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Liu X, Wu J, Peng Y, Liu G, Jin K, Niu Y, Song J, Han W, Chen G, Li B, Zuo Q. Functional Equivalence of Insulin and IGF-1 in the In Vitro Culture of Chicken Primordial Germ Cells. Genes (Basel) 2025; 16:481. [PMID: 40428303 PMCID: PMC12110881 DOI: 10.3390/genes16050481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Chicken Primordial Germ Cells (PGCs) are one of the few germ cells that can be cultured for a long time in vitro, but challenges remain such as low culture efficiency and unclear roles of nutrient factors and signaling pathways. METHOD In this study, protein kinase B (AKT) pathway activator insulin-like growth factor 1 (IGF-1) was screened for its ability to promote cell proliferation by transcriptome results using various inhibitors of pathway activation. The effects of IGF-1 on PGCs were evaluated through EdU assays, qRT-PCR, flow cytometry, and migration experiments. RESULTS This study systematically examined the effects of insulin and IGF-1 on the proliferation, cell cycle, ferroptosis, migration capacity, and establishment efficiency of PGCs. The findings demonstrated that IGF-1 exhibited comparable effects to insulin and could effectively replace insulin in PGC culture systems. CONCLUSIONS The research results are expected to provide a solid theoretical basis for optimizing the chicken PGC cultivation system and promoting its practical application.
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Affiliation(s)
- Xin Liu
- Key Laboratory of Animal Genetics, Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Jun Wu
- Key Laboratory of Animal Genetics, Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Yixiu Peng
- Key Laboratory of Animal Genetics, Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Guangzheng Liu
- Key Laboratory of Animal Genetics, Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Kai Jin
- Key Laboratory of Animal Genetics, Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Yingjie Niu
- Key Laboratory of Animal Genetics, Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Jiuzhou Song
- Animal & Avian Sciences, University of Maryland, College Park, MD 20742, USA
| | - Wei Han
- Poultry Institute, Chinese Academy of Agricultural Sciences Poultry Institute of Jiangsu, Yangzhou 225003, China
| | - Guohong Chen
- Key Laboratory of Animal Genetics, Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Bichun Li
- Key Laboratory of Animal Genetics, Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- College of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, China
| | - Qisheng Zuo
- Key Laboratory of Animal Genetics, Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
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Chaudhry H, Dargham S, Jayyousi A, Al Suwaidi J, Abi Khalil C. Diabetes does not increase in-hospital or short-term mortality in patients undergoing surgical repair for type A aortic dissection: insight from the national readmission database. Cardiovasc Diabetol 2024; 23:436. [PMID: 39643900 PMCID: PMC11622540 DOI: 10.1186/s12933-024-02524-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 11/22/2024] [Indexed: 12/09/2024] Open
Abstract
BACKGROUND Previous studies have reported a protective effect of type 2 diabetes on the incidence and progression of aortic aneurysms. We investigated whether this protective effect extends to aortic dissections. METHODS Data from the US Nationwide Readmission Database (2016-2019) were analyzed. Patients admitted for open surgery repair of acute type A aortic dissection (TAAD) were initially analyzed (index group). Those discharged alive were followed for up to 30 days (readmission group). The co-primary outcomes were in-hospital and 30-day mortality. RESULTS Between 2016 and 2019, 7,324 patients were admitted for open surgical repair of acute TAAD, of whom 965 (13.2%) had diabetes. Patients with diabetes were older and had a higher prevalence of obesity, hypertension, smoking, dyslipidemia, and chronic kidney disease (CKD). 15.2% of patients with diabetes and 14.6% without diabetes died; hence, diabetes did not have a significant impact on in-hospital mortality (adjusted odd ratio [aOR] = 1.02 [0.84-1.24]). Similarly, diabetes was not associated with a higher adjusted risk of atrial fibrillation (aOR = 1.03 [0.89-1.20]), stroke (aOR = 0.83 [0.55-1.26]), cardiogenic shock (aOR = 1.18 [0.98-1.42]), but increased the risk of acute renal failure (aOR = 1.20 [1.04-1.39]). Within 30 days of discharge, 154 (15.9%) patients with diabetes and 952 (15%) from the non-diabetes group were readmitted. Readmitted patients with diabetes were older and had a higher prevalence of cardiovascular comorbidities. We didn't observe any significant difference in the adjusted risk of 30-day mortality between the diabetes and non-diabetes groups (adjusted hazard ratio [aHR] = 0.81 [0.41-1.60]). However, diabetes was associated with a lower risk of readmission (aHR = 0.81 [0.68-0.97]). Age was the most significant predictor of all outcomes. CKD was the most significant predictor of 30-day mortality, with the risk increasing five-fold in patients with diabetes (HR = 5.58 [2.58-6.62]. Cardiovascular-related conditions were the most common causes of readmission in both groups. However, respiratory-related conditions were more prevalent in the diabetes group compared to the non-diabetes group (19.5% vs. 13%, respectively, p = 0.032). CONCLUSIONS Diabetes does not increase in-hospital or short-term mortality in patients undergoing surgical repair for Type A aortic dissection.
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Affiliation(s)
- Hamza Chaudhry
- Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Soha Dargham
- Department of Medical Education, Weill Cornell Medicine- Qatar, Doha, Qatar
- Biostatistics Core, Weill Cornell Medicine- Qatar, Doha, Qatar
| | - Amin Jayyousi
- Department of Endocrinology, Hamad Medical Corporation, Doha, Qatar
| | | | - Charbel Abi Khalil
- Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar.
- Heart hospital, Hamad Medical Corporation, Doha, Qatar.
- Sanford and I. Weill Department of Medicine, Weill Cornell Medicine, New York, USA.
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3
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Cheng CK, Huang Y. Vascular endothelium: The interface for multiplex signal transduction. J Mol Cell Cardiol 2024; 195:97-102. [PMID: 39147197 DOI: 10.1016/j.yjmcc.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/10/2024] [Accepted: 08/12/2024] [Indexed: 08/17/2024]
Abstract
As the innermost monolayer of the vasculature, endothelial cells (ECs) serve as the interface for multiplex signal transduction. Directly exposed to blood-borne factors, both endogenous and exogenous, ECs actively mediate vascular homeostasis and represent a therapeutic target against cardiometabolic diseases. ECs act as the first-line gateway between gut-derived substances and vasculature. Additionally, ECs convert blood flow-exerted hemodynamic forces into downstream biochemical signaling to modulate vascular pathophysiology. Besides, ECs can sense other forms of stimuli, like cell extrusion, thermal stimulation, photostimulation, radiation, magnetic field, noise, and gravity. Future efforts are still needed to deepen our understanding on endothelial biology.
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Affiliation(s)
- Chak Kwong Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China.
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China.
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4
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Lagunas-Rangel FA. Aging insights from heterochronic parabiosis models. NPJ AGING 2024; 10:38. [PMID: 39154047 PMCID: PMC11330497 DOI: 10.1038/s41514-024-00166-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 08/07/2024] [Indexed: 08/19/2024]
Abstract
Heterochronic parabiosis consists of surgically connecting the circulatory systems of a young and an old animal. This technique serves as a model to study circulating factors that accelerate aging in young organisms exposed to old blood or induce rejuvenation in old organisms exposed to young blood. Despite the promising results, the exact cellular and molecular mechanisms remain unclear, so this study aims to explore and elucidate them in more detail.
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5
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Khan H, Abu-Raisi M, Feasson M, Shaikh F, Saposnik G, Mamdani M, Qadura M. Current Prognostic Biomarkers for Abdominal Aortic Aneurysm: A Comprehensive Scoping Review of the Literature. Biomolecules 2024; 14:661. [PMID: 38927064 PMCID: PMC11201473 DOI: 10.3390/biom14060661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 05/29/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
Abdominal aortic aneurysm (AAA) is a progressive dilatation of the aorta that can lead to aortic rupture. The pathophysiology of the disease is not well characterized but is known to be caused by the general breakdown of the extracellular matrix within the aortic wall. In this comprehensive literature review, all current research on proteins that have been investigated for their potential prognostic capabilities in patients with AAA was included. A total of 45 proteins were found to be potential prognostic biomarkers for AAA, predicting incidence of AAA, AAA rupture, AAA growth, endoleak, and post-surgical mortality. The 45 proteins fell into the following seven general categories based on their primary function: (1) cardiovascular health, (2) hemostasis, (3) transport proteins, (4) inflammation and immunity, (5) kidney function, (6) cellular structure, (7) and hormones and growth factors. This is the most up-to-date literature review on current prognostic markers for AAA and their functions. This review outlines the wide pathophysiological processes that are implicated in AAA disease progression.
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Affiliation(s)
- Hamzah Khan
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
| | - Mohamed Abu-Raisi
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
| | - Manon Feasson
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
| | - Farah Shaikh
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
| | - Gustavo Saposnik
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
- Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada
| | - Muhammad Mamdani
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
| | - Mohammad Qadura
- Division of Vascular Surgery, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
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6
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Mourino-Alvarez L, Perales-Sanchez I, Berna-Rico E, Abbad-Jaime de Aragon C, Corbacho-Alonso N, Sastre-Oliva T, Juarez-Alia C, Ballester-Martinez A, Castellanos-Gonzalez M, Llamas-Velasco M, Jaen P, Solis J, Fernandez-Friera L, Mehta NN, Gelfand JM, Barderas MG, Gonzalez-Cantero A. Association of the Complement System with Subclinical Atherosclerosis in Psoriasis: Findings from an Observational Cohort Study. J Invest Dermatol 2024; 144:1075-1087.e2. [PMID: 38036288 DOI: 10.1016/j.jid.2023.10.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/03/2023] [Accepted: 10/18/2023] [Indexed: 12/02/2023]
Abstract
Psoriasis is a chronic and inflammatory disease that affects the skin and joints and is associated with multiple comorbidities and cardiovascular risk factors. Consequently, patients with psoriasis have an increased risk of cardiovascular diseases such as atherosclerosis, a chronic pathology that shares common inflammatory and immune-response mechanisms with psoriasis, including vascular inflammation and complement activation. To better understand the relationship between atherosclerosis and psoriasis, a proteomics study followed by a bioinformatics analysis was carried out, with a subsequent validation step using ELISA and western blotting. When the plasma from patients with psoriasis alone was compared with that from patients with psoriasis and atherosclerosis, 31 proteins of interest related to the complement system and oxygen transport were identified. After the validation phase, 11 proteins appeared to define the presence of subclinical atherosclerosis in patients with psoriasis, indicating the importance of complement cascades in the development of atherosclerotic plaques in individuals with psoriasis. These results are a step forward in understanding the pathological pathways implicated in the cardiovascular risk associated with this population, which may represent an interesting starting point for developing predictive tools that improve the follow-up of these patients and design more effective therapies.
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Affiliation(s)
- Laura Mourino-Alvarez
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, Toledo, Spain; Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, Toledo, Spain
| | - Inés Perales-Sanchez
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, Toledo, Spain; Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, Toledo, Spain
| | - Emilio Berna-Rico
- Department of Dermatology, Hospital Universitario Ramon y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain
| | - Carlota Abbad-Jaime de Aragon
- Department of Dermatology, Hospital Universitario Ramon y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain
| | - Nerea Corbacho-Alonso
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, Toledo, Spain; Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, Toledo, Spain
| | - Tamara Sastre-Oliva
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, Toledo, Spain; Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, Toledo, Spain
| | - Cristina Juarez-Alia
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, Toledo, Spain; Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, Toledo, Spain
| | - Asunción Ballester-Martinez
- Department of Dermatology, Hospital Universitario Ramon y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain
| | | | - Mar Llamas-Velasco
- Department of Dermatology, Hospital Universitario de la Princesa, Madrid, Spain
| | - Pedro Jaen
- Department of Dermatology, Hospital Universitario Ramon y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain
| | - Jorge Solis
- Department of Cardiology, Hospital Universitario Doce de Octubre, Madrid, Spain; Atria Clinic, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
| | - Leticia Fernandez-Friera
- Atria Clinic, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain; HM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM-CIEC, Madrid, Spain
| | - Neha N Mehta
- Department of Cardiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Joel M Gelfand
- Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Maria G Barderas
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, Toledo, Spain; Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, Toledo, Spain.
| | - Alvaro Gonzalez-Cantero
- Department of Dermatology, Hospital Universitario Ramon y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain; Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain.
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7
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Yu MG, Gordin D, Fu J, Park K, Li Q, King GL. Protective Factors and the Pathogenesis of Complications in Diabetes. Endocr Rev 2024; 45:227-252. [PMID: 37638875 PMCID: PMC10911956 DOI: 10.1210/endrev/bnad030] [Citation(s) in RCA: 53] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 06/13/2023] [Accepted: 08/24/2023] [Indexed: 08/29/2023]
Abstract
Chronic complications of diabetes are due to myriad disorders of numerous metabolic pathways that are responsible for most of the morbidity and mortality associated with the disease. Traditionally, diabetes complications are divided into those of microvascular and macrovascular origin. We suggest revising this antiquated classification into diabetes complications of vascular, parenchymal, and hybrid (both vascular and parenchymal) tissue origin, since the profile of diabetes complications ranges from those involving only vascular tissues to those involving mostly parenchymal organs. A major paradigm shift has occurred in recent years regarding the pathogenesis of diabetes complications, in which the focus has shifted from studies on risks to those on the interplay between risk and protective factors. While risk factors are clearly important for the development of chronic complications in diabetes, recent studies have established that protective factors are equally significant in modulating the development and severity of diabetes complications. These protective responses may help explain the differential severity of complications, and even the lack of pathologies, in some tissues. Nevertheless, despite the growing number of studies on this field, comprehensive reviews on protective factors and their mechanisms of action are not available. This review thus focused on the clinical, biochemical, and molecular mechanisms that support the idea of endogenous protective factors, and their roles in the initiation and progression of chronic complications in diabetes. In addition, this review also aimed to identify the main needs of this field for future studies.
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Affiliation(s)
- Marc Gregory Yu
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Daniel Gordin
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
- Department of Nephrology, University of Helsinki and Helsinki University Central Hospital, Stenbäckinkatu 9, FI-00029 Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Tukholmankatu 8, 00290 Helsinki, Finland
| | - Jialin Fu
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Kyoungmin Park
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Qian Li
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - George Liang King
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
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8
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Wang Q, Jiang T, Li R, Zheng T, Han Q, Wang M. Whether serum leptin and insulin-like growth factor-1 are predictive biomarkers for post-stroke depression: A meta-analysis and systematic review. J Psychiatr Res 2024; 169:347-354. [PMID: 38091723 DOI: 10.1016/j.jpsychires.2023.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/24/2023] [Accepted: 12/06/2023] [Indexed: 01/15/2024]
Abstract
Leptin and insulin-like growth factor-1 (IGF-1) may play a role in clinical identification of post-stroke depression (PSD). Here, eight databases (including CNKI, Wanfang, SinoMed, VIP, PubMed, the Cochrane Library, Embase, and the Web of Science) were employed to search for studies on serum leptin and insulin-like growth factor-1 expression levels in patients with PSD. In total, 13 articles were included, of which 6 studies investigated the expression level of serum leptin in patients with PSD, 7 studies explored the serum IGF-1 in PSD patients. Then, the RevMan 5.4 software was used for meta-analysis. The results showed that serum leptin levels were significantly higher in PSD patients than in patients without PSD (SMD = 1.54, 95% CI: 0.84, 2.23; P = 0.006). The result of subgroup analysis showed that the serum leptin levels in PSD patients were significantly higher than those without PSD in acute phase (SMD = 1.38, 95% CI: 0.04, 2.71; P = 0.04), subacute phase (SMD = 2.31, 95% CI: 0.88, 3.73; P = 0.001), and chronic phase (SMD = 1.02, 95% CI: 0.43, 1.60; P = 0.0007); There was no significant difference in serum IGF-1 level between PSD patients and patients without PSD (SMD = 0.49, 95% CI: -0.55, 1.52; P = 0.36). Moreover, the subgroup analysis also showed that there was no statistical difference in acute stage (SMD = 0.36, 95% CI: 0.89, 1.60; P = 0.57). Our study provides evidence to prove that serum leptin level has potential clinical application value as biomarkers for identifying PSD.
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Affiliation(s)
- Qi Wang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Taotao Jiang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Rundong Li
- Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Ting Zheng
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Qian Han
- School of Public Health, Lanzhou University, Lanzhou, 730030, China
| | - Manxia Wang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, China.
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9
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Boutari C, Kokkorakis M, Stefanakis K, Valenzuela-Vallejo L, Axarloglou E, Volčanšek Š, Chakhtoura M, Mantzoros CS. Recent research advances in metabolism, clinical and experimental. Metabolism 2023; 149:155722. [PMID: 37931873 DOI: 10.1016/j.metabol.2023.155722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2023]
Affiliation(s)
- Chrysoula Boutari
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Michail Kokkorakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Konstantinos Stefanakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Laura Valenzuela-Vallejo
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Evangelos Axarloglou
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America
| | - Špela Volčanšek
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Zaloska 7, 1000 Ljubljana, Slovenia; Medical Faculty Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
| | - Marlene Chakhtoura
- Department of Internal Medicine, Division of Endocrinology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America; Department of Medicine, Boston VA Healthcare System, Boston, MA 02130, United States of America.
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10
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Garcia-Iborra M, Castanys-Munoz E, Oliveros E, Ramirez M. Optimal Protein Intake in Healthy Children and Adolescents: Evaluating Current Evidence. Nutrients 2023; 15:nu15071683. [PMID: 37049523 PMCID: PMC10097334 DOI: 10.3390/nu15071683] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/27/2023] [Accepted: 03/28/2023] [Indexed: 03/31/2023] Open
Abstract
High protein intake might elicit beneficial or detrimental effects, depending on life stages and populations. While high protein intake in elder individuals can promote beneficial health effects, elevated protein intakes in infancy are discouraged, since they have been associated with obesity risks later in life. However, in children and adolescents (4–18 years), there is a scarcity of data assessing the effects of high protein intake later in life, despite protein intake being usually two- to three-fold higher than the recommendations in developed countries. This narrative review aimed to revise the available evidence on the long-term effects of protein intake in children and adolescents aged 4–18 years. Additionally, it discusses emerging techniques to assess protein metabolism in children, which suggest a need to reevaluate current recommendations. While the optimal range is yet to be firmly established, available evidence suggests a link between high protein intake and increased Body Mass Index (BMI), which might be driven by an increase in Fat-Free Mass Index (FFMI), as opposed to Fat Mass Index (FMI).
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Affiliation(s)
- Maria Garcia-Iborra
- Abbott Nutrition R & D, Granada University Science Park, 18016 Granada, Spain; (M.G.-I.); (E.C.-M.)
| | - Esther Castanys-Munoz
- Abbott Nutrition R & D, Granada University Science Park, 18016 Granada, Spain; (M.G.-I.); (E.C.-M.)
| | - Elena Oliveros
- Abbott Nutrition R & D, Abbott Laboratories, 18004 Granada, Spain;
| | - Maria Ramirez
- Abbott Nutrition R & D, Abbott Laboratories, 18004 Granada, Spain;
- Correspondence: ; Tel.: +34-669127998
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Laway BA, Rasool A, Baba MS, Misgar RA, Bashir MI, Wani AI, Choh N, Shah O, Lone A, Shah Z. High prevalence of coronary artery calcification and increased risk for coronary artery disease in patients with Sheehan syndrome-A case-control study. Clin Endocrinol (Oxf) 2023; 98:375-382. [PMID: 36567411 DOI: 10.1111/cen.14871] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 11/22/2022] [Accepted: 12/22/2022] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Patients with Sheehan syndrome (SS) are predisposed to coronary artery disease (CAD) due to risk factors like abdominal obesity, dyslipidemia and chronic inflammation. In addition to estimate CAD risk enhancers like high sensitive C reactive protein (hsCRP), apolipoprotein B (ApoB) and lipoprotein A [Lp(a)], this study applies Framingham risk score (FRS) and coronary artery calcium (CAC) score to compute a 10-year probability of cardiovascular (CV) events in SS patients. DESIGN Case-control study Sixty-three SS patients, on a stable hormonal replacement treatment except for growth hormone and 65 age, body mass index and parity-matched controls. MEASUREMENTS Measurement of serum hsCRP, ApoB and Lp(a) and estimation of CAC with 16-row multislice computed tomography scanner. RESULTS The concentrations of hsCRP, ApoB and Lp(a) were significantly higher in SS patients than in controls (p < .01). After calculating FRS, 95.2% of SS patients were classified as low risk, 4.8% as intermediate risk and all controls were classified as low risk for probable CV events. CAC was detected in 50.7% SS patients and 7.6% controls (p = .006). According to the CAC score, 26.9% SS patients were classified as at risk (CAC > 10) for incident CV events as against 1.6% controls. The mean Multi-Ethnic Study of Atherosclerosis (MESA) score was significantly higher in patients with SS than controls. CAC corelated significantly with fasting blood glucose (r = .316), ApoB (r = .549), LP(a) (r = .310) and FRS (r = .294). CONCLUSION Significant number of asymptomatic SS patients have high coronary artery calcium score and are classified at risk for CAD.
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Affiliation(s)
- Bashir Ahmad Laway
- Department of Endocrinology, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
| | - Abid Rasool
- Department of Endocrinology, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
| | - Mohammad Salem Baba
- Department of Endocrinology, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
| | - Raiz Ahmad Misgar
- Department of Endocrinology, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
| | - Mir Iftikhar Bashir
- Department of Endocrinology, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
| | - Arshad Iqbal Wani
- Department of Endocrinology, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
| | - Naseer Choh
- Department of Radiology, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
| | - Omair Shah
- Department of Radiology, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
| | - Ajaz Lone
- Department of Cardiology, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
| | - Zaffar Shah
- Department of Immunology & Molecular Medicine, Sher-I- Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
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Macvanin M, Gluvic Z, Radovanovic J, Essack M, Gao X, Isenovic ER. New insights on the cardiovascular effects of IGF-1. Front Endocrinol (Lausanne) 2023; 14:1142644. [PMID: 36843588 PMCID: PMC9947133 DOI: 10.3389/fendo.2023.1142644] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023] Open
Abstract
INTRODUCTION Cardiovascular (CV) disorders are steadily increasing, making them the world's most prevalent health issue. New research highlights the importance of insulin-like growth factor 1 (IGF-1) for maintaining CV health. METHODS We searched PubMed and MEDLINE for English and non-English articles with English abstracts published between 1957 (when the first report on IGF-1 identification was published) and 2022. The top search terms were: IGF-1, cardiovascular disease, IGF-1 receptors, IGF-1 and microRNAs, therapeutic interventions with IGF-1, IGF-1 and diabetes, IGF-1 and cardiovascular disease. The search retrieved original peer-reviewed articles, which were further analyzed, focusing on the role of IGF-1 in pathophysiological conditions. We specifically focused on including the most recent findings published in the past five years. RESULTS IGF-1, an anabolic growth factor, regulates cell division, proliferation, and survival. In addition to its well-known growth-promoting and metabolic effects, there is mounting evidence that IGF-1 plays a specialized role in the complex activities that underpin CV function. IGF-1 promotes cardiac development and improves cardiac output, stroke volume, contractility, and ejection fraction. Furthermore, IGF-1 mediates many growth hormones (GH) actions. IGF-1 stimulates contractility and tissue remodeling in humans to improve heart function after myocardial infarction. IGF-1 also improves the lipid profile, lowers insulin levels, increases insulin sensitivity, and promotes glucose metabolism. These findings point to the intriguing medicinal potential of IGF-1. Human studies associate low serum levels of free or total IGF-1 with an increased risk of CV and cerebrovascular illness. Extensive human trials are being conducted to investigate the therapeutic efficacy and outcomes of IGF-1-related therapy. DISCUSSION We anticipate the development of novel IGF-1-related therapy with minimal side effects. This review discusses recent findings on the role of IGF-1 in the cardiovascular (CVD) system, including both normal and pathological conditions. We also discuss progress in therapeutic interventions aimed at targeting the IGF axis and provide insights into the epigenetic regulation of IGF-1 mediated by microRNAs.
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Affiliation(s)
- Mirjana Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- Clinic for Internal Medicine, Department of Endocrinology and Diabetes, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Jelena Radovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Magbubah Essack
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Xin Gao
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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13
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Bickel MA, Csik B, Gulej R, Ungvari A, Nyul-Toth A, Conley SM. Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis. Front Endocrinol (Lausanne) 2023; 14:1087053. [PMID: 36755922 PMCID: PMC9900125 DOI: 10.3389/fendo.2023.1087053] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/04/2023] [Indexed: 01/24/2023] Open
Abstract
Age-related cerebrovascular pathologies, ranging from cerebromicrovascular functional and structural alterations to large vessel atherosclerosis, promote the genesis of vascular cognitive impairment and dementia (VCID) and exacerbate Alzheimer's disease. Recent advances in geroscience, including results from studies on heterochronic parabiosis models, reinforce the hypothesis that cell non-autonomous mechanisms play a key role in regulating cerebrovascular aging processes. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert multifaceted vasoprotective effects and production of both hormones is significantly reduced in aging. This brief overview focuses on the role of age-related GH/IGF-1 deficiency in the development of cerebrovascular pathologies and VCID. It explores the mechanistic links among alterations in the somatotropic axis, specific macrovascular and microvascular pathologies (including capillary rarefaction, microhemorrhages, impaired endothelial regulation of cerebral blood flow, disruption of the blood brain barrier, decreased neurovascular coupling, and atherogenesis) and cognitive impairment. Improved understanding of cell non-autonomous mechanisms of vascular aging is crucial to identify targets for intervention to promote cerebrovascular and brain health in older adults.
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Affiliation(s)
- Marisa A. Bickel
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Boglarka Csik
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Rafal Gulej
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Anna Ungvari
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- International Training Program in Geroscience, Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Adam Nyul-Toth
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- International Training Program in Geroscience, Department of Public Health, Semmelweis University, Budapest, Hungary
- Institute of Biophysics, Biological Research Centre, Eötvös Lorand Research Network (ELKH), Szeged, Hungary
| | - Shannon M. Conley
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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Wang Y, Wang Y, He B, Tao C, Han Z, Liu P, Wang Y, Tang C, Liu X, Du J, Jin H. Plasma human growth cytokines in children with vasovagal syncope. Front Cardiovasc Med 2022; 9:1030618. [PMID: 36312268 PMCID: PMC9614254 DOI: 10.3389/fcvm.2022.1030618] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 09/27/2022] [Indexed: 12/05/2022] Open
Abstract
Purpose The study was designed to investigate the profile of plasma human growth cytokines in pediatric vasovagal syncope (VVS). Materials and methods In the discovery set of the study, plasma human growth cytokines were measured using a Quantiboby Human Growth Factor Array in 24 VVS children and 12 healthy controls. Scatter and principal component analysis (PCA) diagrams were used to describe the samples, an unsupervised hierarchical clustering analysis was used to categorize the samples. Subsequently, the cytokines obtained from the screening assays were verified with a suspension cytokine array in the validation set of the study including 53 VVS children and 24 controls. Finally, the factors associated with pediatric VVS and the predictive value for the diagnosis of VVS were determined. Results In the discovery study, the differential protein screening revealed that the plasma hepatocyte growth factor (HGF), transforming growth factor b1 (TGF-b1), insulin-like growth factor binding protein (IGFBP)-4, and IGFBP-1 in children suffering from VVS were higher than those of the controls (all adjust P- value < 0.05). However, the plasma IGFBP-6, epidermal growth factor (EGF), and IGFBP-3 in pediatric VVS were lower than those of the controls (all adjust P- value < 0.01). Meanwhile, the changes of 7 differential proteins were analyzed by volcano plot. Unsupervised hierarchical cluster analysis demonstrated that patients in the VVS group could be successfully distinguished from controls based on the plasma level of seven differential proteins. Further validation experiments showed that VVS patients had significantly higher plasma concentrations of HGF, IGFBP-1, and IGFBP-6, but lower plasma concentrations of EGF and IGFBP-3 than controls. The logistics regression model showed that increased plasma concentration of HGF and IGFBP-1 and decreased plasma concentration of EGF were correlated with the development of pediatric VVS. ROC curve analysis showed that the abovementioned 3 proteins were useful for assisting the diagnosis of VVS. Conclusion Plasma human growth cytokine profiling changed in pediatric VVS. Elevated plasma concentrations of HGF and IGFBP-1, and decreased EGF were associated factors in the development of pediatric VVS. The abovementioned three proteins are helpful for the diagnosis of pediatric VVS.
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Affiliation(s)
- Yuanyuan Wang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Yaru Wang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Bing He
- Department of Pediatrics, People’s Hospital of Wuhan University, Hubei, China
| | - Chunyan Tao
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Zhenhui Han
- Department of Cardiology, Children’s Hospital of Kaifeng, Kaifeng, China
| | - Ping Liu
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Yuli Wang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Chaoshu Tang
- Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
- Department of Physiology and Pathophysiology, Health Science Centre, Peking University, Beijing, China
| | - Xueqin Liu
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Junbao Du
- Department of Pediatrics, Peking University First Hospital, Beijing, China
- Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Hongfang Jin
- Department of Pediatrics, Peking University First Hospital, Beijing, China
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Shin J, Toyoda S, Nishitani S, Onodera T, Fukuda S, Kita S, Fukuhara A, Shimomura I. SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the lung, liver, adipose tissue, and pancreatic cells via IRF1. Metabolism 2022; 133:155236. [PMID: 35688210 PMCID: PMC9173833 DOI: 10.1016/j.metabol.2022.155236] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/11/2022] [Accepted: 06/01/2022] [Indexed: 01/08/2023]
Abstract
BACKGROUND COVID-19 can cause multiple organ damages as well as metabolic abnormalities such as hyperglycemia, insulin resistance, and new onset of diabetes. The insulin/IGF signaling pathway plays an important role in regulating energy metabolism and cell survival, but little is known about the impact of SARS-CoV-2 infection. The aim of this work was to investigate whether SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the host cell/tissue, and if so, the potential mechanism and association with COVID-19 pathology. METHODS To determine the impact of SARS-CoV-2 on insulin/IGF signaling pathway, we utilized transcriptome datasets of SARS-CoV-2 infected cells and tissues from public repositories for a wide range of high-throughput gene expression data: autopsy lungs from COVID-19 patients compared to the control from non-COVID-19 patients; lungs from a human ACE2 transgenic mouse infected with SARS-CoV-2 compared to the control infected with mock; human pluripotent stem cell (hPSC)-derived liver organoids infected with SARS-CoV-2; adipose tissues from a mouse model of COVID-19 overexpressing human ACE2 via adeno-associated virus serotype 9 (AAV9) compared to the control GFP after SARS-CoV-2 infection; iPS-derived human pancreatic cells infected with SARS-CoV-2 compared to the mock control. Gain and loss of IRF1 function models were established in HEK293T and/or Calu3 cells to evaluate the impact on insulin signaling. To understand the mechanistic regulation and relevance with COVID-19 risk factors, such as older age, male sex, obesity, and diabetes, several transcriptomes of human respiratory, metabolic, and endocrine cells and tissue were analyzed. To estimate the association with COVID-19 severity, whole blood transcriptomes of critical patients with COVID-19 compared to those of hospitalized noncritical patients with COVID-19. RESULTS We found that SARS-CoV-2 infection impaired insulin/IGF signaling pathway genes, such as IRS, PI3K, AKT, mTOR, and MAPK, in the host lung, liver, adipose tissue, and pancreatic cells. The impairments were attributed to interferon regulatory factor 1 (IRF1), and its gene expression was highly relevant to risk factors for severe COVID-19; increased with aging in the lung, specifically in men; augmented by obese and diabetic conditions in liver, adipose tissue, and pancreatic islets. IRF1 activation was significantly associated with the impaired insulin signaling in human cells. IRF1 intron variant rs17622656-A, which was previously reported to be associated with COVID-19 prevalence, increased the IRF1 gene expression in human tissue and was frequently found in American and European population. Critical patients with COVID-19 exhibited higher IRF1 and lower insulin/IGF signaling pathway genes in the whole blood compared to hospitalized noncritical patients. Hormonal interventions, such as dihydrotestosterone and dexamethasone, ameliorated the pathological traits in SARS-CoV-2 infectable cells and tissues. CONCLUSIONS The present study provides the first scientific evidence that SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in respiratory, metabolic, and endocrine cells and tissues. This feature likely contributes to COVID-19 severity with cell/tissue damage and metabolic abnormalities, which may be exacerbated in older, male, obese, or diabetic patients.
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Affiliation(s)
- Jihoon Shin
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Department of Diabetes Care Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
| | - Shinichiro Toyoda
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shigeki Nishitani
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Toshiharu Onodera
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shiro Fukuda
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shunbun Kita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Department of Adipose Management, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Atsunori Fukuhara
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Department of Adipose Management, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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Upadhyay PK, Vishwakarma VK, Srivastav RK. Caveolins: Expression of Regulating Systemic Physiological Functions in Various Predicaments. Drug Res (Stuttg) 2022; 72:238-244. [PMID: 35426095 DOI: 10.1055/a-1785-4133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Caveolins are membrane proteins which contains caveolae. They are present in the plasma membrane. Many researchers found that caveolae have been associated with expression of the caveolins in major physiological networks of mammalian cells. Subtypes of caveolin including caveolin-1 and caveolin-2 have been found in micro arteries of rat brain, while caveolin-3 has been found in astrocytes. Caveolin-1 and caveolae play important roles in Alzheimer's disease, cancer, ischemic preconditioning-mediated cardio-protection, postmenopausal alterations in women, and age-related neurodegeneration. Caveolin-1 may modify fatty acid transmembrane flux in adipocytes. The discovery of a link between ischemia preconditioning, cardio-protection, and endothelial nitric oxide synthase has supported cardiovascular research tremendously. Therefore, caveolins are effective in regulation of cellular, cardiovascular, brain, and immune processes. They ascertain new signalling pathways and link the functionalities of these pathways. This review paper focuses on contribution of caveolins in various conditions, caveolin expression at the molecular level and their physiological effects in many organ systems.
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Affiliation(s)
| | | | - Ritesh Kumar Srivastav
- Faculty of Pharmacy, Kamla Nehru Institute of Management & Technology, Sultanpur, UP, India
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17
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Betzmann D, Döring M, Blumenstock G, Erdmann F, Grabow D, Lang P, Binder G. Impact of serum insulin-like growth factor-1 on HSCT outcome in pediatric cancer patients. Transplant Cell Ther 2022; 28:355.e1-355.e9. [PMID: 35405367 DOI: 10.1016/j.jtct.2022.03.027] [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: 10/13/2021] [Revised: 12/20/2021] [Accepted: 03/30/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is associated with severe medical complications and variable outcome depending on the recipient's disease stage and health condition. Biomarkers predicting outcome may have therapeutic relevance in pediatric cancer care. Insulin like growth factor 1 (IGF 1) is a mitogenic and anabolic peptide hormone that is expressed in almost all tissues. This hormone is the major growth factor in childhood. As IGF 1 is decreased in conditions that cause catabolic metabolism, it may reflect the degree of physical robustness of the patient and serve as predictive biomarker for transplant outcome. OBJECTIVES AND STUDY DESIGN We evaluated the impact of pre-transplant serum-IGF 1 on both survival and adverse events in 587 pediatric cancer patients, who underwent autologous or allogeneic HSCT between 1987 and 2014 at the University Children's Hospital Tübingen, Germany. Survival probabilities of the entire cohort and of defined subgroups according to pre-transplant serum-IGF-1 were estimated using the Kaplan-Meier method. RESULTS Mean pre-transplant IGF 1 (n = 498) was low: -1.67 SDS (SD, 1.54). Completeness of follow-up three and ten years post HSCT was 96 % and 83 %, respectively. The ten-year overall survival was 44.8 % (95 % confidence interval [CI], 40.6-48.9). With decreasing IGF-1 SDS, there was a significant increase of transplant-related mortality (p = 0.027), sinusoidal obstruction syndrome (quartiles 4 to 1: 3; 1; 12; 12%; p < 0.001) and thrombotic microangiopathy (quartiles 4 to 1: 0: 0: 2; 5%; p = 0.004). IGF 1 decile 1 showed a significantly poorer outcome (p=0.042) with lower median (12 versus 68 months) and ten-year overall survival (37 % versus 52 %) when compared to decile 2-10. CONCLUSIONS This retrospective study suggests pre-transplant serum-IGF 1 as a predictor of survival and selected vascular adverse events that may have diagnostic and therapeutic relevance in pediatric cancer care.
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Affiliation(s)
- Deborah Betzmann
- University Children's Hospital Tübingen, Hoppe-Seyler-Str.1, 72076 Tübingen, Germany
| | - Michaela Döring
- University Children's Hospital Tübingen, Hoppe-Seyler-Str.1, 72076 Tübingen, Germany
| | - Gunnar Blumenstock
- Department of Clinical Epidemiology and Applied Biometry, University of Tübingen, Silcherstraße 5, 72076 Tübingen, Germany
| | - Friederike Erdmann
- Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) University Medical Center of the Johannes Gutenberg University Mainz, Mainz
| | - Desiree Grabow
- Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) University Medical Center of the Johannes Gutenberg University Mainz, Mainz
| | - Peter Lang
- University Children's Hospital Tübingen, Hoppe-Seyler-Str.1, 72076 Tübingen, Germany
| | - Gerhard Binder
- University Children's Hospital Tübingen, Hoppe-Seyler-Str.1, 72076 Tübingen, Germany.
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Acute and chronic effects of traditional and high-speed resistance training on blood pressure in older adults: A crossover study and systematic review and meta-analysis. Exp Gerontol 2022; 163:111775. [DOI: 10.1016/j.exger.2022.111775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 03/03/2022] [Accepted: 03/21/2022] [Indexed: 11/22/2022]
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Lin KN, Zhang K, Zhao W, Huang SY, Li H. Insulin-like Growth Factor 1 Promotes Cell Proliferation by Downregulation of G-Protein-Coupled Receptor 17 Expression via PI3K/Akt/FoxO1 Signaling in SK-N-SH Cells. Int J Mol Sci 2022; 23:ijms23031513. [PMID: 35163437 PMCID: PMC8835821 DOI: 10.3390/ijms23031513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/10/2022] [Accepted: 01/25/2022] [Indexed: 12/04/2022] Open
Abstract
Insulin-like growth factor 1 (IGF-1) not only regulates neuronal function and development but also is neuroprotective in the setting of acute ischemic stroke. G-protein-coupled receptor 17 (GPR17) expression in brain tissue serves as an indicator of brain damage. As whether IGF-1 regulates GPR17 expression remains unknown, the aim of this study is to investigate how IGF-1 regulates GPR17 expression in vitro. Human neuroblastoma SK-N-SH cells were used. Lentivirus-mediated short hairpin RNA (shRNA) was constructed to mediate the silencing of FoxO1, while adenoviral vectors were used for its overexpression. Verification of the relevant signaling cascade was performed using a FoxO1 inhibitor (AS1842856), a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), and a GPR17 antagonist (cangrelor). Cell proliferation was analyzed using EdU staining; immunofluorescence staining was used to detect the expression and subcellular localization of FoxO1. Chromatin immunoprecipitation was used to analyze the binding of FoxO1 to the GPR17 promoter in SK-N-SH cells. The expression of FoxO1, GPR17, and protein kinase B (also known as Akt) mRNA and protein as well as the levels of FoxO1 and Akt phosphorylation were investigated in this study. IGF-1 was found to downregulate FoxO1 and GPR17 expression in SK-N-SH cells while promoting cell viability and proliferation. Inhibition of FoxO1 and antagonism of GPR17 were found to play a role similar to that of IGF-1. Silencing of FoxO1 by lentivirus-mediated shRNA resulted in the downregulation of FoxO1 and GPR17 expression. The overexpression of FoxO1 via adenoviral vectors resulted in the upregulation of FoxO1 and GPR17 expression. Blocking of PI3K signaling by LY294002 inhibited the effect of IGF-1 on GPR17 suppression. Results from chromatin immunoprecipitation revealed that IGF-1 promotes FoxO1 nuclear export and reduces FoxO1 binding to the GPR17 promoter in SK-N-SH cells. Here, we conclude that IGF-1 enhances cell viability and proliferation in SK-N-SH cells via the promotion of FoxO1 nuclear export and reduction of FoxO1 binding to the GPR17 promoter via PI3K/Akt signaling. Our findings suggest that the enhancement of IGF-1 signaling to antagonize GPR17 serves as a potential therapeutic strategy in the management of acute ischemic stroke.
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Affiliation(s)
- Ka-Na Lin
- Center for Brain Science & Clinical Research Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
| | - Kan Zhang
- Department of Anesthesiology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
| | - Wei Zhao
- Department of Pharmacy, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; (W.Z.); (S.-Y.H.)
| | - Shi-Ying Huang
- Department of Pharmacy, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; (W.Z.); (S.-Y.H.)
| | - Hao Li
- Center for Brain Science & Clinical Research Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
- Department of Pharmacy, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; (W.Z.); (S.-Y.H.)
- Correspondence:
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Maharani N, Soetadji A, Utari A, Naka I, Ohashi J, Mexitalia M. Cytochrome b-245 Alpha Chain Gene Variants and Arterial Function in Indonesian Short Stature Children. Cardiol Res 2022; 12:351-357. [PMID: 34970365 PMCID: PMC8683098 DOI: 10.14740/cr1314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/05/2021] [Indexed: 11/11/2022] Open
Abstract
Background The association between short stature, undernutrition and the risk to cardiovascular disease has been clinically established. Genetic factor, particularly the variants in cytochrome b-245 alpha chain (CYBA) gene, which alter the formation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase level, might affect arterial function. This study aimed to observe the association between single nucleotide variants (SNVs) of the CYBA gene and the arterial function of short stature children to understand the reason why some people with short stature develop cardiovascular disease. Methods A total of 142 genomic deoxyribonucleic acid (DNA) samples have been collected from short stature children in Brebes, Central Java, Indonesia. Four common single-nucleotide polymorphisms (SNPs): C242T (rs4673), A640G (rs1049255), -930A>G (rs9932581) and *49A>G (rs7195830) in the CYBA gene were examined using TaqMan allelic discrimination assay. The arterial function was measured using transthoracic echocardiography and described as aortic stiffness and distensibility index. Statistical analysis was done to find a significant difference in arterial function between genotypes of each SNV. Results A P-value of < 0.05 was considered significant. In rs9932581 (-930A>G) of CYBA gene, the subjects with GG genotype were found to have significantly lower arterial stiffness and higher distensibility compared to AA and AG genotypes. No significant difference was found in the other SNVs. Conclusion The GG genotype in rs9932581 of the CYBA gene might have a protective effect on cardiovascular disease in short stature children.
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Affiliation(s)
- Nani Maharani
- Center for Biomedical Research, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia.,Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
| | - Anindita Soetadji
- Department of Pediatrics, Faculty of Medicine, Universitas Diponegoro/Dr Kariadi Hospital, Semarang, Indonesia
| | - Agustini Utari
- Center for Biomedical Research, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia.,Department of Pediatrics, Faculty of Medicine, Universitas Diponegoro/Dr Kariadi Hospital, Semarang, Indonesia
| | - Izumi Naka
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Jun Ohashi
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Maria Mexitalia
- Department of Pediatrics, Faculty of Medicine, Universitas Diponegoro/Dr Kariadi Hospital, Semarang, Indonesia
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21
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Raghunandan S, Ramachandran S, Ke E, Miao Y, Lal R, Chen ZB, Subramaniam S. Heme Oxygenase-1 at the Nexus of Endothelial Cell Fate Decision Under Oxidative Stress. Front Cell Dev Biol 2021; 9:702974. [PMID: 34595164 PMCID: PMC8476872 DOI: 10.3389/fcell.2021.702974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/17/2021] [Indexed: 12/31/2022] Open
Abstract
Endothelial cells (ECs) form the inner lining of blood vessels and are central to sensing chemical perturbations that can lead to oxidative stress. The degree of stress is correlated with divergent phenotypes such as quiescence, cell death, or senescence. Each possible cell fate is relevant for a different aspect of endothelial function, and hence, the regulation of cell fate decisions is critically important in maintaining vascular health. This study examined the oxidative stress response (OSR) in human ECs at the boundary of cell survival and death through longitudinal measurements, including cellular, gene expression, and perturbation measurements. 0.5 mM hydrogen peroxide (HP) produced significant oxidative stress, placed the cell at this junction, and provided a model to study the effectors of cell fate. The use of systematic perturbations and high-throughput measurements provide insights into multiple regimes of the stress response. Using a systems approach, we decipher molecular mechanisms across these regimes. Significantly, our study shows that heme oxygenase-1 (HMOX1) acts as a gatekeeper of cell fate decisions. Specifically, HP treatment of HMOX1 knockdown cells reversed the gene expression of about 51% of 2,892 differentially expressed genes when treated with HP alone, affecting a variety of cellular processes, including anti-oxidant response, inflammation, DNA injury and repair, cell cycle and growth, mitochondrial stress, metabolic stress, and autophagy. Further analysis revealed that these switched genes were highly enriched in three spatial locations viz., cell surface, mitochondria, and nucleus. In particular, it revealed the novel roles of HMOX1 on cell surface receptors EGFR and IGFR, mitochondrial ETCs (MTND3, MTATP6), and epigenetic regulation through chromatin modifiers (KDM6A, RBBP5, and PPM1D) and long non-coding RNA (lncRNAs) in orchestrating the cell fate at the boundary of cell survival and death. These novel aspects suggest that HMOX1 can influence transcriptional and epigenetic modulations to orchestrate OSR affecting cell fate decisions.
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Affiliation(s)
- Sindhushree Raghunandan
- Department of Bioengineering, University of California, San Diego, San Diego, CA, United States
| | - Srinivasan Ramachandran
- Department of Bioengineering, University of California, San Diego, San Diego, CA, United States
| | - Eugene Ke
- Department of Bioengineering, University of California, San Diego, San Diego, CA, United States
| | - Yifei Miao
- Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA, United States
| | - Ratnesh Lal
- Department of Bioengineering, University of California, San Diego, San Diego, CA, United States.,Department of Mechanical and Aerospace Engineering, University of California, San Diego, San Diego, CA, United States
| | - Zhen Bouman Chen
- Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA, United States
| | - Shankar Subramaniam
- Department of Bioengineering, University of California, San Diego, San Diego, CA, United States.,Department of Computer Science and Engineering, University of California, San Diego, San Diego, CA, United States.,Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, United States
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22
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Masodsai K, Lin YY, Lin SY, Su CT, Lee SD, Yang AL. Aging Additively Influences Insulin- and Insulin-Like Growth Factor-1-Mediated Endothelial Dysfunction and Antioxidant Deficiency in Spontaneously Hypertensive Rats. Biomedicines 2021; 9:biomedicines9060676. [PMID: 34203897 PMCID: PMC8232669 DOI: 10.3390/biomedicines9060676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 11/25/2022] Open
Abstract
This study aimed to investigate the aging-related endothelial dysfunction mediated by insulin and insulin-like growth factor-1 (IGF-1) and antioxidant deficiency in hypertension. Male spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar–Kyoto rats (WKYs) were randomly divided into 24-week-old (younger) and 48-week-old (older) groups, respectively. The endothelial function was evaluated by the insulin- and IGF-1-mediated vasorelaxation of aortic rings via the organ bath system. Serum levels of nitric oxide (NO), malondialdehyde (MDA), catalase, and total antioxidant capacity (TAC) were examined. The insulin- and IGF-1-mediated vasorelaxation was significantly impaired in both 24- and 48-week-old SHRs compared with age-matched WKYs and was significantly worse in the 48-week-old SHR than the 24-week-old SHR. After pretreatments of phosphoinositide 3-kinase (PI3K) or NO synthase (NOS) inhibitors, the insulin- and IGF-1-mediated vasorelaxation became similar among four groups. The serum level of MDA was significantly increased, while the NO, catalase, and TAC were significantly reduced in the 48-week-old SHR compared with the 24-week-old SHR. This study demonstrated that the process of aging additively affected insulin- and IGF-1-mediated endothelial dysfunction in SHRs, which could be partly attributed to the reduced NO production and antioxidant deficiency.
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Affiliation(s)
- Kunanya Masodsai
- Faculty of Sports Science, Chulalongkorn University, Bangkok 10330, Thailand;
- Institute of Sports Sciences, University of Taipei, Taipei 11153, Taiwan;
| | - Yi-Yuan Lin
- Department of Exercise and Health Science, National Taipei University of Nursing and Health Sciences, Taipei 11257, Taiwan;
| | - Sih-Yin Lin
- Institute of Sports Sciences, University of Taipei, Taipei 11153, Taiwan;
| | - Chia-Ting Su
- Department of Occupational Therapy, College of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan;
| | - Shin-Da Lee
- Department of Physical Therapy, Asia University, Taichung 41354, Taiwan;
- Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung 40402, Taiwan
- School of Rehabilitation Medicine, Weifang Medical University, Shandong, Weifang 261000, China
| | - Ai-Lun Yang
- Institute of Sports Sciences, University of Taipei, Taipei 11153, Taiwan;
- Correspondence: or ; Tel.: +886-2-2871-8288 (ext. 5815)
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23
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Munoz K, Wasnik S, Abdipour A, Bi H, Wilson SM, Tang X, Ghahramanpouri M, Baylink DJ. The Effects of Insulin-Like Growth Factor I and BTP-2 on Acute Lung Injury. Int J Mol Sci 2021; 22:ijms22105244. [PMID: 34063554 PMCID: PMC8170877 DOI: 10.3390/ijms22105244] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 12/24/2022] Open
Abstract
Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1β, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.
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Affiliation(s)
- Kevin Munoz
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (K.M.); (S.W.); (A.A.); (X.T.); (M.G.)
| | - Samiksha Wasnik
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (K.M.); (S.W.); (A.A.); (X.T.); (M.G.)
| | - Amir Abdipour
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (K.M.); (S.W.); (A.A.); (X.T.); (M.G.)
- Division of Nephrology, Loma Linda University Medical Center, Loma Linda, CA 92354, USA
| | - Hongzheng Bi
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China;
| | - Sean M. Wilson
- The Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA;
| | - Xiaolei Tang
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (K.M.); (S.W.); (A.A.); (X.T.); (M.G.)
- Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, NY 11548, USA
| | - Mahdis Ghahramanpouri
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (K.M.); (S.W.); (A.A.); (X.T.); (M.G.)
| | - David J. Baylink
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (K.M.); (S.W.); (A.A.); (X.T.); (M.G.)
- Correspondence: ; Tel.: +909-558-4000-49796; Fax: +(909)-558-0428
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Zhao Q, Zhang M, Chu Y, Sun H, Ban B. Association between insulin-like growth factor-1 and systolic blood pressure in children and adolescents with short stature. J Clin Hypertens (Greenwich) 2021; 23:1112-1119. [PMID: 33794039 PMCID: PMC8678828 DOI: 10.1111/jch.14249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/06/2021] [Indexed: 11/27/2022]
Abstract
The relationship between insulin‐like growth factor‐1 (IGF‐1) and systolic blood pressure (SBP) is controversial in adults and children. The purpose of this study was to investigate the relationship between the IGF‐1 standard deviation score (IGF‐1 SDS) and SBP in children with short stature. A cross‐sectional analysis including 1315 children with short stature was conducted from March 2013 to October 2020. We estimated IGF‐1, blood pressure and other laboratory tests, and anthropometric indicators were also evaluated. Subgroup analyses of the pubertal stage, sex, growth hormone levels, thyroid hormone levels, fasting blood glucose levels, and triglyceride levels were performed. A positive association between the IGF‐1 SDS and SBP was observed by univariate analysis (p < .001). We further found a nonlinear association between the IGF‐1 SDS and SBP. The inflection point for the curve was found at an IGF‐1 SDS level of −2.91. In multivariate piecewise linear regression, there was a positive association between the IGF‐1 SDS and SBP when the IGF‐1 SDS was greater than −2.91 (β 1.56, 95% CI: 0.91, 2.22; p < .001). However, we did not observe a significant relationship between the IGF‐1 SDS and SBP when the IGF‐1 SDS level was less than −2.91 (β −0.95, 95% CI −3.17, 1.28; p = .379). This association was consistent across subgroup analyses. The present study demonstrated that there is a nonlinear relationship between the IGF‐1 SDS and SBP in children with short stature. Increased serum IGF‐1 levels were associated with elevated SBP when the IGF‐1 levels reached the inflection point.
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Affiliation(s)
- Qianqian Zhao
- Department of Endocrinology, Qingdao University, Qingdao, China
| | - Mei Zhang
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China.,Chinese Research Center for Behavior Medicine in Growth and Development, Jining, China
| | - Yuntian Chu
- School of Health Management and Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hailing Sun
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China.,Chinese Research Center for Behavior Medicine in Growth and Development, Jining, China
| | - Bo Ban
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China.,Chinese Research Center for Behavior Medicine in Growth and Development, Jining, China
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25
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Li S, Li J, Zhou H, Xiong L. Research progress of IGF-1 and cerebral ischemia. IBRAIN 2021; 7:57-67. [PMID: 37786870 PMCID: PMC10528794 DOI: 10.1002/j.2769-2795.2021.tb00066.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 02/26/2021] [Accepted: 03/20/2021] [Indexed: 10/04/2023]
Abstract
Cerebral ischemic disease is a group of diseases that cause insufficient blood supply to the cerebrum, cerebellum or brain stem for different reasons, resulting in corresponding nervous system symptoms. Cardiovascular disease is the leading cause of death in the world. Among them, the death caused by cerebral ischemia accounts for the vast majority, and it is one of the fatal diseases in the middle-aged and elderly at present. Epidemiologic studies have projected increasing mortality due to cardiovascular disease worldwide (about 23.3 million people by 2030) because of the aging population. However, related studies have shown that insulin-like growth factor I (IGF-1) is a multifunctional cell proliferation regulator. It plays an important role in cerebral ischemia. It is effective in promoting cell differentiation, proliferation and individual development. Studies have shown that IGF-1 signaling pathway is a key pathway controlling cell growth and survival. There may be five mechanisms in cerebral ischemia: prevention of intracellular calcium overload, inhibition of the upregulation of nNOS, IGF-1upregulations activating HIF-1α, regulation of Bcl-2 to resist apoptosis, and enhancement of vascular endothelial function. Three critical nodes in the IGF-1 signaling pathway have been described in cardiomyocytes: protein kinase Akt/mammalian target of rapamycin (mTOR), Ras/Raf/extracellular signal-regulated kinase (ERK), and phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3)/Ca2+. IGF-1 plays an important role in cerebral ischemia and myocardial ischemia, mainly by activating downstream of IGF-1, controlling cell death and differentiation or transcription work, improving the function of heart muscle cells, reducing the myocardial cell apoptosis induced by myocardial infarction, regulating endogenous protection and restoration of cerebral ischemia injury, thus protecting cerebral and myocardial injury. Related studies have shown that bcl-2 exerts great influence on both cerebral ischemia and myocardial ischemia. Therefore, the relevant pathways and targets of cerebral ischemia and myocardial ischemia and the role of IGF-1 in protecting the heart are reviewed in this paper.
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Affiliation(s)
- Shun‐Lian Li
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
- Department of AnesthesiaZunyi Medical UniversityZunyiGuizhouPeople's Republic of China
| | - Jing Li
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
| | - Hong‐Su Zhou
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
| | - Liu‐Lin Xiong
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
- Department of AnesthesiaZunyi Medical UniversityZunyiGuizhouPeople's Republic of China
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26
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Insulin-like growth factor-I predicts sinusoidal obstruction syndrome following pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant 2020; 56:1021-1030. [PMID: 33219341 DOI: 10.1038/s41409-020-01127-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 10/21/2020] [Accepted: 10/30/2020] [Indexed: 02/07/2023]
Abstract
Sinusoidal obstruction syndrome (SOS) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT) initiated through damage of sinusoidal endothelium and inflammation. Insulin-like growth factor-l (IGF-l) maintains and repairs endothelium and intestinal mucosa. We hypothesized that low IGF-l levels may increase the risk of inflammatory complications, such as SOS, in HSCT-patients. We prospectively measured IGF-l concentrations in 121 pediatric patients before, during, and after allogeneic HSCT. Overall, IGF-l levels were significantly reduced compared with healthy sex- and age-matched children. IGF-I levels pre-HSCT and at day 0 were inversely associated with C-reactive protein levels, hyperbilirubinemia, and number of platelet transfusions within the first 21 days post-transplant. Low levels of IGF-I before conditioning and at day of transplant were associated with increased risk of SOS diagnosed by the modified Seattle criteria (pre-HSCT: OR = 1.7 (95% CI: 1.2-2.6, p = 0.01), and the pediatric EBMT criteria (pre-HSCT: 1.7 (1.2-2.5, p = 0.009) and day 0: 1.7 (1.3-2.5, p = 0.001)/SDS decrease in IGF-1). These data suggest that IGF-I is protective against cytotoxic damage and SOS, most likely through trophic effects on endothelial cells and anti-inflammatory properties, and may prove useful as a predictive biomarker of SOS.
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27
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Decreased insulin-like growth factor-1 (IGF-1) concentration correlates with reduced left-ventricle ejection fraction (LVEF) in hemodialysis patients. Int Urol Nephrol 2020; 52:2385-2391. [PMID: 32851575 DOI: 10.1007/s11255-020-02595-8] [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: 04/24/2020] [Accepted: 07/30/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE The main purpose of this study is to determine the correlation between the serum IGF-1 concentration and certain cardiac indexes in hemodialysis patients. METHODS The study was conducted at the Clinical Center of Montenegro and three regional hemodialysis centers. The echocardiographic studies were performed the day after the hemodialysis sessions. Blood samples were taken before dialysis for the measurement of IGF1 and PTH. RESULTS A total of 102 patients were divided into two groups according to their left-ventricular ejection fraction (EF). Patients in the group with the higher EF had higher IGF-1 concentration (p = 0.024). IGF-1 was positively correlated with EF (ρ = 0.251, p = 0.012), and negatively correlated with LVMI (ρ = - 0.621, p < 0.001), SW (ρ = - 0.632, p < 0.001), and LW (ρ = - 0.632, p < 0.001). Multiple linear regression analysis was performed to determine the possible independent association between the EF and IGF-1 and the clinical data. The age of patients, their gender, and smoking habits did not have any combined influence on EF, but IGF-1 had a strong influence and was independently associated with the ejection fraction. CONCLUSION Our results may indicate the possible protective role of IGF-1 in the maintenance of heart structure and function in hemodialysis patients.
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Yoshida T, Delafontaine P. Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy. Cells 2020; 9:cells9091970. [PMID: 32858949 PMCID: PMC7564605 DOI: 10.3390/cells9091970] [Citation(s) in RCA: 350] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 12/18/2022] Open
Abstract
Insulin-like growth factor-1 (IGF-1) is a key growth factor that regulates both anabolic and catabolic pathways in skeletal muscle. IGF-1 increases skeletal muscle protein synthesis via PI3K/Akt/mTOR and PI3K/Akt/GSK3β pathways. PI3K/Akt can also inhibit FoxOs and suppress transcription of E3 ubiquitin ligases that regulate ubiquitin proteasome system (UPS)-mediated protein degradation. Autophagy is likely inhibited by IGF-1 via mTOR and FoxO signaling, although the contribution of autophagy regulation in IGF-1-mediated inhibition of skeletal muscle atrophy remains to be determined. Evidence has suggested that IGF-1/Akt can inhibit muscle atrophy-inducing cytokine and myostatin signaling via inhibition of the NF-κΒ and Smad pathways, respectively. Several miRNAs have been found to regulate IGF-1 signaling in skeletal muscle, and these miRs are likely regulated in different pathological conditions and contribute to the development of muscle atrophy. IGF-1 also potentiates skeletal muscle regeneration via activation of skeletal muscle stem (satellite) cells, which may contribute to muscle hypertrophy and/or inhibit atrophy. Importantly, IGF-1 levels and IGF-1R downstream signaling are suppressed in many chronic disease conditions and likely result in muscle atrophy via the combined effects of altered protein synthesis, UPS activity, autophagy, and muscle regeneration.
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Affiliation(s)
- Tadashi Yoshida
- Heart and Vascular Institute, John W. Deming Department of Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-48, New Orleans, LA 70112, USA
- Department of Physiology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112, USA
- Correspondence: (T.Y.); (P.D.)
| | - Patrice Delafontaine
- Heart and Vascular Institute, John W. Deming Department of Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-48, New Orleans, LA 70112, USA
- Department of Physiology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112, USA
- Correspondence: (T.Y.); (P.D.)
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Filho DM, de Carvalho Ribeiro P, Oliveira LF, Dos Santos ALRT, Parreira RC, Pinto MCX, Resende RR. Enhancing the Therapeutic Potential of Mesenchymal Stem Cells with the CRISPR-Cas System. Stem Cell Rev Rep 2020; 15:463-473. [PMID: 31147819 DOI: 10.1007/s12015-019-09897-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Mesenchymal stem cells (MSCs), also known as multipotent mesenchymal stromal stem cells, are found in the perivascular space of several tissues. These cells have been subject of intense research in the last decade due to their low teratogenicity, as well as their ability to differentiate into mature cells and to secrete immunomodulatory and trophic factors. However, they usually promote only a modest benefit when transplanted in experimental disease models, one of the limitations for their clinical application. The CRISPR-Cas system, in turn, is highlighted as a simple and effective tool for genetic engineering. This system was tested in clinical trials over a relatively short period of time after establishing its applicability to the edition of the mammalian cell genome. Similar to the research evolution in MSCs, the CRISPR-Cas system demonstrated inconsistencies that limited its clinical application. In this review, we outline the evolution of MSC research and its applicability, and the progress of the CRISPR-Cas system from its discovery to the most recent clinical trials. We also propose perspectives on how the CRISPR-Cas system may improve the therapeutic potential of MSCs, making it more beneficial and long lasting.
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Affiliation(s)
- Daniel Mendes Filho
- Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
| | - Patrícia de Carvalho Ribeiro
- Laboratory of Immunology and Experimental Transplantation, São José do Rio Preto Medical School, São José do Rio Preto, São Paulo, Brazil.,Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Lucas Felipe Oliveira
- Department of Physiology, Biological and Natural Sciences Institute, Triangulo Mineiro Federal University, Uberaba, Minas Gerais, Brazil.,National Institute of Science and Technology for Regenerative Medicine (INCT-REGENERA-CNPq), Rio de Janeiro, RJ, Brazil.,Minas Gerais Network for Tissue Engineering and Cell Therapy (REMETTECFAPEMIG), Belo Horizonte, MG, Brazil
| | | | - Ricardo Cambraia Parreira
- Department of Pharmacology, Biological Sciences Institute, Goias Federal University, Goiania, Goias, Brazil.
| | - Mauro Cunha Xavier Pinto
- Department of Pharmacology, Biological Sciences Institute, Goias Federal University, Goiania, Goias, Brazil
| | - Rodrigo Ribeiro Resende
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
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IGF-1 Deficiency Rescue and Intracellular Calcium Blockade Improves Survival and Corresponding Mechanisms in a Mouse Model of Acute Kidney Injury. Int J Mol Sci 2020; 21:ijms21114095. [PMID: 32521790 PMCID: PMC7312627 DOI: 10.3390/ijms21114095] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/03/2020] [Accepted: 06/03/2020] [Indexed: 02/07/2023] Open
Abstract
This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapy, compared to the untreated group, caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 h. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection.
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Báez-Díaz C, Blanco-Blázquez V, Sánchez-Margallo FM, Bayes-Genis A, González I, Abad A, Steendam R, Franssen O, Palacios I, Sánchez B, Gálvez-Montón C, Crisóstomo V. Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model. Sci Rep 2020; 10:7166. [PMID: 32346015 PMCID: PMC7188803 DOI: 10.1038/s41598-020-64097-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 04/03/2020] [Indexed: 12/12/2022] Open
Abstract
Insulin-like growth factor-1 (IGF-1) has demonstrated beneficial effects after myocardial infarction (MI). Microencapsulation of IGF-1 could potentially improve results. We aimed to test the effect of an intracoronary (IC) infusion of microencapsulated IGF-1 in a swine acute MI model. For that purpose IC injection of a 10 ml solution of 5 × 106 IGF-1 loaded microspheres (MSPs) (n = 8, IGF-1 MSPs), 5 × 106 unloaded MSPs (n = 9; MSPs) or saline (n = 7; CON) was performed 48 hours post-MI. Left ventricular ejection fraction (LVEF), indexed ventricular volumes and infarct size (IS) were determined by cardiac magnetic resonance at pre-injection and 10 weeks. Animals were euthanized at 10 weeks, and myocardial fibrosis and vascular density were analysed. End-study LVEF was significantly greater in IGF-1 MSPs compared to MSPs and CON, while ventricular volumes exhibited no significant differences between groups. IS decreased over time in all groups. Collagen volume fraction on the infarct area was significantly reduced in IGF-1 MSPs compared to CON and MSPs. Vascular density analysis of infarct and border zones showed no significant differences between groups. In conclusion, the IC injection of 5 × 106 IGF-1 loaded MSPs in a porcine acute MI model successfully improves cardiac function and limits myocardial fibrosis, which could be clinically relevant.
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Affiliation(s)
- Claudia Báez-Díaz
- Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain.
- CIBERCV, Madrid, Spain.
| | | | | | - Antoni Bayes-Genis
- CIBERCV, Madrid, Spain
- ICREC (Heart Failure and Cardiac Regeneration) Research Programme, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Barcelona, Spain
| | - Irene González
- Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Ana Abad
- Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Rob Steendam
- Innocore Pharmaceuticals, Groningen, The Netherlands
| | | | | | | | - Carolina Gálvez-Montón
- CIBERCV, Madrid, Spain
- ICREC (Heart Failure and Cardiac Regeneration) Research Programme, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Barcelona, Spain
| | - Verónica Crisóstomo
- Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain
- CIBERCV, Madrid, Spain
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Medic Spahic J, Ricci F, Aung N, Hallengren E, Axelsson J, Hamrefors V, Melander O, Sutton R, Fedorowski A. Proteomic analysis reveals sex-specific biomarker signature in postural orthostatic tachycardia syndrome. BMC Cardiovasc Disord 2020; 20:190. [PMID: 32321428 PMCID: PMC7178975 DOI: 10.1186/s12872-020-01465-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 04/05/2020] [Indexed: 12/12/2022] Open
Abstract
Background Postural orthostatic tachycardia syndrome (POTS) is a variant of cardiovascular (CV) autonomic disorder of unknown etiology characterized by an excessive heart rate increase on standing and orthostatic intolerance. In this study we sought to identify novel CV biomarkers potentially implicated in POTS pathophysiology. Methods We conducted a nested case-control study within the Syncope Study of Unselected Population in Malmö (SYSTEMA) cohort including 396 patients (age range, 15–50 years) with either POTS (n = 113) or normal hemodynamic response during passive head-up-tilt test (n = 283). We used a targeted approach to explore changes in cardiovascular proteomics associated with POTS through a sequential two-stage process including supervised principal component analysis and univariate ANOVA with Bonferroni correction. Results POTS patients were younger (26 vs. 31 years; p < 0.001) and had lower BMI than controls. The discovery algorithm identified growth hormone (GH) and myoglobin (MB) as the most specific biomarker fingerprint for POTS. Plasma level of GH was higher (9.37 vs 8.37 of normalised protein expression units (NPX); p = 0.002), whereas MB was lower (4.86 vs 5.14 NPX; p = 0.002) in POTS compared with controls. In multivariate regression analysis, adjusted for age and BMI, and stratified by sex, lower MB level in men and higher GH level in women remained independently associated with POTS. Conclusions Cardiovascular proteomics analysis revealed sex-specific biomarker signature in POTS featured by higher plasma level of GH in women and lower plasma level of MB in men. These findings point to sex-specific immune-neuroendocrine dysregulation and deconditioning as potentially key pathophysiological traits underlying POTS.
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Affiliation(s)
- Jasmina Medic Spahic
- Department of Clinical Sciences, Malmö, Faculty of Medicine, Lund University, Clinical Research Center, 214 28, Malmö, Sweden.,Department of Internal Medicine, Skåne University Hospital, 214 28, Malmö, Sweden
| | - Fabrizio Ricci
- Department of Clinical Sciences, Malmö, Faculty of Medicine, Lund University, Clinical Research Center, 214 28, Malmö, Sweden.,Department of Neuroscience, Imaging and Clinical Sciences, "G. d'Annunzio" University, 66100, Chieti, Italy.,Casa di Cura Villa Serena, Città Sant'Angelo, 65013, Pescara, Italy
| | - Nay Aung
- William Harvey Research Institute, NIHR Cardiovascular Biomedical Research Unit at Barts, Queen Mary University of London, London, UK
| | - Erik Hallengren
- Department of Clinical Sciences, Malmö, Faculty of Medicine, Lund University, Clinical Research Center, 214 28, Malmö, Sweden.,Department of Internal Medicine, Skåne University Hospital, 214 28, Malmö, Sweden
| | - Jonas Axelsson
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Viktor Hamrefors
- Department of Clinical Sciences, Malmö, Faculty of Medicine, Lund University, Clinical Research Center, 214 28, Malmö, Sweden.,Department of Internal Medicine, Skåne University Hospital, 214 28, Malmö, Sweden
| | - Olle Melander
- Department of Clinical Sciences, Malmö, Faculty of Medicine, Lund University, Clinical Research Center, 214 28, Malmö, Sweden.,Department of Internal Medicine, Skåne University Hospital, 214 28, Malmö, Sweden
| | - Richard Sutton
- National Heart and Lung Institute, Imperial College, Hammersmith Hospital Campus, Ducane Road, W12 0NN, London, UK
| | - Artur Fedorowski
- Department of Clinical Sciences, Malmö, Faculty of Medicine, Lund University, Clinical Research Center, 214 28, Malmö, Sweden. .,Department of Cardiology, Skåne University Hospital, Carl-Bertil Laurells gata 9, 214 28, Malmö, Sweden.
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van Bunderen CC, Meijer RI, Lips P, Kramer MH, Serné EH, Drent ML. Titrating Growth Hormone Dose to High-Normal IGF-1 Levels Has Beneficial Effects on Body Fat Distribution and Microcirculatory Function Despite Causing Insulin Resistance. Front Endocrinol (Lausanne) 2020; 11:619173. [PMID: 33633687 PMCID: PMC7899963 DOI: 10.3389/fendo.2020.619173] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/18/2020] [Indexed: 11/29/2022] Open
Abstract
UNLABELLED To clarify the mechanism underlying the described U-shaped relation of both low and high levels of IGF-1 with cardiovascular disease this study explores the effect of decreasing and increasing growth hormone dose in GH deficient adults on (micro)vascular function, body composition and insulin resistance. In this randomized clinical trial, thirty-two subjects receiving GH therapy with an IGF-1 concentration between -1 and 1 SD score (SDS) for at least one year were randomized to receive either a decrease (IGF-1 target level of -2 to -1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24 weeks. Microvascular endothelium (in)dependent vasodilatation and vasomotion, vascular stiffness by pulse wave analysis, and HOMA-IR were measured. At the end of the study 30 subjects (65.6% men, mean age 46.6 (SD 9.9) years) were analyzed. There was a favorable effect of increasing the IGF-1 level on waist circumference compared to decreasing the IGF-1 level (p=0.05), but a detrimental effect on insulin resistance (p=0.03). Decreasing IGF-1 level significantly lowered the endothelial domain of vasomotion (p=0.03), whereas increasing IGF-1 level increased the contribution of the neurogenic domain (p=0.05). This change was related to the favorable change in waist circumference. In conclusion, increasing IGF-1 levels was beneficial for body composition but detrimental with respect to insulin resistance. The contribution of the neurogenic vasomotion domain increased in parallel, and could be explained by the favorable change in waist circumference. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT01877512.
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Affiliation(s)
- Christa C. van Bunderen
- Section of Endocrinology, Neuroscience Campus Amsterdam, Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- *Correspondence: Christa C. van Bunderen,
| | - Rick I. Meijer
- Section of Vascular Medicine, Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Paul Lips
- Section of Endocrinology, Neuroscience Campus Amsterdam, Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Mark H. Kramer
- Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Erik H. Serné
- Section of Vascular Medicine, Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Madeleine L. Drent
- Section of Endocrinology, Neuroscience Campus Amsterdam, Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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Xargay-Torrent S, Dorado-Ceballos E, Benavides-Boixader A, Lizárraga-Mollinedo E, Mas-Parés B, Montesinos-Costa M, De Zegher F, Ibáñez L, Bassols J, López-Bermejo A. Circulating IGF-1 Independently Predicts Blood Pressure in Children With Higher Calcium-Phosphorus Product Levels. J Clin Endocrinol Metab 2020; 105:5601604. [PMID: 31633765 DOI: 10.1210/clinem/dgz101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 10/03/2019] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To study the association between insulin-like growth factor 1 (IGF-1) and blood pressure in children, in particular, the potential interaction with the serum calcium-phosphorus product (Ca*P). METHODS A longitudinal study included 521 children (age 8.8 ± 0.1) from northeastern Spain, of whom 158 were followed-up after 5 years. IGF-1, insulin-like growth factor-binding protein 3 (IGFBP-3), and serum calcium and phosphorus were measured at baseline. Anthropometric (body-mass index [BMI] and waist) and cardiometabolic variables (systolic [SBP] and diastolic blood pressure), pulse pressure, insulin, homeostatic model assessment of insulin resistance [HOMA-IR], high-density lipoprotein [HDL]-cholesterol, and triglycerides) were assessed at baseline and at the end of follow-up. Statistical analysis included Pearson correlations followed by multivariable linear regression analyses. RESULTS Baseline IGF-1 and IGF-1/IGFBP-3 molar ratio positively correlated with baseline and follow-up BMI, waist, SBP, pulse pressure, insulin, HOMA-IR and triglycerides (r 0.138-0.603; all P < 0.05). The associations with SBP were stronger with increasing Ca*P (r 0.261-0.625 for IGF-1; and r 0.174-0.583 for IGF-1/IGFBP-3). After adjusting for confounding variables, baseline IGF-1 and IGF-1/IGFBP-3 remained independently associated with both baseline and follow-up SBP in children in the highest Ca*P tertile (β = 0.245-0.381; P < 0.01; model R2 = 0.246-0.566). CONCLUSIONS Our results suggest that IGF-1 in childhood is an independent predictor of SBP in apparently healthy children, especially in those with high Ca*P levels.
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Affiliation(s)
- Sílvia Xargay-Torrent
- Pediatric Endocrinology Research Group, (Girona Biomedical Research Institute) IDIBGI, Salt, Spain
| | | | - Anna Benavides-Boixader
- Pediatric Endocrinology Research Group, (Girona Biomedical Research Institute) IDIBGI, Salt, Spain
| | | | - Berta Mas-Parés
- Materno-Fetal Metabolic Research Group, (Girona Biomedical Research Institute) IDIBGI, Salt, Spain
| | | | - Francis De Zegher
- Department of Development & Regeneration, University of Leuven, Leuven, Belgium
| | - Lourdes Ibáñez
- Pediatric Endocrinology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Judit Bassols
- Materno-Fetal Metabolic Research Group, (Girona Biomedical Research Institute) IDIBGI, Salt, Spain
| | - Abel López-Bermejo
- Pediatric Endocrinology Research Group, (Girona Biomedical Research Institute) IDIBGI, Salt, Spain
- Department of Pediatrics, Dr. Trueta University Hospital, Girona, Spain
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Galerneau LM, Borel AL, Chabre O, Sapene M, Stach B, Girey-Rannaud J, Tamisier R, Pépin JL, Caron P. The Somatotropic Axis in the Sleep Apnea-Obesity Comorbid Duo. Front Endocrinol (Lausanne) 2020; 11:376. [PMID: 32655494 PMCID: PMC7325876 DOI: 10.3389/fendo.2020.00376] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 05/12/2020] [Indexed: 11/21/2022] Open
Abstract
Background: Growth hormone (GH) stimulates the production of insulin-like growth factor 1 (IGF-1) in most tissues and together GH and IGF-1 profoundly impact adipose tissue deposition, glucose metabolism and cardiovascular function. A low serum IGF-I level has been reported as being associated with obstructive sleep apnea (OSA) and might be one of the mechanisms underlying cardio-metabolic risk in OSA patients. Methods: In a multicenter national study, 817 patients consulting for suspicion of OSA (OSA confirmed for 567 patients) underwent serum IGF-1 measurements. We analyzed the association between an IGF-1 level below the median value of the population and variables related to cardio-metabolic risk: body mass index (BMI) and waist circumference, apnea hypopnea index (AHI), cholesterol and triglycerides (expressed as median and divided into quartiles for continuous variables). Results: After adjustment for age and gender, low IGF-1 levels were associated with increased BMI and AHI (Odds ratios (OR) = 2.83; p < 0.0001 and OR = 3.03, p < 0.0001 for Quartile 4 vs. Quartile1, respectively), with elevated cholesterol levels (OR = 1.36, p = 0.0444), and elevated triglyceride levels (OR = 1.36; p = 0.0008). Conclusions: Both adiposity and sleep apnea synergistically predict low levels of IGF-1 and thus could together contribute toward cardio-metabolic risk. Further work are needed to confirm whether IGF-1 levels allow grading severity and predicting response to treatments to aim at a personalized medicine for patients suffering from OSA.
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Affiliation(s)
- Louis-Marie Galerneau
- Hypoxia PathoPhysiology (HP2) Laboratory, University Grenoble Alpes, Grenoble, France
- *Correspondence: Louis-Marie Galerneau
| | - Anne-Laure Borel
- Hypoxia PathoPhysiology (HP2) Laboratory, University Grenoble Alpes, Grenoble, France
| | - Olivier Chabre
- Endocrinology Department, Pole Digidune, Grenoble Alpes University Hospital, Grenoble, France
| | | | | | | | - Renaud Tamisier
- Hypoxia PathoPhysiology (HP2) Laboratory, University Grenoble Alpes, Grenoble, France
| | - Jean-Louis Pépin
- Hypoxia PathoPhysiology (HP2) Laboratory, University Grenoble Alpes, Grenoble, France
| | - Philippe Caron
- Department of Endocrinology and Metabolic diseases, Pôle Cardiovascular and Metabolic, Larrey University Hospital, Toulouse, France
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Obradovic M, Zafirovic S, Soskic S, Stanimirovic J, Trpkovic A, Jevremovic D, Isenovic ER. Effects of IGF-1 on the Cardiovascular System. Curr Pharm Des 2019; 25:3715-3725. [DOI: 10.2174/1381612825666191106091507] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/29/2019] [Indexed: 11/22/2022]
Abstract
:Cardiovascular (CV) diseases are the most common health problems worldwide, with a permanent increase in incidence. Growing evidence underlines that insulin-like growth factor 1 (IGF-1) is a very important hormone responsible for normal CV system physiology. IGF-1 is an anabolic growth hormone, responsible for cell growth, differentiation, proliferation, and survival. Despite systemic effects, IGF-1 exerts a wide array of influences in the CV system affecting metabolic homeostasis, vasorelaxation, cardiac contractility and hypertrophy, autophagy, apoptosis, and antioxidative processes. The vasodilatory effect of IGF-1, is achieved through the regulation of the activity of endothelial nitric oxide synthase (eNOS) and, at least partly, through enhancing inducible NOS (iNOS) activity. Also, IGF-1 stimulates vascular relaxation through regulation of sodium/potassiumadenosine- triphosphatase. Numerous animal studies provided evidence of diverse influences of IGF-1 in the CV system such as vasorelaxation, anti-apoptotic and prosurvival effects. Human studies indicate that low serum levels of free or total IGF-1 contribute to an increased risk of CV and cerebrovascular disease. Large human trials aiming at finding clinical efficacy and outcome of IGF-1-related therapy are of great interest.:We look forward to the development of new IGF 1 therapies with minor side effects. In this review, we discuss the latest literature data regarding the function of IGF-1 in the CV system in the physiological and pathophysiological conditions.
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Affiliation(s)
- Milan Obradovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Sonja Zafirovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Sanja Soskic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Julijana Stanimirovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Andreja Trpkovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Danimir Jevremovic
- Faculty of Stomatology, Pancevo, University Business Academy, 21000 Novi Sad, Serbia
| | - Esma R. Isenovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
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Norling AM, Gerstenecker AT, Buford TW, Khan B, Oparil S, Lazar RM. The role of exercise in the reversal of IGF-1 deficiencies in microvascular rarefaction and hypertension. GeroScience 2019; 42:141-158. [PMID: 31808026 DOI: 10.1007/s11357-019-00139-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 11/19/2019] [Indexed: 12/18/2022] Open
Abstract
Hypertension has been linked with peripheral and central reductions in vascular density, and with devastating effects on brain function. However, the underlying mechanisms in the relationship between blood pressure and cognitive impairment have yet to be fully elucidated. Here, we review compelling evidence from two lines of inquiry: one that links microvascular rarefaction with insulin-like growth factor 1 (IGF-1) deficiencies, and another which posits that vascular dysfunction precedes hypertension. Based on the findings from experimental and clinical studies, we propose that these lines of evidence converge, and suggest that age-related declines in IGF-1 concentrations precede microvascular rarefaction, initiate an increase in vascular resistance, and therefore are causally linked to onset of hypertension. Physical exercise provides a relevant model for supporting our premise, given the well-established effects of exercise in attenuating vascular dysfunction, hypertension, IGF-1 deficiency, and cognitive decline. We highlight here the role of exercise-induced increases in blood flow in improving vascular integrity and enhancing angiogenesis via the actions of IGF-1, resulting in reversal of rarefaction and hypertension, and enhancement of cerebral blood flow and cognition.
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Affiliation(s)
- Amani M Norling
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.,The UAB Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Alabama, AL, 35294, USA
| | - Adam T Gerstenecker
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.,The UAB Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Alabama, AL, 35294, USA
| | - Thomas W Buford
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Bilal Khan
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Suzanne Oparil
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Ronald M Lazar
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. .,The UAB Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Alabama, AL, 35294, USA.
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Li CH, Tang X, Wasnik S, Wang X, Zhang J, Xu Y, Lau KHW, Nguyen HB, Baylink DJ. Mechanistic study of the cause of decreased blood 1,25-Dihydroxyvitamin D in sepsis. BMC Infect Dis 2019; 19:1020. [PMID: 31791247 PMCID: PMC6888965 DOI: 10.1186/s12879-019-4529-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 10/01/2019] [Indexed: 02/06/2023] Open
Abstract
Background Vitamin D deficiency, determined by blood levels of 25-hydroxyvitamin D [25(OH) D, i.e. the major vitamin D form in blood], has been shown to associate with all-cause mortalities. We recently demonstrated that blood levels of 1,25-dihydroxyvitamin D [1,25(OH)2D, i.e. the active vitamin D] were significantly lower in non-survivors compared to survivors among sepsis patients. Unexpectedly, despite the well documented roles of 1,25(OH)2D in multiple biological functions such as regulation of immune responses, stimulation of antimicrobials, and maintenance of barrier function, 1,25(OH)2D supplementation failed to improve disease outcomes. These previous findings suggest that, in addition to 1,25(OH)2D deficiency, disorders leading to the 1,25(OH)2D deficiency also contribute to mortality among sepsis patients. Therefore, this study investigated the mechanisms leading to sepsis-associated 1,25(OH)2D deficiency. Methods We studied mechanisms known to regulate kidney 25-hydroxylvitamin D 1α-hydroxylase which physiologically catalyzes the conversion of 25(OH) D into 1,25(OH)2D. Such mechanisms included parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 23 (FGF-23), and kidney function. Results We demonstrated in both human subjects and mice that sepsis-associated 1,25(OH)2D deficiency could not be overcome by increased production of PTH which stimulates 1α-hydroxylase. Further studies showed that this failure of PTH to maintain blood 1,25(OH)2D levels was associated with decreased blood levels of IGF-1, increased blood levels of FGF-23, and kidney failure. Since the increase in blood levels of FGF-23 is known to associate with kidney failure, we further investigated the mechanisms leading to sepsis-induced decrease in blood levels of IGF-1. Our data showed that blood levels of growth hormone, which stimulates IGF-1 production in liver, were increased but could not overcome the IGF-1 deficiency. Additionally, we found that the inability of growth hormone to restore the IGF-1 deficiency was associated with suppressed expression and signaling of growth hormone receptor in liver. Conclusions Because FGF-23 and IGF-1 have multiple biological functions besides their role in regulating kidney 1α-hydroxylase, our data suggest that FGF-23 and IGF-1 are warranted for further investigation as potential agents for the correction of 1,25(OH)2D deficiency and for the improvement of survival among sepsis patients.
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Affiliation(s)
- Chih-Huang Li
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, USA.,Department of Emergency Medicine, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Graduate Institute of Clinical Medical Sciences, School of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Xiaolei Tang
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, USA. .,Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, NY, 11548, USA.
| | - Samiksha Wasnik
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, USA
| | - Xiaohua Wang
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, USA.,Division of Infectious Disease, Jinan Infectious Disease Hospital, Shandong University, Jinan, Shandong, China
| | - Jintao Zhang
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, USA.,Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Yi Xu
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, USA
| | - Kin-Hing William Lau
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, USA.,Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California, USA
| | - H Bryant Nguyen
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, USA.,Division of Pulmonary, Critical Care, Hyperbaric and Sleep Medicine, Loma Linda University, Loma Linda, California, USA
| | - David J Baylink
- Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, USA
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Coupal KE, Heeney ND, Hockin BCD, Ronsley R, Armstrong K, Sanatani S, Claydon VE. Pubertal Hormonal Changes and the Autonomic Nervous System: Potential Role in Pediatric Orthostatic Intolerance. Front Neurosci 2019; 13:1197. [PMID: 31798399 PMCID: PMC6861527 DOI: 10.3389/fnins.2019.01197] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 10/22/2019] [Indexed: 12/22/2022] Open
Abstract
Puberty is initiated by hormonal changes in the adolescent body that trigger physical and behavioral changes to reach adult maturation. As these changes occur, some adolescents experience concerning pubertal symptoms that are associated with dysfunction of the autonomic nervous system (ANS). Vasovagal syncope (VVS) and Postural Orthostatic Tachycardia Syndrome (POTS) are common disorders of the ANS associated with puberty that are related to orthostatic intolerance and share similar symptoms. Compared to young males, young females have decreased orthostatic tolerance and a higher incidence of VVS and POTS. As puberty is linked to changes in specific sex and non-sex hormones, and hormonal therapy sometimes improves orthostatic symptoms in female VVS patients, it is possible that pubertal hormones play a role in the increased susceptibility of young females to autonomic dysfunction. The purpose of this paper is to review the key hormonal changes associated with female puberty, their effects on the ANS, and their potential role in predisposing some adolescent females to cardiovascular autonomic dysfunctions such as VVS and POTS. Increases in pubertal hormones such as estrogen, thyroid hormones, growth hormone, insulin, and insulin-like growth factor-1 promote vasodilatation and decrease blood volume. This may be exacerbated by higher levels of progesterone, which suppresses catecholamine secretion and sympathetic outflow. Abnormal heart rate increases in POTS patients may be exacerbated by pubertal increases in leptin, insulin, and thyroid hormones acting to increase sympathetic nervous system activity and/or catecholamine levels. Given the coincidental timing of female pubertal hormone surges and adolescent onset of VVS and POTS in young women, coupled with the known roles of these hormones in modulating cardiovascular homeostasis, it is likely that female pubertal hormones play a role in predisposing females to VVS and POTS during puberty. Further research is necessary to confirm the effects of female pubertal hormones on autonomic function, and their role in pubertal autonomic disorders such as VVS and POTS, in order to inform the treatment and management of these debilitating disorders.
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Affiliation(s)
- Kassandra E Coupal
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Natalie D Heeney
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Brooke C D Hockin
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Rebecca Ronsley
- Department of Pediatrics, BC Children's Hospital, Vancouver, BC, Canada
| | - Kathryn Armstrong
- Children's Heart Centre, BC Children's Hospital, Vancouver, BC, Canada
| | | | - Victoria E Claydon
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
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Erlandsson MC, Lyngfelt L, Åberg ND, Wasén C, Espino RA, Silfverswärd ST, Nadali M, Jood K, Andersson KM, Pullerits R, Bokarewa MI. Low serum IGF1 is associated with hypertension and predicts early cardiovascular events in women with rheumatoid arthritis. BMC Med 2019; 17:141. [PMID: 31327319 PMCID: PMC6643304 DOI: 10.1186/s12916-019-1374-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 06/25/2019] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Since low insulin-like growth factor (IGF) 1 is often linked to inflammation, we analyze whether serum levels of IGF1 are associated with cardiovascular disease (CVD) in rheumatoid arthritis (RA) in a longitudinal observational study. METHODS A CVD risk was estimated (eCVR) in 184 female RA patients (mean age 52 years) and in 132 female patients after ischemic stroke (mean age 56 years) with no rheumatic disease, using the Framingham algorithm. The median level of IGF1 divided the cohorts in IGF1high and IGF1low groups. A 5-year prospective follow-up for new CVD events was completed in all RA patients. The Mantel-Cox analysis and event-free survival curves were prepared. Unsupervised clustering of proteins within the IGF1 signaling pathway was employed to identify their association with eCVR. RESULTS Low IGF1 resulted in a higher eCVR in RA patients (7.2% and 3.3%, p = 0.0063) and in stroke (9.3% and 7.1%, p = 0.033). RA had higher rate for new CVD events at prospective follow-up (OR 4.96, p = 0.028). Hypertension was the major risk factor associated with low IGF1 in RA and stroke. In hypertension, IGF1 was no longer responsible for intracellular activation and lost its correlation to IRS1/2 adaptor proteins. The clustering analysis confirmed that combination of low IGF1 and IRS1/2 with high IL6, insulin, and glucose predisposed to high eCVR and emphasized the functional role of serum IGF1. CONCLUSIONS Low serum IGF1 precedes and predicts development of early CVD events in female RA patients. Hypertension and aberrant IGF1 receptor signaling are highlighted as the important contributors to IGF1-related CVD events.
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Affiliation(s)
- Malin C. Erlandsson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, SE-41345 Gothenburg, Sweden
- Rheumatology Clinic, the Sahlgrenska University Hospital, Gothenburg, Region of West Götaland Sweden
| | - Lovisa Lyngfelt
- Department of Rheumatology and Inflammation Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, SE-41345 Gothenburg, Sweden
| | - N. David Åberg
- Department of Internal Medicine, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Caroline Wasén
- Department of Rheumatology and Inflammation Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, SE-41345 Gothenburg, Sweden
| | - Rachelle A. Espino
- Department of Rheumatology and Inflammation Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, SE-41345 Gothenburg, Sweden
- Keele University, Keele, UK
| | - Sofia Töyrä Silfverswärd
- Department of Rheumatology and Inflammation Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, SE-41345 Gothenburg, Sweden
| | - Mitra Nadali
- Department of Rheumatology and Inflammation Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, SE-41345 Gothenburg, Sweden
- Rheumatology Clinic, the Sahlgrenska University Hospital, Gothenburg, Region of West Götaland Sweden
| | - Katharina Jood
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
- Department of Neurology, the Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Karin M.E. Andersson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, SE-41345 Gothenburg, Sweden
| | - Rille Pullerits
- Department of Rheumatology and Inflammation Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, SE-41345 Gothenburg, Sweden
- Rheumatology Clinic, the Sahlgrenska University Hospital, Gothenburg, Region of West Götaland Sweden
- Department of Clinical Immunology and Transfusion Medicine, the Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Maria I. Bokarewa
- Department of Rheumatology and Inflammation Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, SE-41345 Gothenburg, Sweden
- Rheumatology Clinic, the Sahlgrenska University Hospital, Gothenburg, Region of West Götaland Sweden
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Inflammation-Accelerated Senescence and the Cardiovascular System: Mechanisms and Perspectives. Int J Mol Sci 2018; 19:ijms19123701. [PMID: 30469478 PMCID: PMC6321367 DOI: 10.3390/ijms19123701] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/17/2018] [Accepted: 11/20/2018] [Indexed: 02/07/2023] Open
Abstract
Low-grade chronic inflammation is a common denominator in atherogenesis and related diseases. Solid evidence supports the occurrence of an impairment in the innate and adaptive immune system with senescence, favoring the development of acute and chronic age-related diseases. Cardiovascular (CV) diseases (CVD), in particular, are a leading cause of death even at older ages. Inflammation-associated mechanisms that contribute to CVD development include dysregulated redox and metabolic pathways, genetic modifications, and infections/dysbiosis. In this review, we will recapitulate the determinants and consequences of the immune system dysfunction at older age, with particular focus on the CV system. We will examine the currently available and potential future strategies to counteract accelerated CV aging, i.e., nutraceuticals, probiotics, caloric restriction, physical activity, smoking and alcohol cessation, control of low-grade inflammation sources, senolytic and senescence-modulating drugs, and DNA-targeting drugs.
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Hjortebjerg R. IGFBP-4 and PAPP-A in normal physiology and disease. Growth Horm IGF Res 2018; 41:7-22. [PMID: 29864720 DOI: 10.1016/j.ghir.2018.05.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 05/15/2018] [Accepted: 05/29/2018] [Indexed: 02/07/2023]
Abstract
Insulin-like growth factor (IGF) binding protein-4 (IGFBP-4) is a modulator of the IGF system, exerting both inhibitory and stimulatory effects on IGF-induced cellular growth. IGFBP-4 is the principal substrate for the enzyme pregnancy-associated plasma protein-A (PAPP-A). Through IGF-dependent cleavage of IGFBP-4 in the vicinity of the IGF receptor, PAPP-A is able to increase IGF bioavailability and stimulate IGF-mediated growth. Recently, the stanniocalcins (STCs) were identified as novel inhibitors of PAPP-A proteolytic activity, hereby adding additional members to the seemingly endless list of proteins belonging to the IGF family. Our understanding of these proteins has advanced throughout recent years, and there is evidence to suggest that the role of IGFBP-4 and PAPP-A in defining the relationship between total IGF and IGF bioactivity can be linked to a number of pathological conditions. This review provides an overview of the experimental and clinical findings on the IGFBP-4/PAPP-A/STC axis as a regulator of IGF activity and examines the conundrum surrounding extrapolation of circulating concentrations to tissue action of these proteins. The primary focus will be on the biological significance of IGFBP-4 and PAPP-A in normal physiology and in pathophysiology with emphasis on metabolic disorders, cardiovascular diseases, and cancer. Finally, the review assesses current new trajectories of IGFBP-4 and PAPP-A research.
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Affiliation(s)
- Rikke Hjortebjerg
- Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark; The Danish Diabetes Academy, Odense, Denmark.
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Kværner AS, Hang D, Giovannucci EL, Willett WC, Chan AT, Song M. Trajectories of body fatness from age 5 to 60 y and plasma biomarker concentrations of the insulin-insulin-like growth factor system. Am J Clin Nutr 2018; 108:388-397. [PMID: 30101328 PMCID: PMC6669326 DOI: 10.1093/ajcn/nqy103] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/23/2018] [Indexed: 12/26/2022] Open
Abstract
Background A major pathway through which obesity increases the risk of cardiometabolic diseases and cancer is by inducing hormonal and metabolic abnormalities, including hyperinsulinemia and altered insulin-like growth factor (IGF) signaling. However, little is known about the influence of lifetime adiposity on the relevant biomarkers. Objective The aim of this study was to examine associations of trajectories of body fatness with plasma biomarker concentrations of the insulin-IGF system in 2 large prospective cohorts of US men and women. Design Associations between trajectories of body fatness and concentrations of plasma C-peptide, IGF-I, IGF-binding protein (IGFBP) 1, IGFBP-3, and the IGF-I-to-IGFBP-3 molar ratio was examined in 9386 women of the Nurses' Health Study and 3941 men of the Health Professionals Follow-Up Study. Group-based trajectory modeling was used to create trajectory groups on the basis of self-reported somatotype data at ages 5, 10, 20, 30, and 40 y and body mass index (BMI) at ages 45, 50, 55, and 60 y. We used multivariate linear regression models to examine the associations of trajectories with biomarker concentrations. Results Five trajectories of body fatness were identified: "lean-stable," "lean-moderate increase," "lean-marked increase," "medium-stable/increase," and "medium-marked increase." Compared with the lean-stable group, the lean-marked increase and medium-marked increase groups had significantly higher concentrations of C-peptide (percentage difference-women: 44% and 73%; men: 27% and 51%) and lower concentrations of IGFBP-1 (women: -61% and -78%; men: -47% and -65%). Adjustment for current BMI attenuated the association to null for the medium-marked increase group, but the lean-marked increase group still had modestly higher concentrations of C-peptide (women: 10%; men: 6%) and lower concentrations of IGFBP-1 (women: -18%; men: -21%) than the lean-stable group. Conclusions Adiposity across the life span was associated with higher C-peptide and lower IGFBP-1 concentrations in adulthood. The associations were largely driven by attained adiposity and, to a lesser extent, weight gain in early-middle adulthood. This trial was registered at www.clinicaltrials.gov as NCT03419455.
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Affiliation(s)
- Ane S Kværner
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway,Norwegian National Advisory Unit on Disease-Related Malnutrition, Oslo University Hospital, Oslo, Norway,Departments of Nutrition and Harvard TH Chan School of Public Health, Boston, MA,Departments of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA
| | - Dong Hang
- Departments of Nutrition and Harvard TH Chan School of Public Health, Boston, MA,Departments of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA,Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Edward L Giovannucci
- Departments of Nutrition and Harvard TH Chan School of Public Health, Boston, MA,Departments of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Walter C Willett
- Departments of Nutrition and Harvard TH Chan School of Public Health, Boston, MA,Departments of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Andrew T Chan
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Mingyang Song
- Departments of Nutrition and Harvard TH Chan School of Public Health, Boston, MA,Departments of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA,Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School, Boston, MA,Address correspondence to MS (e-mail: )
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Cediel G, Rueda F, Oxvig C, Oliveras T, Labata C, de Diego O, Ferrer M, Aranda-Nevado MC, Serra-Gregori J, Núñez J, García C, Bayes-Genis A. Prognostic value of the Stanniocalcin-2/PAPP-A/IGFBP-4 axis in ST-segment elevation myocardial infarction. Cardiovasc Diabetol 2018; 17:63. [PMID: 29712555 PMCID: PMC5925828 DOI: 10.1186/s12933-018-0710-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 04/25/2018] [Indexed: 12/21/2022] Open
Abstract
Objective The aim of the present study was to evaluate the prognostic value of the Stanniocalcin-2/PAPP-A/IGFBP-4 axis in patients with ST-segment elevation myocardial infarction (STEMI). Methods Observational cohort study performed in 1085 consecutive STEMI patients treated with early reperfusion between February 2011 and August 2014. Stanniocalcin-2, PAPP-A, and IGFBP-4 were measured using state-of-the art immunoassays. The primary outcome was the composite endpoint of all-cause mortality and readmission due to heart failure (HF). Results Median follow-up was 3.3 years (IQR 1.0–3.7), during which 176 patients (16.2%) presented a composite endpoint. Multivariable cox regression analysis revealed that Stanniocalcin-2 (HR 2.06; 95% CI 1.13–3.75; p = 0.018), IGFBP-4 (HR 1.73; 95% CI 1.14–2.64; p = 0.010), Killip–Kimball class III–IV (HR 1.40; 95% CI 1.13–1.74; p = 0.002), NT-ProBNP (HR 1.21; 95% CI 1.07–1.37; p = 0.002), age (HR 1.06; 95% CI 1.04–1.08; p < 0.001) and left ventricular ejection fraction (HR 0.97; 95% CI 0.95–0.98; p < 0.001) were independent predictors of the composite endpoint. A model containing Stanniocalcin-2 and IGFBP-4 on top of clinical variables significantly improved C-index discrimination (p = 0.036). Stanniocalcin-2 was also identified as independent predictor of all-cause mortality (HR 2.23; 95% CI 1.16–4.29; p = 0.017) and readmission due to HF (HR 3.42; 95% CI 1.22–9.60; p = 0.020). Conclusions In STEMI patients, Stanniocalcin-2 and IGFBP-4 emerged as independent predictors of all-cause death and readmission due to HF. The Stanniocalcin-2/PAPP-A/IGFBP-4 axis exhibits a significant role in STEMI risk stratification.
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Affiliation(s)
- Germán Cediel
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Ferran Rueda
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Claus Oxvig
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Teresa Oliveras
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Carlos Labata
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Oriol de Diego
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Marc Ferrer
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - M Cruz Aranda-Nevado
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Judith Serra-Gregori
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Julio Núñez
- Cardiology Department, Hospital Clínico Universitario, INCLIVA, Departamento de Medicina, CIBERCV Universitat de València, Valencia, Spain
| | - Cosme García
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain.,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain
| | - Antoni Bayes-Genis
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, 08916, Barcelona, Spain. .,Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain.
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Iacobaeus C, Kahan T, Jörneskog G, Bremme K, Andolf E, Thorsell M. Pregnancy-associated plasma protein-A is positively correlated with first-trimester skin microvascular reactivity. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2018; 51:361-367. [PMID: 28397320 DOI: 10.1002/uog.17486] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 03/23/2017] [Accepted: 03/31/2017] [Indexed: 06/07/2023]
Abstract
OBJECTIVE To investigate the relationship between levels of circulating maternal pregnancy-associated plasma protein-A (PAPP-A) and first-trimester maternal vascular function. METHODS This was a cross-sectional study of 53 healthy, non-smoking, nulliparous pregnant women in Stockholm, Sweden. PAPP-A levels and vascular function were assessed during gestational weeks 11-14. Forearm skin microcirculation was investigated by laser Doppler perfusion imaging during iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) to assess endothelium-dependent and -independent microvascular vasodilatation, respectively. Microvascular endothelial function index was calculated as peak ACh/peak SNP. Endothelium-dependent and -independent vasodilatation in the brachial artery was evaluated, respectively, by postischemic hyperemia-induced flow-mediated vasodilatation (FMD) and by response to sublingual intake of glyceryl trinitrate (GTN). RESULTS PAPP-A was correlated with skin microvascular endothelial function index (β = 1.008 (95% CI, 0.34-1.68), r2 = 0.17, P = 0.004). PAPP-A also correlated inversely with FMD (β = -0.052 (95% CI, -0.094 to -0.011), r2 = 0.13, P = 0.014) but did not relate to forearm endothelial function index (i.e. FMD/GTN). The results were retained in multivariate analyses including known confounding factors. CONCLUSIONS First-trimester endothelium-dependent skin microvascular reactivity was positively related to PAPP-A levels. If confirmed, these novel findings suggest that first-trimester skin microvascular reactivity could be a useful early pregnancy marker of placental function. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
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Affiliation(s)
- C Iacobaeus
- Division of Obstetrics and Gynecology, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - T Kahan
- Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - G Jörneskog
- Division of Medicine, Microcirculation Laboratory, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - K Bremme
- Division of Obstetrics and Gynecology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - E Andolf
- Division of Obstetrics and Gynecology, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - M Thorsell
- Division of Obstetrics and Gynecology, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
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Zhang W, Wang W, Kuang L. The relation between insulin-like growth factor 1 levels and risk of depression in ischemic stroke. Int J Geriatr Psychiatry 2018; 33:e228-e233. [PMID: 28833493 DOI: 10.1002/gps.4774] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 07/13/2017] [Indexed: 12/31/2022]
Abstract
BACKGROUND The aim of this study is to evaluate whether lower serum levels of insulin-like growth factor 1 (IGF-1) in the acute phase of ischemic stroke are associated with higher risk of post-stroke depression (PSD) over a 1-year period. METHODS The subjects were first-ever acute ischemic stroke (AIS) patients who were hospitalized from July 1, 2014 to August 31, 2015. The study also included 120 age-matched and sex-matched healthy controls from the same geographical area. Fasting blood samples were collected within 24 hours of admission for IGF-I measurement. Neurological and neuropsychological evaluations were conducted at a 1-year follow-up. RESULTS Two-hundred twenty-five patients were observed for a 1-year follow-up, and 74 of these patients (32.9%, 95%CI: 26.8%-39.0%) were diagnosed with PSD. The depression distribution across the IGF-1 quartiles ranged between 61.4% (first quartile) and 8.9% (fourth quartile). In a multivariate model using the first quartiles of the IGF-1 versus quartiles 2 through 4, together with the significant clinical variables, the marker displayed prognostic information, and the odds ratio (OR) for first quartile was 3.35 [95% CI, 1.88-6.79; P = 0.001]. CONCLUSION The data showed that low serum IGF-1 levels at admission are associated with a high risk of developing PSD, suggesting that these alterations might be involved in the pathophysiology of depression symptoms in stroke patients.
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Affiliation(s)
- Wei Zhang
- Department of Psychiatry, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wo Wang
- Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Li Kuang
- Department of Psychiatry, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Wu JPJ, Cheng B, Roffler SR, Lundy DJ, Yen CYT, Chen P, Lai JJ, Pun SH, Stayton PS, Hsieh PCH. Reloadable multidrug capturing delivery system for targeted ischemic disease treatment. Sci Transl Med 2017; 8:365ra160. [PMID: 27856799 DOI: 10.1126/scitranslmed.aah6228] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 10/01/2016] [Indexed: 12/14/2022]
Abstract
Human clinical trials of protein therapy for ischemic diseases have shown disappointing outcomes so far, mainly because of the poor circulatory half-life of growth factors in circulation and their low uptake and retention by the targeted injury site. The attachment of polyethylene glycol (PEG) extends the circulatory half-lives of protein drugs but reduces their extravasation and retention at the target site. To address this issue, we have developed a drug capture system using a mixture of hyaluronic acid (HA) hydrogel and anti-PEG immunoglobulin M antibodies, which, when injected at a target body site, can capture and retain a variety of systemically injected PEGylated therapeutics at that site. Furthermore, repeated systemic injections permit "reloading" of the capture depot, allowing the use of complex multistage therapies. This study demonstrates this capture system in both murine and porcine models of critical limb ischemia. The results show that the reloadable HA/anti-PEG system has the potential to be clinically applied to patients with ischemic diseases, who require sequential administration of protein drugs for optimal outcomes.
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Affiliation(s)
- Jasmine P J Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Bill Cheng
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Steve R Roffler
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. .,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - David J Lundy
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | | | - Peilin Chen
- Research Center for Applied Sciences, Academia Sinica, Taipei 115, Taiwan
| | - James J Lai
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Suzie H Pun
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Patrick S Stayton
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Patrick C H Hsieh
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. .,Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.,Institute of Medical Genomics and Proteomics and Department of Surgery, National Taiwan University and Hospital, Taipei 100, Taiwan
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Strazhesko ID, Tkacheva ON, Akasheva DU, Dudinskaya EN, Plokhova EV, Pykhtina VS, Kruglikova AS, Brailova NV, Sharashkina NV, Kashtanova DA, Isaykina OY, Pokrovskaya MS, Vygodin VA, Ozerova IN, Skvortsov DA, Boytsov SA. Growth Hormone, Insulin-Like Growth Factor-1, Insulin Resistance, and Leukocyte Telomere Length as Determinants of Arterial Aging in Subjects Free of Cardiovascular Diseases. Front Genet 2017; 8:198. [PMID: 29375617 PMCID: PMC5770739 DOI: 10.3389/fgene.2017.00198] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/20/2017] [Indexed: 11/13/2022] Open
Abstract
Background: Increased arterial stiffness (AS), intima-media thickness (IMT), and the presence of atherosclerotic plaques (PP) have been considered as important aspects of vascular aging. It is well documented that the cardiovascular system is an important target organ for growth hormone (GH) and insulin-like growth factor (IGF)-1 in humans, and GH /IGF-1 deficiency significantly increases the risk for cardiovascular diseases (CVD). The telomere length of peripheral blood leukocytes (LTL) is a biomarker of cellular senescence and that has been proposed as an independent predictor of (CVD). The aim of this study is to determine the role of GH/IGF-1, LTL and their interaction cardiovascular risk factors (CVRF) in the vascular aging. Methods: The study group included 303 ambulatory participants free of known CVD (104 males and 199 females) with a mean age of 51.8 ± 13.3 years. All subjects had one or more CVRF [age, smoking, arterial hypertension, obesity, dyslipidemia, fasting hyperglycemia, insulin resistance-HOMA (homeostatic model assessment) >2.5, or high glycated hemoglobin]. The study sample was divided into the two groups according to age as "younger" (m ≤ 45 years, f ≤ 55 years) and "older" (m > 45 years, f > 55 years). IMT and PP were determined by ultrasonography, AS was determined by measuring the carotid-femoral pulse wave velocity (c-f PWV) using the SphygmoCor system (AtCor Medical). LTL was determined by PCR. Serum IGF-1 and GH concentrations we measured by immunochemiluminescence analysis. Results: Multiple linear regression analysis with adjustment for CVRF indicated that HOMA, GH, IGF-1, and LTL had an independent relationship with all the arterial wall parameters investigated in the younger group. In the model with c-f PWV as a dependent variable, p < 0.001 for HOMA, p = 0.03 for GH, and p = 0.004 for LTL. In the model with IMT as a dependent variable, p = 0.0001 for HOMA, p = 0.044 for GH, and p = 0.004 for IGF-1. In the model with the number of plaques as a dependent variable, p = 0.0001 for HOMA, and p = 0.045 for IGF-1. In the older group, there were no independent significant associations between GH/IGF-1, LTL, HOMA, and arterial wall characteristics. Conclusions: GH/IGF-1, IR, HOMA, and LTL were the important parameters of arterial aging in younger healthy participants.
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Affiliation(s)
- Irina D Strazhesko
- Department of Clinical Cardiology and Molecular Genetics, Federal State Institution National Medical Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.,Department of Age-associated Diseases, Medical Scientific and Educational Center, Lomonosov Moscow State University, Moscow, Russia
| | - Olga N Tkacheva
- Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Dariga U Akasheva
- Department of Fundamental and Applied Aspects of Obesity, Federal State Institution National Medical Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Ekaterina N Dudinskaya
- Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Ekaterina V Plokhova
- Department of Cardiology, Federal Scientific and Clinical Center of the Federal Medico-Biological Agency, Moscow, Russia
| | - Valentina S Pykhtina
- Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Anna S Kruglikova
- Department of Aging and Age-associated Diseases Prevention, Federal State Institution National Medical Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Natalia V Brailova
- Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Natalia V Sharashkina
- Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Daria A Kashtanova
- Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Olesya Y Isaykina
- Department of Primary Prevention of Chronic Non-Communicable Diseases in the Healthcare System, Federal State Institution National Medical Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Mariya S Pokrovskaya
- Biobank, Federal State Institution National Medical Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Vladimir A Vygodin
- Department of Epidemiology of Chronic Non-Communicable Diseases Laboratory of Biostatistics, Federal State Institution National Medical Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Irina N Ozerova
- Department of Biochemical Markers of Chronic Non-Communicable Diseases Research, Federal State Institution National Medical Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Dmitry A Skvortsov
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
| | - Sergey A Boytsov
- National Medical Research Center for Cardiology of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
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Insulin-like growth factor-1 signaling in cardiac aging. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1931-1938. [PMID: 28847512 DOI: 10.1016/j.bbadis.2017.08.029] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 08/22/2017] [Accepted: 08/23/2017] [Indexed: 12/31/2022]
Abstract
Cardiovascular disease (CVD) is the leading cause of death in most developed countries. Aging is associated with enhanced risk of CVD. Insulin-like growth factor-1 (IGF-1) binds to its cognate receptor, IGF-1 receptor (IGF-1R), and exerts pleiotropic effects on cell growth, differentiation, development, and tissue repair. Importantly, IGF-1/IGF-1R signaling is implicated in cardiac aging and longevity. Cardiac aging is an intrinsic process that results in cardiac dysfunction, accompanied by molecular and cellular changes. In this review, we summarize the current state of knowledge regarding the link between the IGF-1/IGF-1R system and cardiac aging. The biological effects of IGF-1R and insulin receptor will be discussed and compared. Furthermore, we describe data regarding how deletion of IGF-1R in cardiomyocytes of aged knockout mice may delay the development of senescence-associated myocardial pathologies. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
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50
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Partial IGF-1 deficiency is sufficient to reduce heart contractibility, angiotensin II sensibility, and alter gene expression of structural and functional cardiac proteins. PLoS One 2017; 12:e0181760. [PMID: 28806738 PMCID: PMC5555709 DOI: 10.1371/journal.pone.0181760] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 07/06/2017] [Indexed: 01/15/2023] Open
Abstract
Circulating levels of IGF-1 may decrease under several circumstances like ageing, metabolic syndrome, and advanced cirrhosis. This reduction is associated with insulin resistance, dyslipidemia, progression to type 2 diabetes, and increased risk for cardiovascular diseases. However, underlying mechanisms between IGF-1 deficiency and cardiovascular disease remain elusive. The specific aim of the present work was to study whether the partial IGF-1 deficiency influences heart and/or coronary circulation, comparing vasoactive factors before and after of ischemia-reperfusion (I/R). In addition, histology of the heart was performed together with cardiac gene expression for proteins involved in structure and function (extracellular matrix, contractile proteins, active peptides); carried out using microarrays, followed by RT-qPCR confirmation of the three experimental groups. IGF-1 partial deficiency is associated to a reduction in contractility and angiotensin II sensitivity, interstitial fibrosis as well as altered expression pattern of genes involved in extracellular matrix proteins, calcium dynamics, and cardiac structure and function. Although this work is descriptive, it provides a clear insight of the impact that partial IGF-1 deficiency on the heart and establishes this experimental model as suitable for studying cardiac disease mechanisms and exploring therapeutic options for patients under IGF-1 deficiency conditions.
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