with senescence, collectively known as the senescence-associated secretory phenotype (SASP), perpetuating the senescence phenomenon. Furthermore, SASP triggers the recruitment of monocytes and macrophages, as well as adjacent VECs and VSMCs into a pro-adhesive and pro-inflammatory senescent state. This pro-inflammatory microenvironment niche not only impacts the functionality of immune cells but also influences the differentiation of myeloid immune cells, thereby amplifying the reduced ability to effectively clear senescent cells of senescent macrophages, promoted calcification of VSMCs. The objective of this paper is to provide a comprehensive review of the contribution of vascular cell senescence to the emergence and advancement of VC. Gaining a comprehensive understanding of the involvement of cellular senescence within the vessel wall is pivotal, especially when it comes to its intersection with VC. This knowledge is essential for advancing groundbreaking anti-aging therapies, aiming to effectively mitigate cardiovascular diseases.
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Affiliation(s)
- Ya-Ping Fang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yu Zhao
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Jia-Yi Huang
- Department of Clinical Medicine, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Xin Yang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yan Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Xiao-Liang Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
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Huss G, Barak S, Reali L, Magendie C, Carrasco-Sanz A, Somekh E, Cohen R, Levy C, Namazova-Baranova L, Vural M, Pettoello-Mantovani M. Drug Shortages in Pediatrics in Europe: The Position of the European Pediatric Societies. J Pediatr 2023; 261:113472. [PMID: 37182656 PMCID: PMC10175075 DOI: 10.1016/j.jpeds.2023.113472] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 04/23/2023] [Indexed: 05/16/2023]
Affiliation(s)
- Gottfried Huss
- European Confederation of Primary Care Pediatricians, Lyon, France
| | - Shimon Barak
- European Confederation of Primary Care Pediatricians, Lyon, France
| | - Laura Reali
- European Confederation of Primary Care Pediatricians, Lyon, France
| | | | - Angel Carrasco-Sanz
- European Confederation of Primary Care Pediatricians, Lyon, France; European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany
| | - Eli Somekh
- European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany
| | - Robert Cohen
- European Confederation of Primary Care Pediatricians, Lyon, France; European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany
| | - Corinne Levy
- European Confederation of Primary Care Pediatricians, Lyon, France; European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany
| | - Leyla Namazova-Baranova
- European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany
| | - Mehmet Vural
- European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany
| | - Massimo Pettoello-Mantovani
- European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany.
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Ya J, Bayraktutan U. Vascular Ageing: Mechanisms, Risk Factors, and Treatment Strategies. Int J Mol Sci 2023; 24:11538. [PMID: 37511296 PMCID: PMC10380571 DOI: 10.3390/ijms241411538] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/10/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Ageing constitutes the biggest risk factor for poor health and adversely affects the integrity and function of all the cells, tissues, and organs in the human body. Vascular ageing, characterised by vascular stiffness, endothelial dysfunction, increased oxidative stress, chronic low-grade inflammation, and early-stage atherosclerosis, may trigger or exacerbate the development of age-related vascular diseases, which each year contribute to more than 3.8 million deaths in Europe alone and necessitate a better understanding of the mechanisms involved. To this end, a large number of recent preclinical and clinical studies have focused on the exponential accumulation of senescent cells in the vascular system and paid particular attention to the specific roles of senescence-associated secretory phenotype, proteostasis dysfunction, age-mediated modulation of certain microRNA (miRNAs), and the contribution of other major vascular risk factors, notably diabetes, hypertension, or smoking, to vascular ageing in the elderly. The data generated paved the way for the development of various senotherapeutic interventions, ranging from the application of synthetic or natural senolytics and senomorphics to attempt to modify lifestyle, control diet, and restrict calorie intake. However, specific guidelines, considering the severity and characteristics of vascular ageing, need to be established before widespread use of these agents. This review briefly discusses the molecular and cellular mechanisms of vascular ageing and summarises the efficacy of widely studied senotherapeutics in the context of vascular ageing.
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Affiliation(s)
- Jingyuan Ya
- Academic Unit of Mental Health and Clinical Neuroscience, Nottingham University, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neuroscience, Nottingham University, Queen's Medical Centre, Nottingham NG7 2UH, UK
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Pettoello-Mantovani M, Cokugras H, Ferrara P, Indrio F, Giardino I, Canpolat N, Kasapçopur Ö, Zeybek AC, Beser OF, Pettoello-Mantovani C, Cokugras FC. Child Brides and Forced Marriages: An Aspect of Child Abuse and Neglect. J Pediatr 2022; 250:116-117.e2. [PMID: 35940291 DOI: 10.1016/j.jpeds.2022.07.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 07/29/2022] [Indexed: 11/17/2022]
Affiliation(s)
- Massimo Pettoello-Mantovani
- European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany; Italian Academy of Pediatrics, Milan, Italy; Association for Scientific Research, Neuchatel, Switzerland.
| | | | - Pietro Ferrara
- European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany; Italian Academy of Pediatrics, Milan, Italy
| | - Flavia Indrio
- European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany
| | - Ida Giardino
- Association for Scientific Research, Neuchatel, Switzerland
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Ferrara P, Ruiz R, Corsello G, Giardino I, Carrasco-Sanz A, Vural M, Namazova-Baranova L, Indrio F, Pop TL, Pettoello-Mantovani M. Adequate Training and Multidisciplinary Support May Assist Pediatricians in Properly Handling and Managing Gender Incongruence and Dysphoria. J Pediatr 2022; 249:121-123.e2. [PMID: 35853484 DOI: 10.1016/j.jpeds.2022.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 07/13/2022] [Indexed: 10/17/2022]
Affiliation(s)
- Pietro Ferrara
- European Pediatric Association/Union of National European Pediatric Societies and Associations (EPA/UNEPSA), Berlin, Germany; Department of Pediatrics, Campus BioMedico University, Rome, Italy
| | - Roberta Ruiz
- Department of Pediatrics, Catholic University of Sacred Hearth, Rome, Italy
| | - Giovanni Corsello
- European Pediatric Association/Union of National European Pediatric Societies and Associations (EPA/UNEPSA), Berlin, Germany; Department of Pediatrics, University of Palermo, Palermo, Italy; Italian Academy of Pediatrics, Milan, Italy
| | - Ida Giardino
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Angel Carrasco-Sanz
- European Pediatric Association/Union of National European Pediatric Societies and Associations (EPA/UNEPSA), Berlin, Germany; European Confederation of Primary Care Pediatrics, Lyon, France
| | - Mehmet Vural
- European Pediatric Association/Union of National European Pediatric Societies and Associations (EPA/UNEPSA), Berlin, Germany; Turkish Pediatric Association, Istanbul, Turkey
| | - Leyla Namazova-Baranova
- European Pediatric Association/Union of National European Pediatric Societies and Associations (EPA/UNEPSA), Berlin, Germany
| | - Flavia Indrio
- European Pediatric Association/Union of National European Pediatric Societies and Associations (EPA/UNEPSA), Berlin, Germany; Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Tudor Lucian Pop
- European Pediatric Association/Union of National European Pediatric Societies and Associations (EPA/UNEPSA), Berlin, Germany; Association for the Scientific Research Activities, Neuchâtel, Switzerland
| | - Massimo Pettoello-Mantovani
- European Pediatric Association/Union of National European Pediatric Societies and Associations (EPA/UNEPSA), Berlin, Germany; Italian Academy of Pediatrics, Milan, Italy; Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy; Association for the Scientific Research Activities, Neuchâtel, Switzerland.
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Tanas R, Gil B, Marsella M, Nowicka P, Pezzoli V, Phelan SM, Queirolo S, Stanford FC, Pettoello-Mantovani M, Bernasconi S. Addressing Weight Stigma and Weight-Based Discrimination in Children: Preparing Pediatricians to Meet the Challenge. J Pediatr 2022; 248:135-136.e3. [PMID: 35714964 PMCID: PMC9999724 DOI: 10.1016/j.jpeds.2022.06.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/09/2022] [Indexed: 11/22/2022]
Affiliation(s)
- Rita Tanas
- Department of Pediatrics, Arcispedale S. Anna, Ferrara, Italy
| | - Begoña Gil
- Comprehensive Childhood Obesity Plan of Andalusia, Health Counseling, Andalusian Government, Sevilla, Spain
| | - Maria Marsella
- Department of Pediatrics, San G. Moscati Hospital, Avellino, Italy
| | - Paulina Nowicka
- Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Solna, Sweden; Department of Food Studies, Nutrition and Dietetics, Uppsala University, Uppsala, Sweden
| | - Valdo Pezzoli
- Pediatric Institute of Southern Switzerland, EOC Lugano, Lugano, Switzerland
| | - Sean M Phelan
- Division of Health Care Delivery Research, Robert D. & Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Sara Queirolo
- Pediatric Institute of Southern Switzerland, EOC Lugano, Lugano, Switzerland
| | - Fatima Cody Stanford
- Departments of Medicine, Neuroendocrine Unit and Pediatrics, Pediatric Endocrinology, Boston, MA; Nutrition Obesity Research Center at Harvard, MGH Weight Center, Massachusetts General Hospital, Boston, MA
| | - Massimo Pettoello-Mantovani
- European Pediatric Association, Union of National Pediatric Societies and Associations, Berlin, Germany; Department of Pediatrics, Scientific Institute "Casa Sollievo," Univeristy of Foggia, Foggia, Italy.
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11
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El Chamieh C, Liabeuf S, Massy Z. Uremic Toxins and Cardiovascular Risk in Chronic Kidney Disease: What Have We Learned Recently beyond the Past Findings? Toxins (Basel) 2022; 14:280. [PMID: 35448889 PMCID: PMC9028122 DOI: 10.3390/toxins14040280] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/10/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022] Open
Abstract
Patients with chronic kidney disease (CKD) have an elevated prevalence of atheromatous (ATH) and/or non-atheromatous (non-ATH) cardiovascular disease (CVD) due to an array of CKD-related risk factors, such as uremic toxins (UTs). Indeed, UTs have a major role in the emergence of a spectrum of CVDs, which constitute the leading cause of death in patients with end-stage renal disease. The European Uremic Toxin Work Group has identified over 100 UTs, more than 25 of which are dietary or gut-derived. Even though relationships between UTs and CVDs have been described in the literature, there are few reviews on the involvement of the most toxic compounds and the corresponding physiopathologic mechanisms. Here, we review the scientific literature on the dietary and gut-derived UTs with the greatest toxicity in vitro and in vivo. A better understanding of these toxins' roles in the elevated prevalence of CVDs among CKD patients might facilitate the development of targeted treatments. Hence, we review (i) ATH and non-ATH CVDs and the respective levels of risk in patients with CKD and (ii) the mechanisms that underlie the influence of dietary and gut-derived UTs on CVDs.
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Affiliation(s)
- Carolla El Chamieh
- Center for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles-Saint-Quentin-en-Yvelines University (UVSQ), INSERM UMRS 1018, F-94807 Villejuif, France;
| | - Sophie Liabeuf
- Pharmacology Department, Amiens University Hospital, F-80000 Amiens, France
- MP3CV Laboratory, EA7517, Jules Verne University of Picardie, F-80000 Amiens, France
| | - Ziad Massy
- Nephrology Department, Ambroise Paré University Hospital, APHP, F-92100 Paris, France
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12
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Laville SM, Couturier A, Lambert O, Metzger M, Mansencal N, Jacquelinet C, Laville M, Frimat L, Fouque D, Combe C, Robinson BM, Stengel B, Liabeuf S, Massy ZA. Urea levels and cardiovascular disease in patients with chronic kidney disease. Nephrol Dial Transplant 2022; 38:gfac045. [PMID: 35544273 PMCID: PMC9869852 DOI: 10.1093/ndt/gfac045] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Elevated serum urea levels are common in moderate-to-advanced CKD. Several studies have shown that urea is a direct and indirect uremic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before renal replacement therapy (RRT) in patients with CKD. METHODS CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 < 10.5, T2:10.5 to 15.1, and T3 ≥ 15.1 mmol/L). Cox proportional hazard models were used to estimate hazard ratios (HRs) for first atheromatous or nonatheromatous cardiovascular (CV) events, and all-cause mortality before RRT. The models were adjusted for baseline comorbidities, laboratory data, and medications. FINDINGS Of the 2507 included patients (median [interquartile range (IQR)] age: 69[61-77]; mean (standard deviation) eGFR 33.5(11.6) mL/min/1.73 m²), 54% had a history of cardiovascular disease. After multiple adjustments for cardiovascular risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and nonatheromatous cardiovascular events than patient in T1 (n events = 451, HR[95%CI]: 1.93[1.39-2.69]). The adjusted HRs for death before RRT (n events = 407) were 1.31[0.97; 1.76] and 1.73[1.22; 2.45] for patients T2 and those in T3, respectively. INTERPRETATION Our data suggested that urea is a predictor of cardiovascular outcomes beyond CV risk factors including eGFR.
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Affiliation(s)
- Solène M Laville
- Department of Clinical Pharmacology, Amiens University Hospital, Amiens, France
- MP3CV Laboratory, EA7517, University of Picardie Jules Verne, Amiens, France
| | - Aymeric Couturier
- Department of Nephrology, Ambroise Paré University Hospital, APHP, Boulogne-Billancourt, Paris, France
| | - Oriane Lambert
- Centre for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles Saint Quentin University, INSERM UMRS, 1018 Villejuif, France
| | - Marie Metzger
- Centre for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles Saint Quentin University, INSERM UMRS, 1018 Villejuif, France
| | - Nicolas Mansencal
- Centre for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles Saint Quentin University, INSERM UMRS, 1018 Villejuif, France
- Department of Cardiology, Ambroise Paré University Hospital, APHP, Boulogne-Billancourt, Paris, France
| | | | | | - Luc Frimat
- Nephrology Department, CHRU de Nancy, Vandoeuvre-lès-Nancy, France
- Lorraine University, APEMAC, Vandoeuvre-lès-Nancy, France
| | - Denis Fouque
- Université de Lyon, CarMeN INSERM, Lyon, France
- Nephrology Department, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Christian Combe
- Service de Néphrologie Transplantation Dialyse Aphérèse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
- INSERM, U1026, Univ Bordeaux Segalen, Bordeaux, France
| | | | - Bénédicte Stengel
- Centre for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles Saint Quentin University, INSERM UMRS, 1018 Villejuif, France
| | - Sophie Liabeuf
- Department of Clinical Pharmacology, Amiens University Hospital, Amiens, France
- MP3CV Laboratory, EA7517, University of Picardie Jules Verne, Amiens, France
| | - Ziad A Massy
- Department of Nephrology, Ambroise Paré University Hospital, APHP, Boulogne-Billancourt, Paris, France
- Centre for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles Saint Quentin University, INSERM UMRS, 1018 Villejuif, France
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ox-LDL-Induced Endothelial Progenitor Cell Oxidative Stress via p38/Keap1/Nrf2 Pathway. Stem Cells Int 2022; 2022:5897194. [PMID: 35140793 PMCID: PMC8820940 DOI: 10.1155/2022/5897194] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 01/09/2023] Open
Abstract
Background Nrf2 which was recently reported to regulate the antioxidant genes and cellular redox regulators was highly expressed in EPCs. However, its role in ox-LDL-induced EPC oxidative stress and apoptosis has not been fully illustrated. Methods EPCs isolated from human peripheral blood mononuclear cells were treated with different concentrations of ox-LDL, Keap1 siRNA, and a specific p38 MAPK inhibitor SB203580 and then used to assay the cytoplasmic Nrf2, nuclear Nrf2, NAD(P) H:quinone oxidoreductase 1 (NQO1) and Bax/Bcl-2 levels with Western blot, NQO1 mRNA levels with RT-PCR, ROS levels with H2DCF-DA, loss/disruption of mitochondrial membrane potential with JC-1, apoptosis with Annexin V and PI, migration with transwell chambers, and tube formation with Matrigel. Results ox-LDL decreased the nuclear Nrf2/Histone H3 to cytoplasmic Nrf2/GAPDH ratio, NQO1 mRNA, and protein levels. ox-LDL enhanced ROS production, induced the loss of membrane potential, and increased the cell shrinkage, pyknotic nuclei, and apoptosis of EPCs. Keap1 siRNA increased Nrf2 nuclear translocation, NQO1 mRNA transcription, and protein expression and prevented ROS generation and formation of JC-1 monomers. ox-LDL increased the activation of p38. SB203580 significantly eliminated ox-LDL induced inhibition of Nrf2 nuclear translocation, depression of NQO1 mRNA transcription, generation of ROS, and formation of JC-1 monomers in EPCs. Keap1 siRNA decreased the Bax/Bcl-2 ratio which was increased by ox-LDL in EPCs. ox-LDL decreased EPC migration and tube formation. Keap1 siRNA preserved the migration and tube formation of EPCs. Conclusion ox-LDL activated EPCs p38/Keap1/Nrf2 pathway and induced oxidative stress, dysfunction, and apoptosis of EPCs.
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Wu S, Hu S, Fan W, Zhang X, Wang H, Li C, Deng J. Nitrite exposure may induce infertility in mice. J Toxicol Pathol 2022; 35:75-82. [PMID: 35221497 PMCID: PMC8828601 DOI: 10.1293/tox.2021-0002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 10/26/2021] [Indexed: 11/19/2022] Open
Affiliation(s)
- Shanshan Wu
- National Health Commission Key Laboratory of Birth Defects Prevention, Henan Key Laboratory of Population Defects Prevention, Henan Institute of Reproduction Health Science and Technology, 26 Jingwu Road, Zhengzhou 450002, China
| | - Sang Hu
- Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Wenjuan Fan
- Luohe Medical College, Luohe City, Henan Province, China
| | - Xiaojing Zhang
- National Health Commission Key Laboratory of Birth Defects Prevention, Henan Key Laboratory of Population Defects Prevention, Henan Institute of Reproduction Health Science and Technology, 26 Jingwu Road, Zhengzhou 450002, China
| | - Haili Wang
- National Health Commission Key Laboratory of Birth Defects Prevention, Henan Key Laboratory of Population Defects Prevention, Henan Institute of Reproduction Health Science and Technology, 26 Jingwu Road, Zhengzhou 450002, China
| | - Chaojie Li
- National Health Commission Key Laboratory of Birth Defects Prevention, Henan Key Laboratory of Population Defects Prevention, Henan Institute of Reproduction Health Science and Technology, 26 Jingwu Road, Zhengzhou 450002, China
| | - Jinbo Deng
- National Health Commission Key Laboratory of Birth Defects Prevention, Henan Key Laboratory of Population Defects Prevention, Henan Institute of Reproduction Health Science and Technology, 26 Jingwu Road, Zhengzhou 450002, China
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15
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Tousian H, Razavi BM, Hosseinzadeh H. In search of elixir: Pharmacological agents against stem cell senescence. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:868-880. [PMID: 34712416 PMCID: PMC8528253 DOI: 10.22038/ijbms.2021.51917.11773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 03/02/2021] [Indexed: 12/13/2022]
Abstract
Stem cell senescence causes different complications. In addition to the aging phenomenon, stem cell senescence has been investigated in various concepts such as cancer, adverse drug effects, and as a limiting factor in cell therapy. This manuscript examines protective medicines and supplements which are capable of hindering stem cell senescence. We searched the databases such as EMBASE, PubMed, and Web of Science with the keywords "stem cell," "progenitor cell," "satellite," "senescence" and excluded the keywords "cancer," "tumor," "malignancy" and "carcinoma" until June 2020. Among these results, we chose 47 relevant studies. Our investigation indicates that most of these studies examined endothelial progenitor cells, hematopoietic stem cells, mesenchymal stem cells, adipose-derived stem cells, and a few others were about less-discussed types of stem cells such as cardiac stem cells, myeloblasts, and induced pluripotent stem cells. From another aspect, 17β-Estradiol, melatonin, metformin, rapamycin, coenzyme Q10, N-acetyl cysteine, and vitamin C were the most studied agents, while the main protective mechanism was through telomerase activity enhancement or oxidative damage ablation. Although many of these studies are in vitro, they are still worthwhile. Stem cell senescence in the in vitro expansion stage is an essential concern in clinical procedures of cell therapy. Moreover, in vitro studies are the first step for further in vivo and clinical studies. It is noteworthy to mention the fact that these protective agents have been used in the clinical setting for various purposes for a long time. Given that, we only need to examine their systemic anti-senescence effects and effective dosages.
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Affiliation(s)
- Hourieh Tousian
- Vice-chancellery of Food and Drug,Shahroud University of Medical Sciences, Shahroud, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Schroth J, Thiemermann C, Henson SM. Senescence and the Aging Immune System as Major Drivers of Chronic Kidney Disease. Front Cell Dev Biol 2020; 8:564461. [PMID: 33163486 PMCID: PMC7581911 DOI: 10.3389/fcell.2020.564461] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 09/16/2020] [Indexed: 12/20/2022] Open
Abstract
Chronic kidney disease (CKD) presents an ever-growing disease burden for the world's aging population. It is characterized by numerous changes to the kidney, including a decrease in renal mass, renal fibrosis, and a diminished glomerular filtration rate. The premature aging phenotype observed in CKD is associated with cellular senescence, particularly of renal tubular epithelial cells (TECs), which contributes to chronic inflammation through the production of a proinflammatory senescence associated secretory phenotype (SASP). When coupled with changes in immune system composition and progressive immune dysfunction, the accumulation of senescent kidney cells acts as a driver for the progression of CKD. The targeting of senescent cells may well present an attractive therapeutic avenue for the treatment of CKD. We propose that the targeting of senescent cells either by direct inhibition of pro-survival pathways (senolytics) or through the inhibition of their proinflammatory secretory profile (senomorphics) together with immunomodulation to enhance immune system surveillance of senescent cells could be of benefit to patients with CKD.
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Affiliation(s)
| | | | - Siân M. Henson
- Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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17
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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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18
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Wang Y, Zhong B, Wu Q, Tong J, Zhu T, Zhang M. Effect of Aldosterone on Senescence and Proliferation Inhibition of Endothelial Progenitor Cells Induced by Sirtuin 1 (SIRT1) in Pulmonary Arterial Hypertension. Med Sci Monit 2020; 26:e920678. [PMID: 32303670 PMCID: PMC7191948 DOI: 10.12659/msm.920678] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Background Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary circulatory resistance. Pulmonary vascular endothelial dysfunction is one of the main causes of primary PAH. Endothelial progenitor cells (EPCs) can proliferate and differentiate into vascular endothelial cells and play an important role in maintaining normal endothelial function. Mineralocorticoid receptor inhibitor has been reported to be used in the treatment of PAH. However, the role and the underlying mechanism of aldosterone (ALDO) in PAH remains unclear. Material/Methods Rats were divided to 4 groups (n=10 per group) and treated with 0.9% normal saline, monocrotaline (MCT), spironolactone (SP), or MCT combined with SP. After the rats were sacrificed with an overdose of pentobarbital sodium, hematoxylin and eosin staining was performed to observe the pulmonary artery pathology section. Sirtuin 1 (SIRT1), p53, and p21 protein expression was detect by western blot. Immunofluorescence staining was performed to verify EPCs. EPCs were treated with different concentrations of ALDO. MTT assay and senescence-associated β-galactosidase staining were used to measure cell viability and senescence. Results MCT increased the vascular arterial wall thickness and wall area, inhibited SIRT1 protein expression and increased p53 and p21 protein expression in the lung tissue of rats, while SP partially reversed this effect. In addition, ALDO inhibited EPCs viability and induced senescence. The expression of p53 and p21 proteins in the EPCs were upregulated and the senescence was accelerated when EPCs were transfected with SIRT1 siRNA. Conclusions ALDO promoted EPCs senescence and inhibited EPCs proliferation by downregulating SIRT1, which regulates the p53/p21 pathway, thus promoting PAH.
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Affiliation(s)
- Yue Wang
- School of Pharmaceutical Engineering and Life Science and School of Nursing, Changzhou University, Changzhou, Jiangsu, China (mainland)
| | - Bin Zhong
- Department of Thoracic and Cardiovascular Surgery, Changzhou No. 2 People's Hospital, Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China (mainland)
| | - Qiyong Wu
- Department of Thoracic and Cardiovascular Surgery, Changzhou No. 2 People's Hospital, Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China (mainland)
| | - Jichun Tong
- Department of Thoracic and Cardiovascular Surgery, Changzhou No. 2 People's Hospital, Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China (mainland)
| | - Tao Zhu
- Department of Thoracic and Cardiovascular Surgery, Changzhou No. 2 People's Hospital, Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China (mainland)
| | - Ming Zhang
- Department of Thoracic and Cardiovascular Surgery, Changzhou No. 2 People's Hospital, Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China (mainland)
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Wang R, Liu L, Liu H, Wu K, Liu Y, Bai L, Wang Q, Qi B, Qi B, Zhang L. Reduced NRF2 expression suppresses endothelial progenitor cell function and induces senescence during aging. Aging (Albany NY) 2019; 11:7021-7035. [PMID: 31494646 PMCID: PMC6756903 DOI: 10.18632/aging.102234] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 08/21/2019] [Indexed: 05/25/2023]
Abstract
Aging is associated with an increased risk of cardiovascular disease. Numerical and functional declines in endothelial progenitor cells (EPCs) limit their capacity for endothelial repair and promote the development of cardiovascular disease. We explored the effects of nuclear factor (erythroid-derived 2)-like 2 (NRF2) on EPC activity during aging. Both in vitro and in vivo, the biological functioning of EPCs decreased with aging. The expression of NRF2 and its target genes (Ho-1, Nqo-1 and Trx) also declined with aging, while Nod-like receptor protein 3 (NLRP3) expression increased. Aging was associated with oxidative stress, as evidenced by increased reactive oxygen species and malondialdehyde levels and reduced superoxide dismutase activity. Nrf2 silencing impaired the functioning of EPCs and induced oxidative stress in EPCs from young mice. On the other hand, NRF2 activation in EPCs from aged mice protected these cells against oxidative stress, ameliorated their biological dysfunction and downregulated the NLRP3 inflammasome. These findings suggest NRF2 can prevent the functional damage of EPCs and downregulate the NLRP3 inflammasome through NF-κB signaling.
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Affiliation(s)
- Ruiyun Wang
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lihua Liu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hongxia Liu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kefei Wu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yun Liu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lijuan Bai
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qian Wang
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Benming Qi
- Department of Otorhinolaryngology, First People’s Hospital of Yunnan Province, Kunming, Yunnan 650000, China
| | - Benling Qi
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lei Zhang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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20
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Schiavone S, Neri M, Maffione AB, Frisoni P, Morgese MG, Trabace L, Turillazzi E. Increased iNOS and Nitrosative Stress in Dopaminergic Neurons of MDMA-Exposed Rats. Int J Mol Sci 2019; 20:E1242. [PMID: 30871034 PMCID: PMC6429174 DOI: 10.3390/ijms20051242] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/28/2019] [Accepted: 03/05/2019] [Indexed: 12/29/2022] Open
Abstract
Several mechanisms underlying 3,4-Methylenedioxy-N-methylamphetamine (MDMA) neurotoxicity have been proposed, including neurochemical alterations and excitotoxicity mediated by reactive oxygen species (ROS), nitric oxide (NO), and reactive nitrogen species (RNS). However, ROS, NO, and RNS sources in the brain are not fully known. We aimed to investigate possible alterations in the expression of the ROS producer NOX enzymes (NOX2, NOX1, and NOX4), NO generators (iNOS, eNOS, and nNOS), markers of oxidative (8-hydroxy-2'-deoxyguanosine, 8OHdG), and nitrosative (3-nitrotyrosine, NT) stress, as well as the colocalization between cells positive for the dopamine transporter (DT1) and cells expressing the neuronal nuclei (NeuN) marker, in the frontal cortex of rats receiving saline or MDMA, sacrificed 6 h, 16 h, or 24 h after its administration. MDMA did not affect NOX2, NOX1, and NOX4 immunoreactivity, whereas iNOS expression was enhanced. The number of NT-positive cells was increased in MDMA-exposed animals, whereas no differences were detected in 8OHdG expression among experimental groups. MDMA and NT markers colocalized with DT1 positive cells. DT1 immunostaining was found in NeuN-positive stained cells. Virtually no colocalization was observed with microglia and astrocytes. Moreover, MDMA immunostaining was not found in NOX2-positive cells. Our results suggest that iNOS-derived nitrosative stress, but not NOX enzymes, may have a crucial role in the pathogenesis of MDMA-induced neurotoxicity, highlighting the specificity of different enzymatic systems in the development of neuropathological alterations induced by the abuse of this psychoactive compound.
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Affiliation(s)
- Stefania Schiavone
- Department of Clinical and Experimental Medicine, University of Foggia, Via Napoli, 20, 71122 Foggia, Italy.
| | - Margherita Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Fossato di Mortara, 70, 44100 Ferrara, Italy.
| | - Angela Bruna Maffione
- Department of Clinical and Experimental Medicine, University of Foggia, Via Napoli, 20, 71122 Foggia, Italy.
| | - Paolo Frisoni
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Fossato di Mortara, 70, 44100 Ferrara, Italy.
| | - Maria Grazia Morgese
- Department of Clinical and Experimental Medicine, University of Foggia, Via Napoli, 20, 71122 Foggia, Italy.
| | - Luigia Trabace
- Department of Clinical and Experimental Medicine, University of Foggia, Via Napoli, 20, 71122 Foggia, Italy.
| | - Emanuela Turillazzi
- Section of Legal Medicine, Department of Surgical, Medical, Molecular and Critical Pathology, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
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21
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Abstract
We evaluated the effect of in vitro digested milk on mature adipocytes 3T3-L1, paying particular attention to its fatty acid composition, and comparing human (HM), donkey (DM), bovine (BM), ovine (OM), caprine (CM) and formula (FM) milk. Cellular viability, apoptosis, oxidative response and gene expression levels of NF-κB p65, HMGB1, SREBP-1c and FAS were evaluated. Digested milk treatments significantly reduced 3T3-L1 mature adipocytes viability and caspase activity compared with control group, but no significant differences were observed among different sources of digested milk. In all digested milk samples, ROS level was higher than the control, however, the digested human and formula milk showed lower levels of ROS than DM, BM, OM and CM samples. Lower capacity of HM and FM to induce oxidative stress in mature adipocytes was ascribed to the peculiar free fatty acids profile of digested milk samples. All milk treatments elicited a significant over-expression of NF-κB p65 in 3T3-L1 adipocytes compared to the control; the lowest gene expression was found in HM, BM, OM and CM, the highest in FM and an intermediate behavior was shown in DM. All digested milk treatments influenced the gene expression of SRBP-1c with FM and HM showing the highest levels. For FAS expression, BM showed the highest level, OM and CM intermediate and FM, HM and DM the lowest levels, however HM and DM had comparable levels to the control.
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22
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Urea Memory: Transient Cell Exposure to Urea Causes Persistent Mitochondrial ROS Production and Endothelial Dysfunction. Toxins (Basel) 2018; 10:toxins10100410. [PMID: 30314315 PMCID: PMC6215169 DOI: 10.3390/toxins10100410] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/07/2018] [Accepted: 10/09/2018] [Indexed: 12/22/2022] Open
Abstract
Urea at post-dialysis levels induces increased ROS in a number of cell types. The aim of this study was to determine whether urea-induced production of ROS remains elevated after urea is no longer present, and, if it does, to characterize its origin and effects. Human arterial endothelial cells were incubated with 20 mM urea for two days, and then cells were incubated for an additional two days in medium alone. Maximal ROS levels induced by initial urea continued at the same level despite urea being absent. These effects were prevented by either MnSOD expression or by Nox1/4 inhibition with GKT13781. Sustained urea-induced ROS caused a persistent reduction in mtDNA copy number and electron transport chain transcripts, a reduction in transcription of mitochondrial fusion proteins, an increase in mitochondrial fission proteins, and persistent expression of endothelial inflammatory markers. The SOD-catalase mimetic MnTBAP reversed each of these. These results suggest that persistent increases in ROS after cells are no long exposed to urea may play a major role in continued kidney damage and functional decline despite reduction of urea levels after dialysis.
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Shao Y, Li X, Wood JW, Ma JX. Mitochondrial dysfunctions, endothelial progenitor cells and diabetic retinopathy. J Diabetes Complications 2018; 32:966-973. [PMID: 30068485 DOI: 10.1016/j.jdiacomp.2018.06.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 06/18/2018] [Accepted: 06/28/2018] [Indexed: 12/11/2022]
Abstract
AIM Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population. Endothelial progenitor cells (EPC) play a vital role in vascular damage repair. This article will review recent progress regarding mitochondrial and EPC dysfunction associated with DR. RESULTS EPCs represent a limited population of adult stem cells possessing vasculogenic potential postnatally; their number and function are changed in DR. Among all the function changes, mitochondrial dysfunction plays an important role in the dysregulation of EPCs, as mitochondria regulate energy balance, and cell fate determination. CONCLUSIONS Although the mechanism for the role of mitochondria dysregulation in EPC function remains elusive, mitochondria of EPCs represent a promising target for the treatment of the vasculopathy presented within DR.
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Affiliation(s)
- Yan Shao
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China; Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA
| | - Xiaorong Li
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China
| | - John W Wood
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA
| | - Jian-Xing Ma
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA.
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24
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Wang RY, Liu LH, Liu H, Wu KF, An J, Wang Q, Liu Y, Bai LJ, Qi BM, Qi BL, Zhang L. Nrf2 protects against diabetic dysfunction of endothelial progenitor cells via regulating cell senescence. Int J Mol Med 2018; 42:1327-1340. [PMID: 29901179 PMCID: PMC6089760 DOI: 10.3892/ijmm.2018.3727] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 06/08/2018] [Indexed: 12/20/2022] Open
Abstract
Diabetes is associated with an increased risk of cardio-vascular disease. A decrease in the number and functionality of endothelial progenitor cells (EPCs) leads to reduced endothelial repair and the development of cardiovascular disease. The aim of the present study was to explore the effect and underlying mechanisms of nuclear factor erythroid 2-related factor 2 (Nrf2) on EPC dysfunction caused by diabetic mellitus. The biological functions of EPCs in streptozotocin-induced diabetic mice were evaluated, including migration, proliferation, angiogenesis and the secretion of vascular endothelial growth factor (VEGF), stromal-derived growth factor (SDF) and nitric oxide (NO). Oxidative stress levels in diabetic EPCs were also assessed by detecting intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). EPC senescence was evaluated by measuring p16 and b-gal expression and observing the senescence-associated secretory phenotype. In addition, the function of EPCs and level of oxidative stress were assessed following Nrf2 silencing or activation. Nrf2 silencing resulted in a decrease of EPC biological functions, accelerated cell senescence and increased oxidative stress, as indicated by ROS and MDA upregulation accompanied with decreased SOD activity. Furthermore, Nrf2 silencing inhibited migration, proliferation and secretion in EPCs, while it increased oxidative stress and cell senescence. Nrf2 activation protected diabetic EPCs against the effects of oxidative stress and cell senescence, ameliorating the biological dysfunction of EPCs derived from mice with diabetes. In conclusion, Nrf2 overexpression protected against oxidative stress-induced functional damage in EPCs derived from diabetic mice by regulating cell senescence.
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Affiliation(s)
- Rui-Yun Wang
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Li-Hua Liu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Hongxia Liu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Ke-Fei Wu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jing An
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Qian Wang
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yun Liu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Li-Juan Bai
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Ben-Ming Qi
- Department of Otorhinolaryngology, First People's Hospital of Yunnan Province, Kunming, Yunnan 650000, P.R. China
| | - Ben-Ling Qi
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Lei Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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25
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Yang M, Teng S, Ma C, Yu Y, Wang P, Yi C. Ascorbic acid inhibits senescence in mesenchymal stem cells through ROS and AKT/mTOR signaling. Cytotechnology 2018; 70:1301-1313. [PMID: 29777434 DOI: 10.1007/s10616-018-0220-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 04/09/2018] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell (MSC) aging seriously affects its function in stem cell transplantation for treatment. Extensive studies have focused on how to inhibit senescence in MSCs. However, the mechanism of senescence in MSC was not clear. In this study, we used D-galactose to induce MSC aging. Then we found that the number of aging cells was increased compared with untreated MSCs. We discovered that ascorbic acid could inhibit the production of reactive oxygen species (ROS) and activation of AKT/mTOR signaling in MSCs caused by D-galactose. Especially, when treated together with a ROS scavenger or AKT inhibitor, the senescent cells were obviously decreased in D-galactose-induced MSCs. Taken together, we identify that ascorbic acid owns the potential to inhibit the senescence of MSCs through ROS and Akt/mTOR signaling. Together, our data supports that ascorbic acid can be used to prevent MSCs from senescence, which can enhance the efficiency of stem cell transplantation in the clinic.
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Affiliation(s)
- Mengkai Yang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Songsong Teng
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chunhui Ma
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Yinxian Yu
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Peilin Wang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chengqing Yi
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
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26
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Sakai Y, Yamamori T, Yoshikawa Y, Bo T, Suzuki M, Yamamoto K, Ago T, Inanami O. NADPH oxidase 4 mediates ROS production in radiation-induced senescent cells and promotes migration of inflammatory cells. Free Radic Res 2017; 52:92-102. [PMID: 29228832 DOI: 10.1080/10715762.2017.1416112] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Excessive DNA damage induced by ionising radiation (IR) to normal tissue cells is known to trigger cellular senescence, a process termed stress-induced premature senescence (SIPS). SIPS is often accompanied by the production of reactive oxygen species (ROS), and this is reported to be important for the initiation and maintenance of SIPS. However, the source of ROS during SIPS after IR and their significance in radiation-induced normal tissue damage remain elusive. In the present study, we tested the hypothesis that the NADPH oxidase (NOX) family of proteins mediates ROS production in SIPS-induced cells after IR and plays a role in SIPS-associated biological events. X-irradiation of primary mouse embryonic fibroblasts (MEFs) resulted in cellular senescence and the concomitant increase of intracellular ROS. Among all six murine NOX isoforms (NOX1-4 and DUOX1/2), only NOX4 was detectable under basal conditions and was upregulated following IR. In addition, radiation-induced ROS production was diminished by genetic or pharmacological inhibition of NOX4. Meanwhile, NOX4 deficiency did not affect the induction of cellular senescence after IR. Furthermore, the migration of human monocytic U937 cells to the culture medium collected from irradiated MEFs was significantly reduced by NOX4 inhibition, suggesting that NOX4 promotes the recruitment of inflammatory cells. Collectively, our findings imply that NOX4 mediates ROS production in radiation-induced senescent cells and contributes to normal tissue damage after IR via the recruitment of inflammatory cells and the exacerbation of tissue inflammation.
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Affiliation(s)
- Yuri Sakai
- a Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine , Hokkaido University , Sapporo , Japan
| | - Tohru Yamamori
- a Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine , Hokkaido University , Sapporo , Japan
| | - Yoji Yoshikawa
- b Department of Medicine and Clinical Science, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Tomoki Bo
- a Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine , Hokkaido University , Sapporo , Japan
| | - Motofumi Suzuki
- c Radiation and Cancer Biology Team , National Institutes for Quantum and Radiobiological Science and Technology , Chiba , Japan
| | - Kumiko Yamamoto
- a Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine , Hokkaido University , Sapporo , Japan
| | - Tetsuro Ago
- b Department of Medicine and Clinical Science, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Osamu Inanami
- a Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine , Hokkaido University , Sapporo , Japan
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Giardino I, D'Apolito M, Brownlee M, Maffione AB, Colia AL, Sacco M, Ferrara P, Pettoello-Mantovani M. Vascular toxicity of urea, a new "old player" in the pathogenesis of chronic renal failure induced cardiovascular diseases. Turk Arch Pediatr 2017; 52:187-193. [PMID: 29483797 DOI: 10.5152/turkpediatriars.2017.6314] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 11/03/2017] [Indexed: 12/30/2022]
Abstract
Chronic kidney disease in children is an irreversible process that may lead to end-stage renal disease. The mortality rate in children with end-stage renal disease who receive dialysis increased dramatically in the last decade, and it is significantly higher compared with the general pediatric population. Furthermore, dialysis and transplant patients, who have developed end-stage renal disease during childhood, live respectively far less as compared with age/race-matched populations. Different reports show that cardiovascular disease is the leading cause of death in children with end-stage renal disease and in adults with childhood-onset chronic kidney disease, and that children with chronic kidney disease are in the highest risk group for the development of cardiovascular disease. Urea, which is generated in the liver during catabolism of amino acids and other nitrogenous metabolites, is normally excreted into the urine by the kidneys as rapidly as it is produced. When renal function is impaired, increasing concentrations of blood urea will steadily accumulate. For a long time, urea has been considered to have negligible toxicity. However, the finding that plasma urea is the only significant predictor of aortic plaque area fraction in an animal model of chronic renal failure -accelerated atherosclerosis, suggests that the high levels of urea found in chronic dialysis patients might play an important role in accelerated atherosclerosis in this group of patients. The aim of this review was to provide novel insights into the role played by urea in the pathogenesis of accelerated cardiovascular disease in renal failure.
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Affiliation(s)
- Ida Giardino
- Research Center of Laboratory Medicine, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Maria D'Apolito
- Department of Pediatrics. Scientific Institute "Casa Sollievo della Sofferenza", University of Foggia, Italy
| | - Michael Brownlee
- Diabetes Research Center and Departments of Internal Medicine and Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Angela Bruna Maffione
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Anna Laura Colia
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Michele Sacco
- Department of Pediatrics. Scientific Institute "Casa Sollievo della Sofferenza", University of Foggia, Italy
| | - Pietro Ferrara
- Campus Bio-Medico University Medical School, Rome, Italy
| | - Massimo Pettoello-Mantovani
- Department of Pediatrics. Scientific Institute "Casa Sollievo della Sofferenza", University of Foggia, Italy.,European Paediatric Association/Union of National European Paediatric Societies and Associations, Berlin, Germany
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