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Picchi E, Di Giuliano F, Pucci N, Sallustio F, Minosse S, Mascolo AP, Marrama F, Ferrazzoli V, Da Ros V, Diomedi M, Federici M, Garaci F. CT Perfusion Imaging in Patients with Acute Ischemic Stroke: The Role of Premorbid Statin Treatment. Tomography 2025; 11:54. [PMID: 40423256 DOI: 10.3390/tomography11050054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/28/2025] [Accepted: 04/29/2025] [Indexed: 05/28/2025] Open
Abstract
BACKGROUND Statins appear to be useful in patients with acute ischemic stroke. Our aim was to evaluate the association between premorbid statin treatment and CT perfusion characteristics of acute ischemic stroke. METHODS A retrospective analysis of patients with acute stroke secondary to occlusion of large vessels in the anterior circulation was performed to assess collateral flow, ischemic core volume, and ischemic penumbra using CT angiography and CT perfusion maps. Fisher's exact test was used to compare baseline characteristics of patients in the two groups. The Wilcoxon rank-sum test for independent groups was used to compare all variables obtained for the two different groups with and without statin use. RESULTS We identified 61 patients, including 29 treated with statins and 32 not treated with statins before stroke onset matched by age, gender, and vascular risk factors except for hypercholesterolemia. The statin group showed lower National Institutes of health Stroke Scale scores at onset (14 ± 6.1 vs. 16 ± 4.5; p = 0.04) and lower volumes of brain tissue characterized by impaired cerebral blood flow (CBF), cerebral blood volume (CBV), and Tmax9.5-25s; otherwise, no statistically significant difference was found in the volume of the Tmax16-25s between the two groups. CONCLUSIONS Premorbid statin treatment is associated with a favorable imaging condition of acute ischemic stroke in terms of ischemic core and ischemic penumbra volume.
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Affiliation(s)
- Eliseo Picchi
- Diagnostic Imaging Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Francesca Di Giuliano
- Neuroradiology Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Noemi Pucci
- Diagnostic Imaging Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Fabrizio Sallustio
- Comprehensive Stroke Center, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Silvia Minosse
- Diagnostic Imaging Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Alfredo Paolo Mascolo
- Comprehensive Stroke Center, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Federico Marrama
- Comprehensive Stroke Center, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Valentina Ferrazzoli
- Neuroradiology Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Valerio Da Ros
- Diagnostic Imaging Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Marina Diomedi
- Comprehensive Stroke Center, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Francesco Garaci
- Diagnostic Imaging Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
- Neuroradiology Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
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Yang Y, Shen H, Guan H, Wang B, Qing M, Liu J, Liu A. Effect of Statin on Clinical Outcomes in Critically Ill Patients with Non-traumatic Subarachnoid Hemorrhage: A Retrospective Analysis Based on MIMIC Database. World Neurosurg 2025; 197:123855. [PMID: 40054847 DOI: 10.1016/j.wneu.2025.123855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Nontraumatic subarachnoid hemorrhage (NSAH) is a type of hemorrhagic stroke with high mortality and low recovery rates. Although statins are commonly used in cardiovascular diseases, their impact on subarachnoid hemorrhage prognosis remains unclear. This study aimed to explore the relationship between statin use and short-term and long-term all-cause mortality in critically ill patients with NSAH. METHODS Data from the Medical Information Mart for Intensive Care IV database were used to categorize critically ill patients with NSAH into statin and nonstatin groups. A Cox proportional hazards model assessed the association between statin use and all-cause mortality. Subgroup analyses were conducted to examine the consistency of statin effects on mortality. RESULTS The study included 750 patients, with 43% male. One-month mortality was 21%, and intensive care unit mortality was 17%. Cox regression analysis showed that statin use was independently associated with reduced intensive care unit mortality (hazard ratio [HR = 0.52; P = 0.010), 1-month mortality (HR = 0.49; P < 0.001), 3-month mortality (HR = 0.62; P = 0.012), and 1-year mortality (HR = 0.70; P = 0.040). Subgroup analyses showed no significant interactions. Simvastatin and atorvastatin both significantly reduced 1-month mortality. CONCLUSIONS Statin use may improve mortality outcomes in critically ill patients with NSAH, suggesting their potential benefit in this population.
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Affiliation(s)
- Yibo Yang
- People's Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, China; The Second Affiliated Hospital, Department of Neurosurgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Hui Shen
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Cerebrovascular Disease Department, Neurological Disease Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Hao Guan
- People's Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, China
| | - Bing Wang
- The Second Affiliated Hospital, Department of Neurosurgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Mei Qing
- Department of Neurology, Beijing Pinggu Hospital, Beijing, China
| | - Jiachun Liu
- Cerebrovascular Disease Department, Neurological Disease Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China; Department of Neurosurgery, Beijing Hospital, Beijing, China
| | - Aihua Liu
- People's Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, China; The Second Affiliated Hospital, Department of Neurosurgery, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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3
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Bosman M, Krüger D, Roth L, Martinet W, De Meyer GRY, Van Craenenbroeck EM, Guns PJ. Prior exposure to doxorubicin exacerbates atherosclerotic plaque formation in apolipoprotein-E-deficient mice on a high-fat diet. Atherosclerosis 2025; 403:119168. [PMID: 40154137 DOI: 10.1016/j.atherosclerosis.2025.119168] [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: 08/20/2024] [Revised: 02/24/2025] [Accepted: 03/19/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND AND AIMS Epidemiological data suggest that anthracyclines, such as doxorubicin (DOX), promote atherosclerosis in cancer survivors. However, this has not been established experimentally so far. Here, we investigated whether DOX pre-exposure exacerbates atherosclerotic plaque formation (Study 1) as well as the impact of DOX on plaque progression (Study 2). Further, we evaluated the role of alpha-1-antichymotrypsin (Serpina3n) and thrombospondin-1 (Thbs1) in these plaques as we previously identified these proteins to be associated with DOX-induced cardiovascular disease. METHODS In Study 1, DOX (4 mg/kg body weight/week) was administered for three weeks to apolipoprotein-E-deficient mice followed by a high-fat plaque-promoting diet for 8 weeks. In Study 2, mice were fed a high-fat diet for 17 weeks with DOX administered concomitantly from the third week of diet for three weeks. Plaque size and composition were assessed in the thoracic aorta, brachiocephalic artery and proximal ascending aorta. RESULTS Prior DOX exposure increased plaque size along the aortic tree, regardless of sex. This was accompanied by enhanced cell death (increased TUNEL positivity) as well as elevated Serpina3n and Thbs1 in plaques of DOX-treated mice. DOX did not change total cholesterol, HDL and LDL plasma concentrations. Conversely, concomitant DOX exposure did not enhance plaque size nor affect overall plaque composition along the aortic tree, highlighting the importance of experimental design. CONCLUSIONS Early DOX exposure exacerbated plaque development in mice, providing first experimental evidence for anthracycline chemotherapy as a possible risk factor for atherosclerosis in cancer patients.
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Affiliation(s)
- Matthias Bosman
- Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
| | - Dustin Krüger
- Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium
| | - Lynn Roth
- Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium
| | - Wim Martinet
- Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium
| | - Guido R Y De Meyer
- Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium
| | - Emeline M Van Craenenbroeck
- Research Group Cardiovascular Diseases, University of Antwerp, B-2610, Antwerp, Belgium; Department of Cardiology, Antwerp University Hospital (UZA), Drie Eikenstraat 655, B-2650, Edegem, Belgium
| | - Pieter-Jan Guns
- Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium
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Liu JC, Lei SY, Zhang DH, He QY, Sun YY, Zhu HJ, Qu Y, Zhou SY, Yang Y, Li C, Guo ZN. The pleiotropic effects of statins: a comprehensive exploration of neurovascular unit modulation and blood-brain barrier protection. Mol Med 2024; 30:256. [PMID: 39707228 DOI: 10.1186/s10020-024-01025-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024] Open
Abstract
The blood-brain barrier (BBB) is the most central component of the neurovascular unit (NVU) and is crucial for the maintenance of the internal environment of the central nervous system and the regulation of homeostasis. A multitude of neuroprotective agents have been developed to exert neuroprotective effects and improve the prognosis of patients with ischemic stroke. These agents have been designed to maintain integrity and promote BBB repair. Statins are widely used as pharmacological agents for the treatment and prevention of ischemic stroke, making them a cornerstone in the pharmacological armamentarium for this condition. The primary mechanism of action is the reduction of serum cholesterol through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which results in a decrease in low-density lipoprotein cholesterol (LDL-C) and an increase in cholesterol clearance. Nevertheless, basic and clinical research has indicated that statins may exert additional pleiotropic effects beyond LDL-C reduction. Previous studies on ischemic stroke have demonstrated that statins can enhance neurological function, reduce inflammation, and promote angiogenic and synaptic processes following ischemic stroke. The BBB has been increasingly recognized for its role in the development and progression of ischemic stroke. Statins have also been found to play a potential BBB protective role by affecting members of the NVU. This review aimed to provide a comprehensive theoretical basis for the clinical application of statins by systematically detailing how statins influence the BBB, particularly focusing on the regulation of the function of each member of the NVU.
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Affiliation(s)
- Jia-Cheng Liu
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Shuang-Yin Lei
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Dian-Hui Zhang
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Qian-Yan He
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Ying-Ying Sun
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Hong-Jing Zhu
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Yang Qu
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Sheng-Yu Zhou
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
| | - Yi Yang
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China
- Jilin Provincial Key Laboratory of Cerebrovascular Disease, Xinmin Street 1#, Changchun, 130021, China
| | - Chao Li
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China.
| | - Zhen-Ni Guo
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China.
- Jilin Provincial Key Laboratory of Cerebrovascular Disease, Xinmin Street 1#, Changchun, 130021, China.
- Neuroscience Research Center, The First Hospital of Jilin University, Xinmin Street 1#, Changchun, 130021, China.
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Wang Y, Zhang L, Lyu T, Cui L, Zhao S, Wang X, Wang M, Wang Y, Li Z. Association of DNA methylation/demethylation with the functional outcome of stroke in a hyperinflammatory state. Neural Regen Res 2024; 19:2229-2239. [PMID: 38488557 PMCID: PMC11034580 DOI: 10.4103/1673-5374.392890] [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: 06/12/2023] [Revised: 10/07/2023] [Accepted: 11/13/2023] [Indexed: 04/24/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202410000-00024/figure1/v/2024-02-06T055622Z/r/image-tiff Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effect of DNA methylation on stroke at high levels of inflammation is unclear. In this study, we constructed a hyperinflammatory cerebral ischemia mouse model and investigated the effect of hypomethylation and hypermethylation on the functional outcome. We constructed a mouse model of transient middle cerebral artery occlusion and treated the mice with lipopolysaccharide to induce a hyperinflammatory state. To investigate the effect of DNA methylation on stroke, we used small molecule inhibitors to restrain the function of key DNA methylation and demethylation enzymes. 2,3,5-Triphenyltetrazolium chloride staining, neurological function scores, neurobehavioral tests, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR and western blot assay were used to evaluate the effects after stroke in mice. We assessed changes in the global methylation status by measuring DNA 5-mc and DNA 5-hmc levels in peripheral blood after the use of the inhibitor. In the group treated with the DNA methylation inhibitor, brain tissue 2,3,5-triphenyltetrazolium chloride staining showed an increase in infarct volume, which was accompanied by a decrease in neurological scores and worsening of neurobehavioral performance. The levels of inflammatory factors interleukin 6 and interleukin-1 beta in ischemic brain tissue and plasma were elevated, indicating increased inflammation. Related inflammatory pathway exploration showed significant overactivation of nuclear factor kappa B. These results suggested that inhibiting DNA methylation led to poor functional outcome in mice with high inflammation following stroke. Further, the effects were reversed by inhibition of DNA demethylation. Our findings suggest that DNA methylation regulates the inflammatory response in stroke and has an important role in the functional outcome of hyperinflammatory stroke.
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Affiliation(s)
- Yubo Wang
- Vascular Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Ling Zhang
- Vascular Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Tianjie Lyu
- Vascular Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Lu Cui
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shunying Zhao
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xuechun Wang
- Vascular Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Meng Wang
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- National Center for Healthcare Quality Management in Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yongjun Wang
- Vascular Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- National Center for Healthcare Quality Management in Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, China
- Beijing Engineering Research Center of Digital Healthcare for Neurological Diseases, Beijing, China
| | - Zixiao Li
- Vascular Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- National Center for Healthcare Quality Management in Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, China
- Beijing Engineering Research Center of Digital Healthcare for Neurological Diseases, Beijing, China
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Blackstone J, Williams T, Nicholas JM, Bordea E, De Angelis F, Bianchi A, Calvi A, Doshi A, John N, Apap Mangion S, Wade C, Merry R, Barton G, Lyle D, Jarman E, Mahad D, Shehu A, Arun T, McDonnell G, Geraldes R, Craner M, Hillier C, Ganesalingam J, Fisniku L, Hobart J, Spilker C, Robertson N, Kalra S, Pluchino S, Harikrishnan S, Mattoscio M, Harrower T, Young C, Lee M, Chhetri S, Ahmed F, Rog D, Silber E, Gallagher P, Duddy M, Straukiene A, Nicholas R, Rice C, Nixon SJ, Beveridge J, Hawton A, Tebbs S, Braisher M, Giovannoni G, Ciccarelli O, Greenwood J, Thompson AJ, Hunter R, Pavitt S, Pearson O, Evangelou N, Sharrack B, Galea I, Chandran S, Ford HL, Frost C, Chataway J. Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK. BMJ Open 2024; 14:e086414. [PMID: 39284697 PMCID: PMC11409264 DOI: 10.1136/bmjopen-2024-086414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 08/16/2024] [Indexed: 09/20/2024] Open
Abstract
INTRODUCTION There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. METHODS AND ANALYSIS MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. ETHICS AND DISSEMINATION The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS NCT03387670; ISRCTN82598726.
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Affiliation(s)
- James Blackstone
- Comprehensive Clinical Trials Unit, University College London, London, UK
| | - Thomas Williams
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Jennifer M Nicholas
- Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK
| | - Ekaterina Bordea
- Comprehensive Clinical Trials Unit, University College London, London, UK
| | - Floriana De Angelis
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Alessia Bianchi
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Alberto Calvi
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Anisha Doshi
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Nevin John
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Sean Apap Mangion
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Charles Wade
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Rachel Merry
- Comprehensive Clinical Trials Unit, University College London, London, UK
| | - Gil Barton
- Comprehensive Clinical Trials Unit, University College London, London, UK
| | - Dawn Lyle
- Anne Rowling Regenerative Neurology Clinic, NHS Lothian, Edinburgh, UK
| | - Elisabeth Jarman
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Don Mahad
- Anne Rowling Regenerative Neurology Clinic, NHS Lothian, Edinburgh, UK
| | - Abdullah Shehu
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Tarunya Arun
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Gavin McDonnell
- Belfast City Hospital Health and Social Services Trust, Belfast, UK
| | - Ruth Geraldes
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Matthew Craner
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | | | - Leonora Fisniku
- University Hospitals Sussex NHS Foundation Trust, Brighton, UK
| | - Jeremy Hobart
- University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Cord Spilker
- Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
| | | | - Seema Kalra
- University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, UK
| | - Stefano Pluchino
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- University of Cambridge, Cambridge, UK
| | | | - Miriam Mattoscio
- Barking Havering and Redbridge University Hospitals NHS Trust, Romford, UK
| | - Timothy Harrower
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Carolyn Young
- The Walton Centre NHS Foundation Trust, Liverpool, UK
- Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Martin Lee
- Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
| | - Suresh Chhetri
- Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
| | - Fayyaz Ahmed
- Hull University Teaching Hospitals NHS Trust, Hull, UK
| | - David Rog
- Department of Neurology, Salford Royal NHS Foundation Trust, Salford, UK
| | - Eli Silber
- Department of Neurology, Lewisham and Greenwich NHS Trust, London, UK
| | | | - Martin Duddy
- Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | | | | | | | | | | | | | - Susan Tebbs
- Comprehensive Clinical Trials Unit, University College London, London, UK
| | - Marie Braisher
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | | | - Olga Ciccarelli
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - John Greenwood
- Institute of Ophthalmology, University College London, London, UK
| | - Alan J Thompson
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Rachael Hunter
- Department of Primary Care and Population Health, University College London Research, London, UK
| | | | | | | | - Basil Sharrack
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Ian Galea
- Clinical & Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
| | - Siddharthan Chandran
- Anne Rowling Regenerative Neurology Clinic, NHS Lothian, Edinburgh, UK
- Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK
| | - Helen L Ford
- Centre for Neurosciences, Leeds General Infirmary, Leeds, UK
| | - Chris Frost
- Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK
| | - Jeremy Chataway
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
- National Institute for Health Research, Biomedical Research Centre, University College London Hospitals, London, UK
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7
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Gong C, Liu C, Wang Y, Chen L, Yuan J, Zhang J, Xiaoming L, Chen Y, Huang L, Xu T, Chen Y. Effect of statin treatment on clinical outcomes in cardioembolic stroke with endovascular thrombectomy. J Neurointerv Surg 2024; 16:947-954. [PMID: 37586821 DOI: 10.1136/jnis-2023-020619] [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: 05/28/2023] [Accepted: 08/03/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND While statins have been widely used in patients with large-artery atherosclerotic stroke, their effectiveness in patients with cardioembolic large vessel occlusion (CE-LVO) undergoing endovascular treatment (EVT) remains unclear. This study aimed to evaluate whether combining statin therapy with EVT could improve clinical outcomes in patients with acute ischemic stroke caused by CE-LVO in the anterior circulation. METHODS We performed a retrospective screening on patients with CE-LVO in the anterior circulation who underwent EVT in 27 hospitals across China between 2018 and 2021. The primary outcome measure was functional independence, defined as a 90-day modified Rankin Scale (mRS) score of 0 to 2. Safety outcomes included 90-day mortality and symptomatic intracranial hemorrhage (sICH). RESULTS A total of 510 patients with CE-LVO in the anterior circulation undergoing EVT were included in this study. Of these, 404 (79.2%) patients received statin treatment (statin group), while 106 (20.8%) did not (non-statin group). Statin treatment was significantly associated with improved functional independence (adjusted OR (aOR) 2.072, 95% CI 1.197 to 3.586, P=0.009). Moreover, statin use was associated with a lower rate of 90-day mortality (aOR 0.343, 95% CI 0.197 to 0.596, P<0.001) and a lower rate of sICH (aOR 0.153, 95% CI 0.072 to 0.325, P<0.001). CONCLUSION Statin treatment was associated with improved clinical outcomes and reduced risks of mortality and sICH in patients with CE-LVO in the anterior circulation undergoing EVT.
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Affiliation(s)
- Chen Gong
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chang Liu
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - You Wang
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liyuan Chen
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jinxian Yuan
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Zhang
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Xiaoming
- Department of Intensive Care Unit, Chongqing University Cancer Hospital, Chongqing, China
| | - Yanru Chen
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liping Huang
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tao Xu
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yangmei Chen
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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8
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Rehman S, Nadeem A, Akram U, Sarwar A, Quraishi A, Siddiqui H, Malik MAJ, Nabi M, Ul Haq I, Cho A, Mazumdar I, Kim M, Chen K, Sepehri S, Wang R, Balar AB, Lakhani DA, Yedavalli VS. Molecular Mechanisms of Ischemic Stroke: A Review Integrating Clinical Imaging and Therapeutic Perspectives. Biomedicines 2024; 12:812. [PMID: 38672167 PMCID: PMC11048412 DOI: 10.3390/biomedicines12040812] [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: 02/29/2024] [Revised: 03/28/2024] [Accepted: 04/01/2024] [Indexed: 04/28/2024] Open
Abstract
Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects of ischemic stroke research, emphasizing crucial mechanisms, therapeutic approaches, and the role of clinical imaging in disease management. It discusses the multifaceted role of Netrin-1, highlighting its potential in promoting neurovascular repair and mitigating post-stroke neurological decline. It also examines the impact of blood-brain barrier permeability on stroke outcomes and explores alternative therapeutic targets such as statins and sphingosine-1-phosphate signaling. Neurocardiology investigations underscore the contribution of cardiac factors to post-stroke mortality, emphasizing the importance of understanding the brain-heart axis for targeted interventions. Additionally, the review advocates for early reperfusion and neuroprotective agents to counter-time-dependent excitotoxicity and inflammation, aiming to preserve tissue viability. Advanced imaging techniques, including DWI, PI, and MR angiography, are discussed for their role in evaluating ischemic penumbra evolution and guiding therapeutic decisions. By integrating molecular insights with imaging modalities, this interdisciplinary approach enhances our understanding of ischemic stroke and offers promising avenues for future research and clinical interventions to improve patient outcomes.
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Affiliation(s)
- Sana Rehman
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Arsalan Nadeem
- Department of Medicine, Allama Iqbal Medical College, Lahore 54700, Pakistan;
| | - Umar Akram
- Department of Medicine, Allama Iqbal Medical College, Lahore 54700, Pakistan;
| | - Abeer Sarwar
- Department of Medicine, Fatima Memorial Hospital College of Medicine and Dentistry, Lahore 54000, Pakistan; (A.S.); (H.S.)
| | - Ammara Quraishi
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan;
| | - Hina Siddiqui
- Department of Medicine, Fatima Memorial Hospital College of Medicine and Dentistry, Lahore 54000, Pakistan; (A.S.); (H.S.)
| | | | - Mehreen Nabi
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Ihtisham Ul Haq
- Department of Medicine, Amna Inayat Medical College, Sheikhupura 54300, Pakistan;
| | - Andrew Cho
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Ishan Mazumdar
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Minsoo Kim
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Kevin Chen
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Sadra Sepehri
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Richard Wang
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Aneri B. Balar
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Dhairya A. Lakhani
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
| | - Vivek S. Yedavalli
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (M.N.); (A.C.); (I.M.); (M.K.); (K.C.); (S.S.); (R.W.); (A.B.B.); (D.A.L.); (V.S.Y.)
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9
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Thomas RG, Kim JH, Kim JH, Yoon J, Choi KH, Jeong YY. Treatment of Ischemic Stroke by Atorvastatin-Loaded PEGylated Liposome. Transl Stroke Res 2024; 15:388-398. [PMID: 36639607 DOI: 10.1007/s12975-023-01125-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/16/2022] [Accepted: 01/04/2023] [Indexed: 01/15/2023]
Abstract
There is insufficient evidence on the effect of nanoparticles, particularly liposomes loaded with a statin, on acute ischemic stroke. We investigated the impact of atorvastatin-loaded PEG (polyethylene glycol) conjugated liposomes (LipoStatin) on the outcomes in rats with cerebral ischemia-reperfusion. PEGylated liposome loaded with atorvastatin was developed as a nanoparticle to specifically accumulate in an ischemic region and release the drug to ameliorate the harmful effects of the stroke. LipoStatin was administered to rats with transient middle cerebral artery occlusion through the tail vein immediately after reperfusion (LipoStatin group). LipoStatin efficiently accumulated at the cerebral ischemic injury site of the rat. The LipoStatin group showed a significantly reduced infarct volume (p < 0.01) in brain micro-MR imaging and improved neurological function recovery compared to the control group (p < 0.05). In addition, markedly improved brain metabolism using fluorine-18 fluorodeoxyglucose micro-PET/CT imaging was demonstrated in the LipoStatin group compared with the control group (p < 0.01). Mechanistically, as a result of evaluation through IL-1 beta, TNF-alpha, ICAM-1, and Iba-1 mRNA expression levels at 5 days after cerebral ischemia, LipoStatin showed significant anti-inflammatory effects. Protein expression of occludin, JAM-A, Caveolin-1, and eNOS by western blot at 3 days and fluorescent images at 7 days showed considerable recovery of blood-brain barrier breakdown and endothelial dysfunction. PEGylated LipoStatin can be more effectively delivered to the ischemic brain and may have significant neuroprotective effects. Thus, PEGylated LipoStatin can be further developed as a promising targeted therapy for ischemic stroke and other major vascular diseases.
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Affiliation(s)
- Reju George Thomas
- Department of Radiology, Chonnam National University Medical School and Hwasun Hospital, 322 Seoyang-Ro, Hwasun-Eup, Hwasun-Gun, Jeollanam-Do, 58128, South Korea
| | - Ja-Hae Kim
- Department of Nuclear Medicine, Chonnam National University Medical School and Hospital, Gwangju, South Korea
| | - Ji-Hye Kim
- Department of Neurology, Chonnam National University Medical School and Hwasun Hospital, 322 Seoyang-Ro, Hwasun-Eup, Hwasun-Gun, Jeollanam-Do, 58128, South Korea
| | - Jungwon Yoon
- School of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju, South Korea
| | - Kang-Ho Choi
- Department of Neurology, Chonnam National University Medical School and Hwasun Hospital, 322 Seoyang-Ro, Hwasun-Eup, Hwasun-Gun, Jeollanam-Do, 58128, South Korea.
| | - Yong-Yeon Jeong
- Department of Radiology, Chonnam National University Medical School and Hwasun Hospital, 322 Seoyang-Ro, Hwasun-Eup, Hwasun-Gun, Jeollanam-Do, 58128, South Korea.
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10
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Arabi SM, Chambari M, Bahrami LS, Hadi S, Sahebkar A. Statin Therapy and Flow-Mediated Dilation: A Systematic Review and Dose-Response Meta-Analysis Using the GRADE of Data from Randomized Controlled Trials. Curr Hypertens Rev 2024; 20:90-100. [PMID: 38385489 DOI: 10.2174/0115734021280797240212091416] [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: 10/26/2023] [Revised: 01/14/2024] [Accepted: 01/22/2024] [Indexed: 02/23/2024]
Abstract
INTRODUCTION A previous meta-analysis reported the positive effects of statin therapy on endothelial function. However, the obtained result had several limitations that necessitated updating the information in this field. Therefore, a systematic and meta-analysis review was conducted to determine whether statin therapy could improve endothelial function, as assessed by flow-- mediated dilation (FMD). METHODS MEDLINE, SciVerse Scopus, and Clarivate Analytics Web of Science were searched to identify randomized placebo-controlled trials assessing the impact of statin therapy on FMD. A random-effects model was used for meta-analysis to calculate the mean difference in weight. Meta- regression and subgroup analyses were used to identify sources of heterogeneity. In addition, nonlinear dose-response, quality of evidence, influence analysis, and publication bias evaluation were assessed using standard methods. RESULT Thirty-five trials (41 arms) involving 2178 participants were included in the meta-analysis study. Statin treatment significantly improved FMD [weighted mean difference (WMD): 1.7%, 95% CI: 1.3-2.2, p < 0.001). However, significant heterogeneity was observed (I2=97.9%, p < 0.001). The results of the subgroup analysis showed that health status can contribute to heterogeneity. Non-linear dose-response analysis revealed the most significant improvement in FMD with atorvastatin at a dose of 20 mg/day and simvastatin at 80 mg/day. CONCLUSION Statin therapy significantly improved endothelial function, as assessed by FMD. These changes are clinically significant, but their use should be approached with caution.
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Affiliation(s)
- Seyyed Mostafa Arabi
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahla Chambari
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Leila Sadat Bahrami
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saeid Hadi
- Department of Health, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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11
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Williams EI, Betterton RD, Stanton JA, Moreno-Rodriguez VM, Lochhead JJ, Davis TP, Ronaldson PT. Oatp (Organic Anion Transporting Polypeptide)-Mediated Transport: A Mechanism for Atorvastatin Neuroprotection in Stroke. Stroke 2023; 54:2875-2885. [PMID: 37750296 PMCID: PMC10615849 DOI: 10.1161/strokeaha.123.043649] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 08/13/2023] [Accepted: 08/31/2023] [Indexed: 09/27/2023]
Abstract
BACKGROUND Drug discovery for stroke is challenging as indicated by poor clinical translatability. In contrast, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (ie, statins) improve poststroke neurological outcomes. This property requires transport across the blood-brain barrier via an endogenous uptake transporter (ie, Oatp1a4 [organic anion transporting polypeptide 1a4]). Our goal was to study Oatp1a4 as a drug delivery mechanism because the blood-brain barrier cannot be assumed to be completely open for all drugs in ischemic stroke. METHODS Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (90 minutes) followed by reperfusion for up to 7 days. Atorvastatin (20 mg/kg, IV) was administered 2 hours following intraluminal suture removal. Involvement of Oatp-mediated transport was determined using fexofenadine (3.2 mg/kg, IV), a competitive Oatp inhibitor. Oatp1a4 transport activity was measured by in situ brain perfusion. Infarction volumes/brain edema ratios and neuronal nuclei expression were determined using 2,3,5-triphenyltetrazolium chloride-stained brain tissue slices and confocal microscopy, respectively. Poststroke functional outcomes were assessed via neurological deficit scores and rotarod analysis. RESULTS At 2-hour post-middle cerebral artery occlusion, [3H]atorvastatin uptake was increased in ischemic brain tissue. A single dose of atorvastatin significantly reduced post-middle cerebral artery occlusion infarction volume, decreased brain edema ratio, increased caudoputamen neuronal nuclei expression, and improved functional neurological outcomes. All middle cerebral artery occlusion positive effects of atorvastatin were attenuated by fexofenadine coadministration (ie, an Oatp transport inhibitor). CONCLUSIONS Our data demonstrate that neuroprotective effects of atorvastatin may require central nervous system delivery by Oatp-mediated transport at the blood-brain barrier, a mechanism that persists despite increased cerebrovascular permeability in ischemic stroke. These novel and translational findings support utility of blood-brain barrier transporters in drug delivery for neuroprotective agents.
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Affiliation(s)
- Erica I. Williams
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Robert D. Betterton
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Joshua A. Stanton
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | | | - Jeffrey J. Lochhead
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Thomas P. Davis
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Patrick T. Ronaldson
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
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12
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Goldstein LB, Toth PP, Dearborn-Tomazos JL, Giugliano RP, Hirsh BJ, Peña JM, Selim MH, Woo D. Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2023; 43:e404-e442. [PMID: 37706297 DOI: 10.1161/atv.0000000000000164] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
The objective of this scientific statement is to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive low-density lipoprotein cholesterol lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke. The writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize existing evidence and to identify gaps in current knowledge. Although some retrospective, case control, and prospective longitudinal studies suggest that statins and low-density lipoprotein cholesterol lowering are associated with cognitive impairment or dementia, the preponderance of observational studies and data from randomized trials do not support this conclusion. The risk of a hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is nonsignificant, and achieving very low levels of low-density lipoprotein cholesterol does not increase that risk. Data reflecting the risk of hemorrhagic stroke with lipid-lowering treatment among patients with a history of hemorrhagic stroke are not robust and require additional focused study.
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13
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Lietzau G, Sienkiewicz W, Karwacki Z, Dziewiątkowski J, Kaleczyc J, Kowiański P. The Effect of Simvastatin on the Dynamics of NF-κB-Regulated Neurodegenerative and Neuroprotective Processes in the Acute Phase of Ischemic Stroke. Mol Neurobiol 2023; 60:4935-4951. [PMID: 37204689 PMCID: PMC10415422 DOI: 10.1007/s12035-023-03371-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/27/2023] [Indexed: 05/20/2023]
Abstract
Statins are lipid-lowering drugs that act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-limiting enzyme in cholesterol biosynthesis. Animal studies have shown neuroprotective effects of statins in cerebral stroke. However, the underlying mechanisms are not fully understood. The nuclear factor-kappa B (NF-κB) transcription factor is involved in the regulation of apoptosis in stroke. Different dimers of NF-κB regulate the gene expression of proteins involved in both neurodegeneration and neuroprotection. We aimed to determine whether simvastatin improves stroke outcome via inhibition of the RelA/p65-containing subunit and downregulation of stroke-induced pro-apoptotic genes or via activation of NF-κB dimers containing the c-Rel subunit and upregulation of anti-apoptotic genes during the acute stroke phase. Eighteen-month-old Wistar rats, subjected to permanent MCAO or sham surgery, were administered simvastatin (20 mg/kg b.w.) or saline for 5 days before the procedure. Stroke outcome was determined by measuring cerebral infarct and assessing motor functions. The expression of NF-κB subunits in various cell populations was investigated using immunofluorescence/confocal microscopy. RelA and c-Rel were detected by WB. The NF-κB-DNA binding activity was investigated using EMSA, and expression of Noxa, Puma, Bcl-2, and Bcl-x genes was analyzed by qRT-PCR. Results showed a 50% infarct size reduction and significant motor function improvement in the simvastatin-treated animals which correlated with a decrease in RelA and a transient increase in the c-Rel level in the nucleus, normalization of the NF-κB-DNA binding activity, and downregulation of the NF-κB-regulated genes. Our results provide new insights into the statin-mediated neuroprotective action against stroke based on NF-κB pathway inhibition.
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Affiliation(s)
- Grazyna Lietzau
- Division of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Waldemar Sienkiewicz
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego 13, 10-719 Olsztyn, Poland
| | - Zbigniew Karwacki
- Department of Neuroanaesthesiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland
| | - Jerzy Dziewiątkowski
- Division of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Jerzy Kaleczyc
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego 13, 10-719 Olsztyn, Poland
| | - Przemysław Kowiański
- Division of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
- Institute of Health Sciences, Pomeranian University in Słupsk, Bohaterów Westerplatte 64, 76-200 Słupsk, Poland
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14
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Costantine MM, Clifton RG, Boekhoudt TM, Lawrence K, Gyamfi-Bannerman C, Wisner KL, Grobman W, Caritis SN, Simhan HN, Hebert MF, Longo M, Saade GR. Long-term neurodevelopmental follow-up of children exposed to pravastatin in utero. Am J Obstet Gynecol 2023; 229:153.e1-153.e12. [PMID: 36842489 PMCID: PMC10440254 DOI: 10.1016/j.ajog.2023.02.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 02/16/2023] [Accepted: 02/16/2023] [Indexed: 02/28/2023]
Abstract
BACKGROUND Preeclampsia, especially before term, increases the risk of child neurodevelopmental adverse outcomes. Biological plausibility, preclinical studies, and pilot clinical trials conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Obstetric-Fetal Pharmacology Research Centers Network support the safety and use of pravastatin to prevent preeclampsia. OBJECTIVE This study aimed to determine the effect of antenatal pravastatin treatment in high-risk pregnant individuals on their child's health, growth, and neurodevelopment. STUDY DESIGN This was an ancillary follow-up cohort study of children born to mothers who participated in the Obstetric-Fetal Pharmacology Research Centers Network pilot trials of pravastatin vs placebo in individuals at high risk of preeclampsia (ClinicalTrials.gov; identifier NCT01717586). After obtaining written informed consent (and assent as appropriate), the parent was instructed to complete the Child Behavior Checklist. To assess the child's motor, cognitive, and developmental outcomes, a certified and blinded study psychologist completed child motor, cognitive, emotional, and behavioral assessments using validated tools. Given the small number of individuals in the studies, the 10- and 20-mg pravastatin groups were combined into 1 group, and the results of the pravastatin group were compared with that of the placebo group. RESULTS Of 40 children born to mothers in the original trial, 30 (15 exposed in utero to pravastatin and 15 to placebo) were enrolled in this follow-up study. The time of follow-up, which was 4.7 years (interquartile range, 2.5-6.9), was not different between children in the pravastatin group and children in the placebo group. There was no difference in the child's body mass index percentiles per sex and corrected age, the rates of extremes of body mass index percentiles, or the report of any other medical or developmental complications between the 2 groups. No child born in the pravastatin group had any limitation in motor assessment compared with 2 children (13.3%) who walked with difficulty and 4 children (26.7%) who had reduced manual abilities in the placebo group. Moreover, children born to mothers who received pravastatin had a higher general mean conceptual ability score (98.2±16.7 vs 89.7±11.0; P=.13) and a lower frequency (15.4% vs 35.7%; P=.38) of having a score of <85 (ie, 1 standard deviation lower than the mean) compared with those in the placebo group. Finally, there was no difference in the parents' report on the Child Behavior Checklist between the 2 groups. CONCLUSION This study reported on the long-term neuromotor, cognitive, and behavioral outcomes among children exposed to pravastatin in utero during the second and third trimesters of pregnancy. Although the data were limited by the original trial's sample size, no identifiable long-term neurodevelopmental safety signal was evident with the use of pravastatin during pregnancy. This favorable neonatal risk-benefit analysis justifies continued research using pravastatin in clinical trials.
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Affiliation(s)
- Maged M Costantine
- Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH; Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX.
| | | | | | - Kirsten Lawrence
- Department of Obstetrics and Gynecology, Columbia University, New York, NY
| | | | - Katherine L Wisner
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL
| | - William Grobman
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL
| | - Steve N Caritis
- Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Hyagriv N Simhan
- Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Mary F Hebert
- Department of Pharmacy and Obstetrics and Gynecology, University of Washington, Seattle, WA
| | - Monica Longo
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD
| | - George R Saade
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
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15
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The opposite effect of convulsant drugs on neuronal and endothelial nitric oxide synthase - A possible explanation for the dual proconvulsive/anticonvulsive action of nitric oxide. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2023; 73:59-74. [PMID: 36692466 DOI: 10.2478/acph-2023-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/21/2022] [Indexed: 01/25/2023]
Abstract
Nitric oxide (NO) participates in processes such as endothelium-dependent vasodilation and neurotransmission/neuromodulation. The role of NO in epilepsy is controversial, attributing it to anticonvulsant but also proconvulsant properties. Clarification of this dual effect of NO might lead to the development of new antiepileptic drugs. Previous results in our laboratory indicated that this contradictory role of NO in seizures could depend on the nitric oxide synthase (NOS) isoform involved, which could play opposite roles in epileptogenesis, one of them being proconvulsant but the other anticonvulsant. The effect of convulsant drugs on neuronal NO (nNO) and endothelial NO (eNO) levels was investigated. Considering the distribution of neuronal and endothelial NOS in neurons and astrocytes, resp., primary cultures of neurons and astrocytes were used as a study model. The effects of convulsant drugs pentylenetetrazole, thiosemicarbazide, 4-aminopyridine and bicuculline on NO levels were studied, using a spectrophotometric method. Their effects on NO levels in neurons and astrocytes depend on the concentration and time of treatment. These convulsant drugs caused an increase in nNO, but a decrease in eNO was proportional to the duration of treatment in both cases. Apparently, nNO possesses convulsant properties mediated by its effect on the glutamatergic and GABAergic systems, probably through GABAA receptors. Anticonvulsant properties of eNO may be the consequence of its effect on endothelial vasodilation and its capability to induce angiogenesis. Described effects last as seizures do. Considering the limitations of these kinds of studies and the unexplored influence of inducible NO, further investigations are required.
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Deng T, He W, Yao X, Chen J, Liu X, Liu L, Zhang T, Lu H. Safety and efficacy of short-term dual antiplatelet therapy combined with intensive rosuvastatin in acute ischemic stroke. Clinics (Sao Paulo) 2023; 78:100171. [PMID: 36738644 PMCID: PMC9932359 DOI: 10.1016/j.clinsp.2023.100171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 12/07/2022] [Accepted: 01/04/2023] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE To investigate the safety and efficacy of short-term (7-day) Dual Antiplatelet Therapy (DAPT) with intensive rosuvastatin in Acute Ischemic Stroke (AIS). METHODS In this study, patients with AIS in the emergency department of the hospital from October 2016 to December 2019 were registered and divided into the control group (Single Antiplatelet Therapy [SAPT] + rosuvastatin) and the study group (7-day DAPT + intensive rosuvastatin) according to the therapy regimens. The generalized linear model was used to compare the National Institute of Health Stroke Scale (NIHSS) scores between the two groups during the 21-day treatment. A Cox regression model was used to compare recurrent ischemic stroke, bleeding events, Statin-Induced Liver Injury (SILI), and Statin-Associated Myopathy (SAM) between the two groups during the 90-day follow-up. RESULTS Comparison of NIHSS scores after 21-day treatment: NIHSS scores in the study group decreased significantly, 0.273-times as much as that in the control group (Odds Ratio [OR] 0.273; 95% Confidence Interval [95% CI] 0.208-0.359; p < 0.001). Comparison of recurrent ischemic stroke during the 90-day follow-up: The therapy of the study group reduced the risk of recurrent stroke by 65% (7.76% vs. 22.82%, Hazard Ratio [HR] 0.350; 95% CI 0.167-0.730; p = 0.005). Comparison of bleeding events: There was no statistical difference between the two groups (7.79% vs. 6.71%, HR = 1.076; 95% CI 0.424-2.732; p = 0.878). No cases of SILI and SAM were found. CONCLUSIONS Short-term DAPT with intensive rosuvastatin effectively relieved the clinical symptoms and significantly reduced the recurrent stroke for patients with mild-to-moderate AIS within 90 days, without increasing bleeding events, SILI and SAM.
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Affiliation(s)
- Ting Deng
- Emergency Department, China Rehabilitation Research Center Beijing Bo'ai Hospital, Beijing, China
| | - Wei He
- Emergency Department, China Rehabilitation Research Center Beijing Bo'ai Hospital, Beijing, China
| | - Xiaohua Yao
- Emergency Department, China Rehabilitation Research Center Beijing Bo'ai Hospital, Beijing, China
| | - Jingmian Chen
- Emergency Department, China Rehabilitation Research Center Beijing Bo'ai Hospital, Beijing, China
| | - Xiaomeng Liu
- Emergency Department, China Rehabilitation Research Center Beijing Bo'ai Hospital, Beijing, China
| | - Lushan Liu
- Emergency Department, China Rehabilitation Research Center Beijing Bo'ai Hospital, Beijing, China
| | - Tong Zhang
- Neurology Department, China Rehabilitation Research Center Beijing Bo'ai Hospital, Beijing, China.
| | - Haitao Lu
- Neurology Department, China Rehabilitation Research Center Beijing Bo'ai Hospital, Beijing, China.
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Khizroeva J, Bitsadze V, Tincani A, Makatsariya A, Arslanbekova M, Babaeva N, Tsibizova V, Shkoda A, Makatsariya N, Tretyakova M, Solopova A, Gadaeva Z, Vorobev A, Khamani I, Aslanova Z, Nakaidze I, Mischenko A, Grigoreva K, Kunesko N, Egorova E, Mashkova T. Hydroxychloroquine in obstetric antiphospholipid syndrome: rationale and results of an observational study of refractory cases. J Matern Fetal Neonatal Med 2022; 35:6157-6164. [PMID: 34044735 DOI: 10.1080/14767058.2021.1908992] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 03/23/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND The current recommended therapy of obstetric antiphospholipid syndrome (APS) is a long-term anticoagulant therapy that affects the final event, namely, when the thrombosis has already occurred. Unfortunately, this schedule is not always effective and fails despite the correct risk stratification and an adequate adjusted dose. MATERIALS AND METHODS From 2013 to 2020 we observed 217 women with antiphospholipid antibodies and obstetric morbidities who were treated with conventional treatment protocol (aspirin low doses ± LMWH). Among them 150 (69.1%) successfully completed pregnancy with delivery and live birth on the background of LMWH and aspirin therapy and in 67 (30.9%) women despite a traditional therapy regimen, obstetric complications were noted. Later, 56 of these 67 women became pregnant again and were offered traditional therapy plus hydroxychloroquine. Fifteen women refused HCQ treatment due to possible potential side effects. The final cohort consisted of 41 women with positive antiphospholipid antibodies and obstetric and thrombotic complications who received LMWH, aspirin low doses and HCQ at a dose of 200-400mg per day from the beginning of pregnancy. RESULTS Forty-one aPL women treated with HCQ after failed previous anticoagulant therapy had live births in 32 cases (78%). Adding of HCQ to the combination of LMWH and LDA showed good overall obstetric results and increased the number of live births in another 32 women. So, a total of 182 (83.8%) of initial 217 aPL-women ended their pregnancies with live birth after adding the HCQ to the traditional therapy with LMWH and low doses of aspirin. CONCLUSION In 20-30% of cases the live birth despite anticoagulation cannot be achieved. Perhaps APS is not just anticoagulation. The study of pathophysiological mechanisms suggests that some patients will benefit from other therapy (in addition to anticoagulant). Therapy that affects the early effects of aPL on target cells (monocytes, endothelial cells, etc.) or before binding to receptors-this therapy will be preferable and potentially less harmful than the officially accepted one to date. From this point of view, HCQ looks promising and can be used as an alternative candidate for women with refractory obstetric antiphospholipid syndrome. Adding HCQ should be considered in some selected patients with failed pregnancy after treatment with anticoagulants.
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Affiliation(s)
- Jamilya Khizroeva
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Victoria Bitsadze
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Angela Tincani
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
- Unit of Rheumatology and Clinical Immunology, ASST Spedali Civili, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Alexander Makatsariya
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Madina Arslanbekova
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Nigar Babaeva
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Valentina Tsibizova
- Almazov National Medical Research Centre, Saint Petersburg, Health Ministry of Russian Federation, Saint Petersburg, Russia
| | | | - Natalya Makatsariya
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Maria Tretyakova
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Antonina Solopova
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Zumrad Gadaeva
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Alexander Vorobev
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Inessa Khamani
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Zamilya Aslanova
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Inga Nakaidze
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Alexander Mischenko
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Kristina Grigoreva
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Nart Kunesko
- Moscow's Department of Health, Center for family planning and reproduction (CPSIR), Moscow, Russia
| | - Elena Egorova
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Tamara Mashkova
- The First I.M. Sechenov Moscow State Medical University (Sechenov University), Moscow, Russia
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Pre-Stroke Statin Use Is Associated with Mild Neurological Deficits at the Onset of Acute Ischemic Stroke. J Cardiovasc Dev Dis 2022; 9:jcdd9110396. [DOI: 10.3390/jcdd9110396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022] Open
Abstract
Pre-stroke statin use reduces infarct size. Therefore, this retrospective study aimed to investigate whether pre-stroke statin use is associated with mild neurological deficits (mND) at the onset of acute ischemic stroke (AIS). We included patients with AIS admitted to our institution within 24 h of stroke onset between 2011 and 2019. We collected data on age, sex, pre-stroke use of statins, the National Institutes of Health Stroke Scale (NIHSS) score, the serum biomarker levels, and stroke subtypes at admission. In addition, we defined mND as an NIHSS score ≤3 points. We conducted a logistic regression analysis using variables for pre-stroke statin initiation, calculated the propensity scores for pre-stroke statin use, and implemented propensity score matching (PSM). Finally, we used the McNemar test to evaluate whether pre-stroke statin administration significantly affected mND. Of 4370 patients, 2615 met our inclusion criteria. Among the 594 patients with pre-stroke statin use, 308 presented with mND. After PSM, 555 patients received pre-stroke statin treatment, while 286 patients with pre-stroke statin use presented with mND at admission (p = 0.0411). The binary matched pairs contingency table of mND was not symmetrical (p = 0.0385). Pre-stroke statin use is thus associated with mND at the onset of AIS.
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19
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Aaron SE, Tomoto T, Zhang R, Thyfault JP, Vidoni ED, Montgomery RN, Burns JM, Billinger SA. Statin contribution to middle cerebral artery blood flow velocity in older adults at risk for dementia. Eur J Appl Physiol 2022; 122:2417-2426. [PMID: 35960268 PMCID: PMC9830632 DOI: 10.1007/s00421-022-05022-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 08/02/2022] [Indexed: 01/12/2023]
Abstract
PURPOSE It is plausible that statins could improve cerebral blood flow through pleiotropic mechanisms. The purpose of this investigation was to assess the contribution of statins to cerebrovascular variables in older adults with dyslipidemia and familial history of dementia. Furthermore, we explored the interaction between statin use and sex due to prevalent bias in statin trials. METHODS Middle cerebral artery blood flow velocity (MCAv) was measured using transcranial Doppler ultrasound. Continuous supine rest recordings lasted 8 min. Participants included in analyses were statin (n = 100) or non-statin users (n = 112). RESULTS MCAv and cerebrovascular conductance were significantly higher in statin users (p = 0.047; p = 0.04), and pulsatility index (PI) was significantly lower in statin users (p < 0.01). An interaction effect between statin use and sex was present for PI (p = 0.02); female statin users had significantly lower cerebrovascular resistance than the other three groups. CONCLUSION In this cross-sectional analysis, statin use was positively associated with cerebrovascular variables in older adults at risk for dementia. Female statin users had significantly higher resting MCAv and cerebrovascular conductance than female non-statin users. The greatest contribution of statin use was the association with reduced cerebrovascular resistance. Given that cerebrovascular dysregulation is one of the earliest changes in Alzheimer's disease and related dementia pathology, targeting the cerebrovasculature with statins may be a promising prevention strategy.
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Affiliation(s)
- Stacey E Aaron
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Tsubasa Tomoto
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA
- Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
| | - Rong Zhang
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA
- Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - John P Thyfault
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
- Research Service, Kansas City Veterans Affairs Medical Center, Kansas City, KS, USA
- Center for Children's Healthy Lifestyles and Nutrition, Kansas City, MO, USA
- University of Kansas Alzheimer's Research Disease Center, Fairway, KS, USA
| | - Eric D Vidoni
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
- University of Kansas Alzheimer's Research Disease Center, Fairway, KS, USA
| | - Robert N Montgomery
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, KS, USA
| | - Jeffrey M Burns
- University of Kansas Alzheimer's Research Disease Center, Fairway, KS, USA
| | - Sandra A Billinger
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
- University of Kansas Alzheimer's Research Disease Center, Fairway, KS, USA.
- Department of Physical Medicine and Rehabilitation, University of Kansas Medical Center, Kansas City, KS, USA.
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20
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Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehyde as Drug Candidates for the Treatment of Sickle Cell Disease. Molecules 2022; 27:molecules27206835. [PMID: 36296435 PMCID: PMC9610770 DOI: 10.3390/molecules27206835] [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: 09/16/2022] [Revised: 10/06/2022] [Accepted: 10/08/2022] [Indexed: 11/29/2022] Open
Abstract
Sickle cell disease (SCD) is caused by a single-point mutation, and the ensuing deoxygenation-induced polymerization of sickle hemoglobin (HbS), and reduction in bioavailability of vascular nitric oxide (NO), contribute to the pathogenesis of the disease. In a proof-of-concept study, we successfully incorporated nitrate ester groups onto two previously studied potent antisickling aromatic aldehydes, TD7 and VZHE039, to form TD7-NO and VZHE039-NO hybrids, respectively. These compounds are stable in buffer but demonstrated the expected release of NO in whole blood in vitro and in mice. The more promising VZHE039-NO retained the functional and antisickling activities of the parent VZHE039 molecule. Moreover, VZHE039-NO, unlike VZHE039, significantly attenuated RBC adhesion to laminin, suggesting this compound has potential in vivo RBC anti-adhesion properties relevant to vaso-occlusive events. Crystallographic studies show that, as with VZHE039, VZHE039-NO also binds to liganded Hb to make similar protein interactions. The knowledge gained during these investigations provides a unique opportunity to generate a superior candidate drug in SCD with enhanced benefits.
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Ghori A, Prinz V, Nieminen-Kehlä M, Bayerl SH, Kremenetskaia I, Riecke J, Krechel H, Broggini T, Scherschinski L, Licht T, Keshet E, Vajkoczy P. Vascular Endothelial Growth Factor Augments the Tolerance Towards Cerebral Stroke by Enhancing Neurovascular Repair Mechanism. Transl Stroke Res 2022; 13:774-791. [PMID: 35175562 PMCID: PMC9391249 DOI: 10.1007/s12975-022-00991-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/05/2021] [Accepted: 01/26/2022] [Indexed: 11/30/2022]
Abstract
The breakdown of the blood-brain barrier (BBB) is a critical event in the development of secondary brain injury after stroke. Among the cellular hallmarks in the acute phase after stroke are a downregulation of tight-junction molecules and the loss of microvascular pericyte coverage and endothelial sealing. Thus, a rapid repair of blood vessel integrity and re-stabilization of the BBB is considered an important strategy to reduce secondary brain damage. However, the mechanisms underlying BBB disruption remain poorly understood. Especially, the role of VEGF in this context remains inconclusive. With the conditional and reversible VEGF expression systems, we studied the time windows of deleterious and beneficial VEGF actions on blood vessel integrity in mice. Using genetic systems for gain of function and loss of function experiments, we activated and inhibited VEGF signaling prior and simultaneously to ischemic stroke onset. In both scenarios, VEGF seems to play a vital role in containing the stroke-induced damage after cerebral ischemia. We report that the transgenic overexpression of VEGF (GOF) prior to the stroke stabilizes the vasculature and prevents blood-brain barrier disruption in young and aged animals after stroke. Whereas inhibition of signals for endogenous VEGF (LOF) prior to stroke results in bigger infarction with massive brain swelling and enhanced BBB permeability, furthermore, activating or blocking VEGF signaling after ischemic stroke onset had comparable effects on BBB repair and cerebral edema. VEGF can function as an anti-permeability factor, and a VEGF-based therapy in the context of stroke prevention and recovery has an enormous potential.
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Affiliation(s)
- Adnan Ghori
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Vincent Prinz
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | | | - Simon. H. Bayerl
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Irina Kremenetskaia
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Jana Riecke
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Hanna Krechel
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Thomas Broggini
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Lea Scherschinski
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Tamar Licht
- Department of Developmental Biology and Cancer Research, Hebrew University Hadassah Medical School, 91120 Jerusalem, Israel
| | - Eli Keshet
- Department of Developmental Biology and Cancer Research, Hebrew University Hadassah Medical School, 91120 Jerusalem, Israel
| | - Peter Vajkoczy
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
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22
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Degrush E, Shazeeb MS, Drachman D, Vardar Z, Lindsay C, Gounis MJ, Henninger N. Cumulative effect of simvastatin, L-arginine, and tetrahydrobiopterin on cerebral blood flow and cognitive function in Alzheimer's disease. Alzheimers Res Ther 2022; 14:134. [PMID: 36115980 PMCID: PMC9482313 DOI: 10.1186/s13195-022-01076-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 08/24/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND AND OBJECTIVES Vascular disease is a known risk factor for Alzheimer's disease (AD). Endothelial dysfunction has been linked to reduced cerebral blood flow. Endothelial nitric oxide synthase pathway (eNOS) upregulation is known to support endothelial health. This single-center, proof-of-concept study tested whether the use of three medications known to augment the eNOS pathway activity improves cognition and cerebral blood flow (CBF). METHODS Subjects with mild AD or mild cognitive impairment (MCI) were sequentially treated with the HMG-CoA reductase synthesis inhibitor simvastatin (weeks 0-16), L-arginine (weeks 4-16), and tetrahydrobiopterin (weeks 8-16). The primary outcome of interest was the change in CBF as measured by MRI from baseline to week 16. Secondary outcomes included standard assessments of cognition. RESULTS A total of 11 subjects were deemed eligible and enrolled. One subject withdrew from the study after enrollment, leaving 10 subjects for data analysis. There was a significant increase in CBF from baseline to week 8 by ~13% in the limbic and ~15% in the cerebral cortex. Secondary outcomes indicated a modest but significant increase in the MMSE from baseline (24.2±3.2) to week 16 (26.0±2.7). Exploratory analysis indicated that subjects with cognitive improvement (reduction of the ADAS-cog 13) had a significant increase in their respective limbic and cortical CBF. CONCLUSIONS Treatment of mild AD/MCI subjects with medications shown to augment the eNOS pathway was well tolerated and associated with modestly increased cerebral blood flow and cognitive improvement. TRIAL REGISTRATION This study is registered in https://www. CLINICALTRIALS gov ; registration identifier: NCT01439555; date of registration submitted to registry: 09/23/2011; date of first subject enrollment: 11/2011.
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Affiliation(s)
- Elizabeth Degrush
- Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA.
- Department of Psychiatry, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA.
| | - Mohammed Salman Shazeeb
- Image Processing and Analysis Core (iPAC), Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
- New England Center for Stroke Research, Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - David Drachman
- Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA
| | - Zeynep Vardar
- Image Processing and Analysis Core (iPAC), Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
- New England Center for Stroke Research, Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Clifford Lindsay
- Image Processing and Analysis Core (iPAC), Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Matthew J Gounis
- Image Processing and Analysis Core (iPAC), Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
- New England Center for Stroke Research, Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Nils Henninger
- Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA
- Department of Psychiatry, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA
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Katole NT, Kale JS, Salankar HV. Evaluation of the Antinociceptive Action of Simvastatin in Mice. Cureus 2022; 14:e26910. [PMID: 35983393 PMCID: PMC9376206 DOI: 10.7759/cureus.26910] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 07/16/2022] [Indexed: 11/22/2022] Open
Abstract
Introduction: Statins are well-established agents for dyslipidemia and have successfully been used for the prevention of coronary artery diseases for a long time; this is attributed not only to their lipid-lowering action but also to their pleiotropic actions. Recently many pleiotropic actions of statins have been explored, but very few studies were done to explore statins' antinociceptive action; therefore, the current study was planned to evaluate the antinociceptive activity of Simvastatin in different pain models in mice. Materials and Methods: Antinociceptive activity of Simvastatin was evaluated by using Eddy's hot plate method (central analgesic model), acetic acid-induced writhing method (peripheral analgesic model), and biphasic formalin-induced paw licking method. Twenty-four mice were divided into four groups (n = 6 in each): Vehicle control group, simvastatin 5mg/kg, simvastatin 20mg/kg, and positive control group. Results: In the hot plate method, as compared to the vehicle control group, Simvastatin 20mg/kg group showed a significant rise in the reaction time to the corresponding time interval (p<0.001). While the simvastatin 5mg/kg group did not show any significant analgesic activity in the hot plate test. In the acetic acid writhing method, both test groups show a significant delay in the onset of writhing and a decrease in the number of writhes as compared to the vehicle control group (P<0.001). While in the formalin test, both groups show dose-dependent analgesic activity in both the early and late phases. Conclusion: Simvastatin exhibits analgesic activity in both central as well as peripheral models of analgesia, but central analgesia shows only at higher concentrations. Similarly, it inhibits inflammatory pain more predominantly than neurogenic, and hence simvastatin can be used in inflammatory conditions like rheumatoid arthritis and osteoarthritis particularly when there is coexisting dyslipidemia.
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Pham A, Polic A, Nguyen L, Thompson JL. Statins in Pregnancy: Can We Justify Early Treatment of Reproductive Aged Women? Curr Atheroscler Rep 2022; 24:663-670. [PMID: 35699821 DOI: 10.1007/s11883-022-01039-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2022] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW Statins are the pillar of secondary prevention in reducing cardiovascular disease in high-risk adults. However, statin discontinuation is the standard recommendation in pregnant and lactating patients. This review evaluates whether we can justify the early treatment of reproductive aged women with statin therapy. RECENT FINDINGS Statins have several potential benefits including its antioxidant, anti-inflammatory, and anti-thrombogenic properties that may prevent the worsening of atherosclerosis in high-risk women. Nevertheless, most studies on statins and teratogenicity have a limited sample size and the effects of long-term statin use on fetal and neonatal health remain unknown. Not all statins may be safe and pravastatin's cholesterol-lowering properties may be too limited to provide much maternal benefit in pregnancy. While emerging evidence supports the use of pravastatin in pregnancy, we need to better assess the risk of early cardiovascular disease and acute progression of atherosclerosis before and during pregnancy to better understand the risks and benefits of statin use.
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Affiliation(s)
- Amelie Pham
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Medical Center North, 1161 21stAvenue, South B-1100, Nashville, TN, 37212, USA
| | - Aleksandra Polic
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Medical Center North, 1161 21stAvenue, South B-1100, Nashville, TN, 37212, USA
| | - Lynsa Nguyen
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Medical Center North, 1161 21stAvenue, South B-1100, Nashville, TN, 37212, USA
| | - Jennifer L Thompson
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Medical Center North, 1161 21stAvenue, South B-1100, Nashville, TN, 37212, USA.
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Mo W, Chen Z, Zhang X, Dai G, Ma D, Pan J, Zhang X, Wu G, Fan W. N6-Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) as a Novel Mediator of Statin Effects in Human Endothelial Cells. Arterioscler Thromb Vasc Biol 2022; 42:644-658. [PMID: 35296150 DOI: 10.1161/atvbaha.121.317295] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND N6-methyladenosine (m6A) plays a critical role in various biological processes. However, no study has addressed the role of m6A modification in the statin-induced protection of endothelial cells (ECs). METHODS Quantitative real-time polymerase chain reaction and Western blotting analyses were used to study the expression of m6A regulatory genes in atorvastatin-treated ECs. Gain- and loss-of-function assays, methylated RNA immunoprecipitation analysis, and dual-luciferase reporter assays were performed to clarify the function of FTO (fat mass and obesity-associated protein) in ECs. RESULTS Atorvastatin decreased FTO protein expression in ECs. The knockdown of FTO enhanced the mRNA and protein expression of KLF2 (Kruppel-like factor 2) and eNOS (endothelial NO synthase) but attenuated TNFα (tumor necrosis factor alpha)-induced VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) expression, as well as the adhesion of monocytes to ECs. Conversely, FTO overexpression significantly upregulated the mRNA and protein levels of VCAM-1 and ICAM-1, downregulated those of KLF2 and eNOS, and strongly attenuated the atorvastatin-mediated induction of KLF2 and eNOS expression. Subsequent investigations demonstrated that KLF2 and eNOS are functionally critical targets of FTO. Mechanistically, FTO interacted with KLF2 and eNOS transcripts and regulated their expression in an m6A-dependent manner. After FTO silencing, KLF2 and eNOS transcripts with higher levels of m6A modification in their 3' untranslated regions were captured by YTHDF3 (YT521-B homology m6A RNA-binding protein 3), resulting in mRNA stabilization and the induction of KLF2 and eNOS protein expression. CONCLUSIONS FTO might serve as a novel molecular target to modulate endothelial function in vascular diseases.
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Affiliation(s)
- Wentao Mo
- Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China (W.M., Z.C., X.Z., D.M., J.P., X.Z., G.W.).,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, Guangdong, China (W.M., Z.C., X.Z., G.D., D.M., J.P., X.Z., G.W., W.F.)
| | - Ziqi Chen
- Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China (W.M., Z.C., X.Z., D.M., J.P., X.Z., G.W.).,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, Guangdong, China (W.M., Z.C., X.Z., G.D., D.M., J.P., X.Z., G.W., W.F.)
| | - Xiaozhe Zhang
- Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China (W.M., Z.C., X.Z., D.M., J.P., X.Z., G.W.).,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, Guangdong, China (W.M., Z.C., X.Z., G.D., D.M., J.P., X.Z., G.W., W.F.)
| | - Gang Dai
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China (G.D., W.F.).,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, Guangdong, China (W.M., Z.C., X.Z., G.D., D.M., J.P., X.Z., G.W., W.F.)
| | - Dongwei Ma
- Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China (W.M., Z.C., X.Z., D.M., J.P., X.Z., G.W.).,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, Guangdong, China (W.M., Z.C., X.Z., G.D., D.M., J.P., X.Z., G.W., W.F.)
| | - Jiajie Pan
- Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China (W.M., Z.C., X.Z., D.M., J.P., X.Z., G.W.).,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, Guangdong, China (W.M., Z.C., X.Z., G.D., D.M., J.P., X.Z., G.W., W.F.)
| | - Xinxia Zhang
- Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China (W.M., Z.C., X.Z., D.M., J.P., X.Z., G.W.).,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, Guangdong, China (W.M., Z.C., X.Z., G.D., D.M., J.P., X.Z., G.W., W.F.)
| | - Guifu Wu
- Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China (W.M., Z.C., X.Z., D.M., J.P., X.Z., G.W.).,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, Guangdong, China (W.M., Z.C., X.Z., G.D., D.M., J.P., X.Z., G.W., W.F.).,Guangdong Innovative Engineering and Technology Research Center for Assisted Circulation, Sun Yat-sen University, Shenzhen, Guangdong, China (G.W.)
| | - Wendong Fan
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China (G.D., W.F.).,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, Guangdong, China (W.M., Z.C., X.Z., G.D., D.M., J.P., X.Z., G.W., W.F.)
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Evaluating the Role of Statins in Prevention of Preeclampsia: Deeper Insights into Maternal Cardiometabolic Changes. J Clin Lipidol 2022; 16:403-416. [DOI: 10.1016/j.jacl.2022.04.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 04/11/2022] [Accepted: 04/25/2022] [Indexed: 12/22/2022]
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Smith DD, Costantine MM. The role of statins in the prevention of preeclampsia. Am J Obstet Gynecol 2022; 226:S1171-S1181. [PMID: 32818477 PMCID: PMC8237152 DOI: 10.1016/j.ajog.2020.08.040] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/26/2020] [Accepted: 08/14/2020] [Indexed: 02/03/2023]
Abstract
Preeclampsia is a common hypertensive disorder of pregnancy associated with considerable neonatal and maternal morbidities and mortalities. However, the exact cause of preeclampsia remains unknown; it is generally accepted that abnormal placentation resulting in the release of soluble antiangiogenic factors, coupled with increased oxidative stress and inflammation, leads to systemic endothelial dysfunction and the clinical manifestations of the disease. Statins have been found to correct similar pathophysiological pathways that underlie the development of preeclampsia. Pravastatin, specifically, has been reported in various preclinical and clinical studies to reverse the pregnancy-specific angiogenic imbalance associated with preeclampsia, to restore global endothelial health, and to prevent oxidative and inflammatory injury. Human studies have found a favorable safety profile for pravastatin, and more recent evidence does not support the previous teratogenic concerns surrounding statins in pregnancy. With reassuring and positive findings from pilot studies and strong biological plausibility, statins should be investigated in large clinical randomized-controlled trials for the prevention of preeclampsia.
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Affiliation(s)
- Devin D Smith
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH.
| | - Maged M Costantine
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH
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Costantine MM, West H, Wisner KL, Caritis S, Clark S, Venkataramanan R, Stika CS, Rytting E, Wang X, Ahmed MS. A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia. Am J Obstet Gynecol 2021; 225:666.e1-666.e15. [PMID: 34033812 DOI: 10.1016/j.ajog.2021.05.018] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia. OBJECTIVE We previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks' gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin. STUDY DESIGN This was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight. RESULTS Of note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects. CONCLUSION This study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.
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Affiliation(s)
- Maged M Costantine
- Department of Obstetrics and Gynecology, the Ohio State University, Columbus, OH; Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX.
| | - Holly West
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
| | - Katherine L Wisner
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL
| | - Steve Caritis
- Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Shannon Clark
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
| | - Raman Venkataramanan
- Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Catherine S Stika
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL
| | - Erik Rytting
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
| | - Xiaoming Wang
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
| | - Mahmoud S Ahmed
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
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Pierzchlińska A, Droździk M, Białecka M. A Possible Role for HMG-CoA Reductase Inhibitors and Its Association with HMGCR Genetic Variation in Parkinson's Disease. Int J Mol Sci 2021; 22:12198. [PMID: 34830081 PMCID: PMC8620375 DOI: 10.3390/ijms222212198] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/03/2021] [Accepted: 11/08/2021] [Indexed: 12/22/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease characterised by both motor- and non-motor symptoms, including cognitive impairment. The aetiopathogenesis of PD, as well as its protective and susceptibility factors, are still elusive. Neuroprotective effects of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors-statins-via both cholesterol-dependent and independent mechanisms have been shown in animal and cell culture models. However, the available data provide conflicting results on the role of statin treatment in PD patients. Moreover, cholesterol is a vital component for brain functions and may be considered as protective against PD. We present possible statin effects on PD under the hypothesis that they may depend on the HMG-CoA reductase gene (HMGCR) variability, such as haplotype 7, which was shown to affect cholesterol synthesis and statin treatment outcome, diminishing possible neuroprotection associated with HMG-CoA reductase inhibitors administration. Statins are among the most prescribed groups of drugs. Thus, it seems important to review the available data in the context of their possible neuroprotective effects in PD, and the HMG-CoA reductase gene's genetic variability.
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Affiliation(s)
- Anna Pierzchlińska
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.P.); (M.B.)
| | - Marek Droździk
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Monika Białecka
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.P.); (M.B.)
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Mele C, Maggioni G, Giordano A, Lunardon C, Balsamo F, Mazzone A, Pistarini C. A Retrospective Study on Statins and Post-stroke Patients: What About Functional Outcome and Follow-Up in a Stroke Rehabilitation Cohort? Front Neurol 2021; 12:744732. [PMID: 34744982 PMCID: PMC8567028 DOI: 10.3389/fneur.2021.744732] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 09/23/2021] [Indexed: 12/26/2022] Open
Abstract
Objective: Statins exert pleiotropic effects by influencing several mechanisms, including synaptogenesis, neurogenesis, cerebral flow regulation, and angiogenesis. Results from in vitro and animal models suggest that statins could have beneficial effect on functional recovery and outcome after stroke events. However, results in human studies are still controversial. The aim of our study was to evaluate the role of statin in influencing functional outcome and subsequent clinical follow-up in a large cohort of post-stroke rehabilitation patients. Methods: This retrospective study consecutively enrolled 413 adult patients with stroke event, admitted to the division of Neurorehabilitation of the IRCCS ICS Maugeri, Veruno (Italy), for an individual rehabilitation program between 2015 and 2017. Follow-up lasted 3–5 years after discharge. Demographic data, etiology, classification, and anatomical site of stroke lesion, functional assessment, use and duration of statin therapy, and death during hospitalization were collected at baseline and on discharge. Clinical data on subsequent follow-up were also evaluated, considering these as variables: stroke recurrence, bone fractures, cardiovascular complications, and death. Results: In our cohort, 177 patients (42.9%) were prescribed statin therapy, of whom 50 (28.2%) before the stroke event and 127 (71.8%) at the beginning of the rehabilitation process. The use and type of statin therapy as well as the duration of treatment were not associated with recovery and functional outcome, regardless of confounders including sex, age, etiology, and site of stroke lesion, and initial functional level. For what concern post-discharge clinical follow-up, the use of statin therapy was significantly associated with a lower risk of bone fractures (OR = 0.095, CI 95%: 0.012–0.743, p = 0.01) independently from age, sex, initial and final functional level, and comorbidities. Conclusions: The use of statins does not seem to influence the functional outcome in post-stroke patients. However, they could exert a protective role against bone fractures during post-discharge follow-up, suggesting further evaluation on this topic.
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Affiliation(s)
- Chiara Mele
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Giorgio Maggioni
- Neurorehabilitation Division, Istituti Clinici Scientifici Maugeri SPA SB, Institute of Veruno, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Novara, Italy
| | - Andrea Giordano
- Bioengineering Division, Istituti Clinici Scientifici Maugeri SPA SB, Institute of Veruno, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Novara, Italy
| | - Clara Lunardon
- Neurorehabilitation Division, Istituti Clinici Scientifici Maugeri SPA SB, Institute of Veruno, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Novara, Italy
| | - Francesca Balsamo
- Neurorehabilitation Division, Istituti Clinici Scientifici Maugeri SPA SB, Institute of Veruno, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Novara, Italy
| | - Alessandra Mazzone
- Bioengineering Division, Istituti Clinici Scientifici Maugeri SPA SB, Institute of Veruno, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Novara, Italy
| | - Caterina Pistarini
- Department of Physical and Rehabilitation Medicine, Istituti Clinici Scientifici Maugeri SPA SB, Institute of Genoa Nervi, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genoa, Italy
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Zhao L, Li J, Kälviäinen R, Jolkkonen J, Zhao C. Impact of drug treatment and drug interactions in post-stroke epilepsy. Pharmacol Ther 2021; 233:108030. [PMID: 34742778 DOI: 10.1016/j.pharmthera.2021.108030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/01/2021] [Accepted: 11/01/2021] [Indexed: 12/21/2022]
Abstract
Stroke is a huge burden on our society and this is expected to grow in the future due to the aging population and the associated co-morbidities. The improvement of acute stroke care has increased the survival rate of stroke patients, and many patients are left with permanent disability, which makes stroke the main cause of adult disability. Unfortunately, many patients face other severe complications such as post-stroke seizures and epilepsy. Acute seizures (ASS) occur within 1 week after the stroke while later occurring unprovoked seizures are diagnosed as post-stroke epilepsy (PSE). Both are associated with a poor prognosis of a functional recovery. The underlying neurobiological mechanisms are complex and poorly understood. There are no universal guidelines on the management of PSE. There is increasing evidence for several risk factors for ASS/PSE, however, the impacts of recanalization, drugs used for secondary prevention of stroke, treatment of stroke co-morbidities and antiseizure medication are currently poorly understood. This review focuses on the common medications that stroke patients are prescribed and potential drug interactions possibly complicating the management of ASS/PSE.
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Affiliation(s)
- Lanqing Zhao
- Department of Sleep Medicine Center, The Shengjing Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China
| | - Jinwei Li
- Department of Stroke Center, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China
| | - Reetta Kälviäinen
- Kuopio Epilepsy Center, Neurocenter, Kuopio University Hospital, Full Member of ERN EpiCARE, Kuopio, Finland; Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Jukka Jolkkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
| | - Chuansheng Zhao
- Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China.
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Cooper LL, Wang N, Beiser AS, Romero JR, Aparicio HJ, Lioutas VA, Benjamin EJ, Larson MG, Vasan RS, Mitchell GF, Seshadri S, Hamburg NM. Digital Peripheral Arterial Tonometry and Cardiovascular Disease Events: The Framingham Heart Study. Stroke 2021; 52:2866-2873. [PMID: 34192894 PMCID: PMC8378441 DOI: 10.1161/strokeaha.120.031102] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 01/21/2021] [Accepted: 03/29/2021] [Indexed: 11/29/2022]
Abstract
Background and Purpose Novel noninvasive measures of vascular function are emerging as subclinical markers for cardiovascular disease (CVD) and may be useful to predict CVD events. The purpose of our prospective study was to assess associations between digital peripheral arterial tonometry (PAT) measures and first-onset major CVD events in a sample of FHS (Framingham Heart Study) participants. Methods Using a fingertip PAT device, we assessed pulse amplitude in Framingham Offspring and Third Generation participants (n=3865; mean age, 55±14 years; 52% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia. The PAT ratio (relative hyperemia index) was calculated as the post-to-pre occlusion pulse signal ratio in the occluded arm, relative to the same ratio in the control (nonoccluded) arm, and corrected for baseline vascular tone. Baseline pulse amplitude and PAT ratio during hyperemia are measures of pressure pulsatility and microvascular function in the finger, respectively. We used Cox proportional hazards regression to relate PAT measures in the fingertip to incident CVD events. Results During follow-up (median, 9.2 years; range, 0.04–10.0 years), 270 participants (7%) experienced new-onset CVD events (n=270). In multivariable models adjusted for cardiovascular risk factors, baseline pulse amplitude (hazard ratio [HR] per 1 SD, 1.04 [95% CI, 0.90–1.21]; P=0.57) and PAT ratio (HR, 0.95 [95% CI, 0.84–1.08]; P=0.43) were not significantly related to incident composite CVD events, including myocardial infarction or heart failure. However, higher PAT ratio (HR, 0.76 [95% CI, 0.61–0.94]; P=0.013), but not baseline pulse amplitude (HR, 1.15 [95% CI, 0.89–1.49]; P=0.29), was related to lower risk for incident stroke. In a sensitivity analysis by stroke subtype, higher PAT ratio was related to lower risk of incident ischemic stroke events (HR, 0.68 [95% CI, 0.53–0.86]; P=0.001). Conclusions Novel digital PAT measures may represent a marker of stroke risk in the community.
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Affiliation(s)
- Leroy L. Cooper
- Biology Department, Vassar College, Poughkeepsie, NY (L.L.C.)
| | - Na Wang
- Biostatistics and Epidemiology Data Analytics Center (N.W.), Boston University School of Public Health, MA
| | - Alexa S. Beiser
- Department of Biostatistics (A.S.B., M.G.L.), Boston University School of Public Health, MA
- Boston University and NHLBI’s Framingham Study, MA (A.S.B., J.R.R., H.J.A., E.J.B., M.G.L., R.S.V., S.S.)
- Department of Neurology (A.S.B., H.J.A.), Boston University School of Medicine, MA
| | - José Rafael Romero
- Boston University and NHLBI’s Framingham Study, MA (A.S.B., J.R.R., H.J.A., E.J.B., M.G.L., R.S.V., S.S.)
| | - Hugo J. Aparicio
- Boston University and NHLBI’s Framingham Study, MA (A.S.B., J.R.R., H.J.A., E.J.B., M.G.L., R.S.V., S.S.)
- Department of Neurology (A.S.B., H.J.A.), Boston University School of Medicine, MA
| | - Vasileios-Arsenios Lioutas
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (V.-A.L.)
| | - Emelia J. Benjamin
- Department of Epidemiology (E.J.B., R.S.V.), Boston University School of Public Health, MA
- Boston University and NHLBI’s Framingham Study, MA (A.S.B., J.R.R., H.J.A., E.J.B., M.G.L., R.S.V., S.S.)
- Cardiology and Preventive Medicine Sections, Department of Medicine (E.J.B., R.S.V.), Boston University School of Medicine, MA
- Whitaker Cardiovascular Institute (E.J.B., R.S.V., N.M.H.), Boston University School of Medicine, MA
- Evans Department of Medicine, Boston University School of Medicine, Boston Medical Center, MA (E.J.B., R.S.V., N.M.H.)
| | - Martin G. Larson
- Department of Biostatistics (A.S.B., M.G.L.), Boston University School of Public Health, MA
- Boston University and NHLBI’s Framingham Study, MA (A.S.B., J.R.R., H.J.A., E.J.B., M.G.L., R.S.V., S.S.)
| | - Ramachandran S. Vasan
- Department of Epidemiology (E.J.B., R.S.V.), Boston University School of Public Health, MA
- Boston University and NHLBI’s Framingham Study, MA (A.S.B., J.R.R., H.J.A., E.J.B., M.G.L., R.S.V., S.S.)
- Cardiology and Preventive Medicine Sections, Department of Medicine (E.J.B., R.S.V.), Boston University School of Medicine, MA
- Whitaker Cardiovascular Institute (E.J.B., R.S.V., N.M.H.), Boston University School of Medicine, MA
- Evans Department of Medicine, Boston University School of Medicine, Boston Medical Center, MA (E.J.B., R.S.V., N.M.H.)
| | | | - Sudha Seshadri
- Boston University and NHLBI’s Framingham Study, MA (A.S.B., J.R.R., H.J.A., E.J.B., M.G.L., R.S.V., S.S.)
- Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio (S.S.)
| | - Naomi M. Hamburg
- Whitaker Cardiovascular Institute (E.J.B., R.S.V., N.M.H.), Boston University School of Medicine, MA
- Evans Department of Medicine, Boston University School of Medicine, Boston Medical Center, MA (E.J.B., R.S.V., N.M.H.)
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Schäfer AM, Meyer zu Schwabedissen HE, Grube M. Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications. Pharmaceutics 2021; 13:pharmaceutics13060834. [PMID: 34199715 PMCID: PMC8226904 DOI: 10.3390/pharmaceutics13060834] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/30/2021] [Accepted: 05/31/2021] [Indexed: 12/17/2022] Open
Abstract
The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.
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Affiliation(s)
- Anima M. Schäfer
- Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland; (A.M.S.); (H.E.M.z.S.)
| | - Henriette E. Meyer zu Schwabedissen
- Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland; (A.M.S.); (H.E.M.z.S.)
| | - Markus Grube
- Center of Drug Absorption and Transport (C_DAT), Department of Pharmacology, University Medicine of Greifswald, 17489 Greifswald, Germany
- Correspondence: ; Tel./Fax: +49-3834-865636
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Chu Z, Liu Z, Li W, Xu D, Pang L. Simvastatin attenuates delayed encephalopathy induced by carbon monoxide poisoning in rats by regulating oxidative stress, inflammation and NF-κB pathway. Mol Cell Toxicol 2021; 17:187-193. [DOI: 10.1007/s13273-021-00124-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2021] [Indexed: 01/03/2023]
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Mizuma A, Yenari MA. Clinical perspectives on ischemic stroke. Exp Neurol 2021; 338:113599. [PMID: 33440204 PMCID: PMC7904589 DOI: 10.1016/j.expneurol.2021.113599] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 12/13/2020] [Accepted: 01/07/2021] [Indexed: 01/01/2023]
Abstract
Treatments for acute stroke have improved over the past years, but have largely been limited to revascularization strategies. The topic of neuroprotection, or strategies to limit brain tissue damage or even reverse it, has remained elusive. Thus, the clinical mainstays for stroke management have focused on prevention. The lack of clinical translation of neuroprotective therapies which have shown promise in the laboratory may, in part, be due to a historic inattention to comorbidities suffered by a majority of stroke patients. With the advent of more stroke models that include one or more relevant comorbidities, it may be possible to identify effective treatments that may translate into new treatments at the clinical level. In the meantime, we review comorbidities in stroke patients, modification of stroke risk factors and available acute stroke treatments in the clinic.
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Affiliation(s)
- Atsushi Mizuma
- Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Neurology, Tokai University School of Medicine, Isehara, Japan
| | - Midori A Yenari
- Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
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Chan AY, Choi EH, Yuki I, Suzuki S, Golshani K, Chen JW, Hsu FP. Cerebral vasospasm after subarachnoid hemorrhage: Developing treatments. BRAIN HEMORRHAGES 2021. [DOI: 10.1016/j.hest.2020.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Palladino R, Marrie RA, Majeed A, Chataway J. Evaluating the Risk of Macrovascular Events and Mortality Among People With Multiple Sclerosis in England. JAMA Neurol 2021; 77:820-828. [PMID: 32364569 DOI: 10.1001/jamaneurol.2020.0664] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Importance People with multiple sclerosis (MS) are associated with an increased risk of cardiovascular disease and mortality; however, evidence from population-based studies is sparse. Objective To assess whether the risk of macrovascular events and mortality differs among people with MS compared with a matched population without MS in England. Design, Setting, and Participants A population-based retrospective matched cohort study was conducted in general practices registered with the Clinical Practice Research Datalink in England between January 1, 1987, and September 30, 2018, with a mean (SD) follow-up of 11.3 (6.5) years. A total of 12 251 patients with MS were matched with up to 6 people without MS (n = 72 572) by age, sex, and general practice. People with 3 or more diagnoses of MS recorded during the study period were included. The first MS diagnosis was considered as index date. Exposures Multiple sclerosis status. Analyses were also stratified by sex. Main Outcomes and Measures Main outcomes were acute coronary syndrome, cerebrovascular disease, any macrovascular disease (including peripheral arterial disease), and mortality (all-cause mortality and cardiovascular disease-specific mortality). Cox proportional hazards regression and Fine and Gray proportional subhazard regression models were used to assess differences in rates. Results A total of 12 251 people with MS (66.9% women; mean [SD] age, 44.9 [13.3] years) were matched with 72 572 people without MS (69.8% women; mean [SD] age, 44.9 [13.3] years). As compared with people without MS, people with MS were associated with a 28% increased hazard of acute coronary syndrome (hazard ratio [HR], 1.28; 95% CI, 1.09-1.51), 59% increased hazard of cerebrovascular disease (HR, 1.59; 95% CI, 1.32-1.92), 32% increased hazard of any macrovascular disease (HR, 1.32; 95% CI, 1.15-1.52), 3.5-fold increased hazard of all-cause mortality (HR, 3.46; 95% CI, 3.28-3.65), and 1.5-fold increased hazard in cardiovascular disease mortality (HR, 1.47; 95% CI, 1.27-1.71). Differences in macrovascular events were more pronounced among women than men. Mortality risk was also higher for women than men. Treatment with lipid-lowering medications (mainly statins) was associated with lower mortality rates among people with MS. Conclusions and Relevance This study suggests that MS is associated with an increased risk of cardiovascular and cerebrovascular disease that is not completely accounted for by traditional vascular risk factors. Given the adverse effects of these comorbidities on outcomes in patients with MS, further investigation is needed.
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Affiliation(s)
- Raffaele Palladino
- Department of Primary Care and Public Health, School of Public Health, Imperial College of London, London, United Kingdom.,Department of Public Health, Federico II University, Naples, Italy
| | - Ruth Ann Marrie
- Department of Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.,Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Azeem Majeed
- Department of Primary Care and Public Health, School of Public Health, Imperial College of London, London, United Kingdom
| | - Jeremy Chataway
- Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom.,National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, United Kingdom
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Bruning T, Al-Khaled M. Do statins reduce the mortality rate in stroke patients treated with systemic thrombolysis in a 5-year. Neural Regen Res 2021; 16:1807-1812. [PMID: 33510087 PMCID: PMC8328772 DOI: 10.4103/1673-5374.306088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The present study investigated the association between pre-treatment with a cholesterol-lowering drug (statin) or new setting hereon and the effect on the mortality rate in patients with acute ischemic stroke who received intravenous systemic thrombolysis. During a 5-year period (starting in October 2008), 542 consecutive stroke patients who received intravenous systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA) at the Department of Neurology, University Hospital Schleswig-Holstein, Campus Lübeck, Germany, were included. Patients were characterized according to statins. The primary endpoint was mortality; it was assessed twice: in hospital and 3 months after discharge. The secondary outcome was the rate of symptomatic intracerebral hemorrhage. Of the 542 stroke patients examined (mean age 72 ± 13 years; 51% women, mean National Institutes of Health Stroke Scale (NIHSS) score 11), 138 patients (25.5%) had been pre-treated with statin, while in 190 patients (35.1%) statin therapy was initiated during their stay in hospital, whereas 193 (35.6%) never received statins. Patients pre-treated with statin were older and more frequently had previous illnesses (arterial hypertension, diabetes mellitus and previous cerebral infarctions), but were comparably similarly affected by the stroke (NIHSS 11 vs. 11; P = 0.76) compared to patients who were not on statin treatment at the time of cerebral infarction. Patients pretreated with statin did not differ in 3-month mortality from those newly treated to a statin (7.6% vs. 8%; P = 0.9). Interestingly, the group of patients pretreated with statin showed a lower rate of in hospital mortality (6.6% vs. 17.0; P = 0.005) and 3-month mortality (10.7% vs. 23.7%; P = 0.005) than the group of patients who had no statin treatment at all. The same effect was seen for patients newly adjusted to a statin during the hospital stay compared to patients who did not receive statins (3-month mortality: 7.1% vs. 23.7%; P < 0.001). With a good functional outcome (mRS ≤ 2), 60% of patients were discharged, the majority (69.6%; P < 0.001) of whom received a statin at discharge. The rate of symptomatic intracerebral hemorrhages in the course of cranial computed tomography was independent of whether the patients were pretreated with a statin or not (8.8% vs. 8.7%, P = 0.96). Pre-treatment with statin as well as new adjustment could reveal positive effect on prognosis of intravenous thrombolyzed stroke patients. Further investigations are required. The study was approved by the Ethic Committee of the University of Lübeck (approval No. 4-147).
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Affiliation(s)
- Toralf Bruning
- Department of Neurology, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Mohamed Al-Khaled
- Department of Neurology, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
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Abstract
Ras proteins mediate extracellular and cytoplasmic signaling networks via receptor tyrosine kinase. The Ras pathway induces activation of signaling molecules involved in cell proliferation and growth, cell survival and apoptosis, metabolism, and motility. Although Ras mutations in breast cancer are not frequently reported, hyperactivation of Ras signaling plays an important role in breast cancer growth and progression. Oncogenic Ras activation occurs via loss of Ras GTPase-activating proteins, overexpression of growth factor receptor, and stimulation by various cytokines. Effective control of oncogenic Ras is one of the therapeutic strategies in breast cancer. The mechanisms of intracellular localization, activation, and signaling pathway of Ras in cancer have been used to develop therapeutic candidates. Recent studies have reported an effective therapy for breast cancer by inhibition of enzymes involved in the posttranslational modification of Ras, such as farnesyltransferase and geranylgeranyltransferase 1, and anti-cancer therapies targeting the epidermal growth factor receptor (EGFR). Emerging targets involved in EGF-mediated Ras activity in breast cancer have shed new insight into Ras activation in breast cancer progression. These alternative mechanisms for Ras signaling pathway may suggest novel therapeutic approaches for targeting Ras in breast cancer. In spite of the difficulties in targeting Ras protein, important discoveries highlight the direct inhibition of Ras activity. Further studies may elucidate the effects of targeting Ras protein and the clinical relevance thereof.
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Chen S, Xu P, Fang Y, Lenahan C. The Updated Role of the Blood Brain Barrier in Subarachnoid Hemorrhage: From Basic and Clinical Studies. Curr Neuropharmacol 2020; 18:1266-1278. [PMID: 32928088 PMCID: PMC7770644 DOI: 10.2174/1570159x18666200914161231] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/05/2020] [Accepted: 08/05/2020] [Indexed: 12/15/2022] Open
Abstract
Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke associated with high mortality and morbidity. The blood-brain-barrier (BBB) is a structure consisting primarily of cerebral microvascular endothelial cells, end feet of astrocytes, extracellular matrix, and pericytes. Post-SAH pathophysiology included early brain injury and delayed cerebral ischemia. BBB disruption was a critical mechanism of early brain injury and was associated with other pathophysiological events. These pathophysiological events may propel the development of secondary brain injury, known as delayed cerebral ischemia. Imaging advancements to measure BBB after SAH primarily focused on exploring innovative methods to predict clinical outcome, delayed cerebral ischemia, and delayed infarction related to delayed cerebral ischemia in acute periods. These predictions are based on detecting abnormal changes in BBB permeability. The parameters of BBB permeability are described by changes in computed tomography (CT) perfusion and magnetic resonance imaging (MRI). Kep seems to be a stable and sensitive indicator in CT perfusion, whereas Ktrans is a reliable parameter for dynamic contrast-enhanced MRI. Future prediction models that utilize both the volume of BBB disruption and stable parameters of BBB may be a promising direction to develop practical clinical tools. These tools could provide greater accuracy in predicting clinical outcome and risk of deterioration. Therapeutic interventional exploration targeting BBB disruption is also promising, considering the extended duration of post-SAH BBB disruption.
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Affiliation(s)
- Sheng Chen
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou,
Zhejiang Province, China
| | - PengLei Xu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou,
Zhejiang Province, China
| | - YuanJian Fang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou,
Zhejiang Province, China
| | - Cameron Lenahan
- Burrell College of Osteopathic Medicine, Las Cruces, NM, USA,Center for Neuroscience Research, School of Medicine, Loma Linda University, Loma Linda, CA, USA
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The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins. Int J Mol Sci 2020; 21:ijms21228745. [PMID: 33228116 PMCID: PMC7699354 DOI: 10.3390/ijms21228745] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022] Open
Abstract
Statins are a class of drugs used to lower low-density lipoprotein cholesterol and are amongst the most prescribed medications worldwide. Most statins work as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), but statin intolerance from pleiotropic effects have been proposed to arise from non-specific binding due to poor enzyme-ligand sensitivity. Yet, research into the physicochemical properties of statins, and their interactions with off-target sites, has not progressed much over the past few decades. Here, we present a concise perspective on the role of statins in lowering serum cholesterol levels, and how their reported interactions with phospholipid membranes offer a crucial insight into the mechanism of some of the more commonly observed pleiotropic effects of statin administration. Lipophilicity, which governs hepatoselectivity, is directly related to the molecular structure of statins, which dictates interaction with and transport through membranes. The structure of statins is therefore a clinically important consideration in the treatment of hypercholesterolaemia. This review integrates the recent biophysical studies of statins with the literature on the physiological effects and provides new insights into the mechanistic cause of statin pleiotropy, and prospective means of understanding the cholesterol-independent effects of statins.
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Paul S, Candelario-Jalil E. Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies. Exp Neurol 2020; 335:113518. [PMID: 33144066 DOI: 10.1016/j.expneurol.2020.113518] [Citation(s) in RCA: 431] [Impact Index Per Article: 86.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/20/2020] [Accepted: 10/23/2020] [Indexed: 12/12/2022]
Abstract
Stroke is the leading cause of disability and thesecond leading cause of death worldwide. With the global population aged 65 and over growing faster than all other age groups, the incidence of stroke is also increasing. In addition, there is a shift in the overall stroke burden towards younger age groups, particularly in low and middle-income countries. Stroke in most cases is caused due to an abrupt blockage of an artery (ischemic stroke), but in some instances stroke may be caused due to bleeding into brain tissue when a blood vessel ruptures (hemorrhagic stroke). Although treatment options for stroke are still limited, with the advancement in recanalization therapy using both pharmacological and mechanical thrombolysis some progress has been made in helping patients recover from ischemic stroke. However, there is still a substantial need for the development of therapeutic agents for neuroprotection in acute ischemic stroke to protect the brain from damage prior to and during recanalization, extend the therapeutic time window for intervention and further improve functional outcome. The current review has assessed the past challenges in developing neuroprotective strategies, evaluated the recent advances in clinical trials, discussed the recent initiative by the National Institute of Neurological Disorders and Stroke in USA for the search of novel neuroprotectants (Stroke Preclinical Assessment Network, SPAN) and identified emerging neuroprotectants being currently evaluated in preclinical studies. The underlying molecular mechanism of each of the neuroprotective strategies have also been summarized, which could assist in the development of future strategies for combinational therapy in stroke treatment.
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Affiliation(s)
- Surojit Paul
- Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
| | - Eduardo Candelario-Jalil
- Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA
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Role of the Platelets and Nitric Oxide Biotransformation in Ischemic Stroke: A Translative Review from Bench to Bedside. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2979260. [PMID: 32908630 PMCID: PMC7474795 DOI: 10.1155/2020/2979260] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 07/27/2020] [Indexed: 12/13/2022]
Abstract
Ischemic stroke remains the fifth cause of death, as reported worldwide annually. Endothelial dysfunction (ED) manifesting with lower nitric oxide (NO) bioavailability leads to increased vascular tone, inflammation, and platelet activation and remains among the major contributors to cardiovascular diseases (CVD). Moreover, temporal fluctuations in the NO bioavailability during ischemic stroke point to its key role in the cerebral blood flow (CBF) regulation, and some data suggest that they may be responsible for the maintenance of CBF within the ischemic penumbra in order to reduce infarct size. Several years ago, the inhibitory role of the platelet NO production on a thrombus formation has been discovered, which initiated the era of extensive studies on the platelet-derived nitric oxide (PDNO) as a platelet negative feedback regulator. Very recently, Radziwon-Balicka et al. discovered two subpopulations of human platelets, based on the expression of the endothelial nitric oxide synthase (eNOS-positive or eNOS-negative platelets, respectively). The e-NOS-negative ones fail to produce NO, which attenuates their cyclic guanosine monophosphate (cGMP) signaling pathway and-as result-promotes adhesion and aggregation while the e-NOS-positive ones limit thrombus formation. Asymmetric dimethylarginine (ADMA), a competitive NOS inhibitor, is an independent cardiovascular risk factor, and its expression alongside with the enzymes responsible for its synthesis and degradation was recently shown also in platelets. Overproduction of ADMA in this compartment may increase platelet activation and cause endothelial damage, additionally to that induced by its plasma pool. All the recent discoveries of diverse eNOS expression in platelets and its role in regulation of thrombus formation together with studies on the NOS inhibitors have opened a new chapter in translational medicine investigating the onset of acute cardiovascular events of ischemic origin. This translative review briefly summarizes the role of platelets and NO biotransformation in the pathogenesis and clinical course of ischemic stroke.
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Yuan Y, Khan S, Stewart DJ, Courtman DW. Engineering blood outgrowth endothelial cells to optimize endothelial nitric oxide synthase and extracellular matrix production for coating of blood contacting surfaces. Acta Biomater 2020; 109:109-120. [PMID: 32302726 DOI: 10.1016/j.actbio.2020.04.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 12/26/2022]
Abstract
Coverage of blood contacting surfaces by a functional endothelial layer is likely required to induce and maintain homeostasis. Blood outgrowth endothelial cells (BOECs), cultured from human peripheral blood monocytes, are readily available and functional autologous endothelial source that may represent a reasonable alternative to vascular derived cells. Endothelial nitric oxide synthase (eNOS) produces NO, an important factor that regulates homeostasis at the blood-contacting surface. We found that BOECs express markedly lower levels of eNOS protein (34% ± 13%, Western blot) and mRNA (29% ± 17%, qRT-PCR), as well as exhibiting reduced activity (49% ± 18%, Nitrite analysis) when compared to human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells. HUVECs grown on fibronectin, type I collagen, or laminin -coated surfaces exhibited significant reduction of eNOS mRNA and protein expression. However, no decrease in eNOS levels was observed in BOECs. Interestingly BOECs expressed significantly higher Collagen (Col) I compared to HUVECs, and blocking Col I synthesis significantly enhanced eNOS expression in BOECs. Inhibition of β1 integrin, focal adhesion kinase (FAK), or actin polymerization increased eNOS in both BOECs and HUVECs suggesting involvement of a signaling pathway culminating in stabilization of the cytoskeleton. Finally, we demonstrated that a Rho-associated protein kinases (ROCK) inhibitor, as a disruptor of actin stabilization, enhanced both eNOS expression and bioactivity. Taken together, our findings demonstrate that cell-ECM interactions are fundamental to the regulation of eNOS in BOECs and suggest that disruption of key intracellular pathways (such as ROCK) may be necessary to enhance functional activity of an endothelialized surface. STATEMENT OF SIGNIFICANCE: Development of biocompatible blood-contacting biomaterial surfaces has not been possible to date, leading many investigators to believe that a complete autologous endothelial layer will be necessary. Blood outgrowth endothelial cells (BOECs), cultured from human peripheral blood monocytes, are readily available and functional autologous endothelial source. Endothelial nitric oxide synthase (eNOS) produces NO, an important factor that regulates homeostasis at the blood-contacting surface. In this study, we show that eNOS displays limited expression in cultured BOECs. We further demonstrate that a strong negative regulation of eNOS is mediated by collagen substrates and that treatment with ROCK inhibitor could enhance both eNOS expression and activity in BOECs and help to rapidly establish a functional autologous endothelial layer on cardiovascular biomaterials.
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Affiliation(s)
- Yifan Yuan
- Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; Department of Anaesthesiology, Yale University, 10 Amistad Rd, New Haven, CT 06519, United States
| | - Saad Khan
- Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
| | - Duncan J Stewart
- Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; Department of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - David W Courtman
- Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada; Department of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
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Zhao W, Xiao ZJ, Zhao SP. The Benefits and Risks of Statin Therapy in Ischemic Stroke: A Review of the Literature. Neurol India 2020; 67:983-992. [PMID: 31512619 DOI: 10.4103/0028-3886.266274] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Statins are effective cholesterol-lowering drugs for reducing the risks of mortality and morbidity of cardiovascular diseases. Increasing evidence has shown that statin use is associated with a significant beneficial effect in patients with ischemic stroke. Both pre-stroke and post-stroke statin use has been found to be beneficial in ischemic stroke. Furthermore, good adherence is associated with a better clinical outcome, and statin withdrawal is associated with a poor functional outcome in patients with ischemic stroke. High-intensity statin therapy is advocated for the treatment of ischemic stroke. However, there are concerns regarding the adverse effects associated with statin use in ischemic stroke such as intracranial hemorrhage. In this review, we summarize the beneficial effect of statin use in ischemic stroke and discuss the potential risks associated with statin therapy.
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Affiliation(s)
- Wang Zhao
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Zhi-Jie Xiao
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Shui-Ping Zhao
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
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Kwater A, Gąsowski J, Wizner B, Kasprzyk Z, Cwynar M, Rewiuk K, Grodzicki T. Cardiovascular risk factors as determinants of cerebral blood flow - a cross-sectional and 6-year follow-up study. Blood Press 2020; 29:182-190. [PMID: 31983242 DOI: 10.1080/08037051.2020.1715785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Purpose: The parameters of cerebral blood flow are modulated by many factors. The aim of the study was to prospectively assess the relationship between the number of the established cardiovascular risk factors and hemodynamic parameters of cerebral blood flow.Material and methods: The study was cross-sectional baseline and 6-year follow-up data analysis. We analyzed data regarding cardiovascular risk factors, medications use, and ultrasonographically (transcranial Doppler) obtained mean cerebral blood flow velocity (mCBFV), pulsatility (PI), resistance (RI) indexes of middle cerebral artery.Results: After 6.0 ± 0.6 years of follow-up, there was increase in systolic (p = .047), and decrease in diastolic (p = .005) blood pressure, resulting in greater pulse pressure (p < .001). Although intima-media thickness increased during follow-up (p = .019), PI, RI and mCBFV did not differ between baseline and follow-up. In the cohort without follow-up (n = 112), we observed strong association between number of studied cardiovascular risk factors and lower mCBFV, and higher PI and RI (all p < .001), in the cohort with 6 year follow-up (n = 53), we confirmed similar association for mCBFV and PI (p = .002) at baseline, and mCBFV (p = .024) after follow-up. During follow-up, more patients were treated with vasoactive medications (p < .05). Also the median (interquartile range) of total number of taken drugs at follow-up 2 (1-3) was greater than at baseline 1 (0-2), (p < .001). The addition of vasoactive medications during follow-up was associated with increase of the mCBFV (0.012 ± 0.02 m/s, p = .013).Conclusion: The parameters of the cerebral blood flow are adversely influenced by accretion of cardiovascular risk factors, both at baseline and after 6 years of follow-up. The addition of a vasoactive medication during follow-up is associated with an increase of the mCBFV, a possibly beneficial effect.
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Affiliation(s)
- Aleksander Kwater
- Department of Internal Medicine and Gerontology, Jagiellonian University Medical College, Kraków, Poland
| | - Jerzy Gąsowski
- Department of Internal Medicine and Gerontology, Jagiellonian University Medical College, Kraków, Poland
| | - Barbara Wizner
- Department of Internal Medicine and Gerontology, Jagiellonian University Medical College, Kraków, Poland
| | | | - Marcin Cwynar
- Department of Internal Medicine and Gerontology, Jagiellonian University Medical College, Kraków, Poland
| | - Krzysztof Rewiuk
- Department of Internal Medicine and Gerontology, Jagiellonian University Medical College, Kraków, Poland
| | - Tomasz Grodzicki
- Department of Internal Medicine and Gerontology, Jagiellonian University Medical College, Kraków, Poland
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Zamani A, Powell KL, May A, Semple BD. Validation of reference genes for gene expression analysis following experimental traumatic brain injury in a pediatric mouse model. Brain Res Bull 2020; 156:43-49. [PMID: 31904409 DOI: 10.1016/j.brainresbull.2019.12.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 12/02/2019] [Accepted: 12/30/2019] [Indexed: 01/01/2023]
Abstract
Quantitative polymerase chain reaction (qPCR) is the gold standard method in targeted analysis of messenger RNA (mRNA) levels in a tissue. To minimize methodological errors, a reference gene (or a combination of reference genes) is routinely used for normalization to account for technical variables such as RNA quality and sample size. While presumed to have stable expression, reference genes in the brain can change during normal development, as well as in response to injury, such as traumatic brain injury (TBI). This study is the first to evaluate the stability of reference genes in a controlled cortical impact (CCI) model in the pediatric mouse brain, using two methods of qPCR normalization for optimal reference gene selection. Three week old mice were subjected to unilateral CCI at two severity of injuries (mild or severe), compared to sham controls. At 1 and 8 weeks post-injury, the ipsilateral hemisphere was analyzed to determine reference gene stability. Five commonly-used reference genes were compared: tyrosine 3 monooxygenase/tryptophan 5 monooxygenase activation protein zeta (Ywhaz), cyclophilin A (Ppia), hypoxanthine phosphoribosyl transferase (Hprt), glyceraldehyde-3-phosphate dehydrogenase (Gapdh) and β-actin (Actb). Ppia and Hprt were chosen as the most stable combination of genes using GeNORM software analysis. These results highlight the instability of several commonly used reference genes after TBI, and provide a selection of validated genes for future gene expression analyses in the injured pediatric mouse brain.
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Affiliation(s)
- Akram Zamani
- Department of Neuroscience, Monash University, Melbourne, VIC, 3004, Australia.
| | - Kim L Powell
- Department of Neuroscience, Monash University, Melbourne, VIC, 3004, Australia; Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, VIC, 3052, Australia
| | - Ashleigh May
- Department of Neuroscience, Monash University, Melbourne, VIC, 3004, Australia
| | - Bridgette D Semple
- Department of Neuroscience, Monash University, Melbourne, VIC, 3004, Australia; Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, VIC, 3052, Australia
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Statin Therapy in Ischemic Stroke Models: A Meta-Analysis. Transl Stroke Res 2019; 11:590-600. [PMID: 31788761 DOI: 10.1007/s12975-019-00750-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 10/29/2019] [Accepted: 10/30/2019] [Indexed: 01/05/2023]
Abstract
Statins, drugs known for lipid lowering capabilities and reduction of cardiovascular disease, have demonstrated neuroprotective effects following ischemic stroke in retrospective clinical and animal studies. However, dosing (methods, time, type of statin, and quantity) varies across studies, limiting the clinical applicability of these findings. Furthermore, a comprehensive review of statins in edema and blood-brain barrier (BBB) breakdown is needed to provide insight on diverse, less explored neuroprotective effects. In the present study, we conduct a meta-analysis of publications evaluating statin administration in animal models of ischemic stroke. We review statins' most effective dosing regimen in four outcomes-infarct, edema, BBB breakdown, and functional outcome-to characterize several parameters of benefit associated with statin administration. A search term was constructed to identify experimental murine studies exploring statin use after transient middle cerebral artery occlusion (tMCAO) in PubMed, Web of Science, and Embase. Extracted data included statin type, dose, time and method of administration, and the four predetermined outcomes (functional outcome, edema, BBB breakdown, and infarction). A meta-analysis and stratified meta-regression were conducted using the standardized mean difference (SMD) method for continuous measurements. Included publications were assessed for bias using SYRCLE's RoB tool for animal studies. A total of 24 studies were included. Statin administration significantly reduced infarct volume (p < 0.0001), edema volume (p < 0.002), and neurological deficit (p < 0.0001). Simvastatin and pravastatin were most effective in reducing infarct volume when compared with atorvastatin (p = 0.0475, p = 0.0004) and rosuvastatin (p = 0.0036, p < 0.0001). Pravastatin outperformed all others in functional outcome. Subcutaneous (SC) injection was most effective in all outcomes. Statin therapy reduced BBB breakdown according to our systematic review. Mean study quality was 4.6/10. While statin therapy evidently improves neurological outcome following ischemic stroke, this analysis adds to our understanding of dosing and statins' effects on edema and BBB breakdown. These findings will aid the design of future studies investigating statin use and have larger implications for the clinical care of ischemic stroke patients.
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Gorabi AM, Kiaie N, Hajighasemi S, Banach M, Penson PE, Jamialahmadi T, Sahebkar A. Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications. J Clin Med 2019; 8:2051. [PMID: 31766595 PMCID: PMC6947613 DOI: 10.3390/jcm8122051] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/16/2019] [Accepted: 11/20/2019] [Indexed: 12/27/2022] Open
Abstract
In addition to their cholesterol-lowering effects, statins are associated with pleiotropic effects including improvements in heart failure (HF), reduced blood pressure, prevention of the rupture of atherosclerotic plaques and improved angiogenesis. In addition to these cardiovascular benefits, statins have been implicated in the treatment of neurological injuries, cancer, sepsis, and cirrhosis. These cholesterol-independent beneficial effects of statins are predominantly mediated through signaling pathways leading to increased production and bioavailability of nitric oxide (NO). In this review, the mechanistic pathways and therapeutic effects of statin-mediated elevations of NO are described and discussed.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran 1411713138, Iran; (A.M.G.); (N.K.)
| | - Nasim Kiaie
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran 1411713138, Iran; (A.M.G.); (N.K.)
| | - Saeideh Hajighasemi
- Department of Medical Biotechnology, Faculty of Paramedicine, Qazvin University of Medical Sciences, Qazvin 1531534199, Iran;
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 93-338 Lodz, Poland;
- Polish Mother’s Memorial Hospital Research Institute (PMMHRI), 93-338 Lodz, Poland
| | - Peter E. Penson
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK;
| | - Tannaz Jamialahmadi
- Halal Research Center of IRI, FDA, Tehran 1411713138, Iran;
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
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50
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Chen J, Zhang J, Shaik NF, Yi B, Wei X, Yang XF, Naik UP, Summer R, Yan G, Xu X, Sun J. The histone deacetylase inhibitor tubacin mitigates endothelial dysfunction by up-regulating the expression of endothelial nitric oxide synthase. J Biol Chem 2019; 294:19565-19576. [PMID: 31719145 DOI: 10.1074/jbc.ra119.011317] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/06/2019] [Indexed: 01/03/2023] Open
Abstract
Endothelial nitric oxide (NO) synthase (eNOS) plays a critical role in the maintenance of blood vessel homeostasis. Recent findings suggest that cytoskeletal dynamics play an essential role in regulating eNOS expression and activation. Here, we sought to test whether modulation of cytoskeletal dynamics through pharmacological regulation of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation affects eNOS expression and endothelial function in vitro and in vivo We found that tubulin acetylation inducer (tubacin), a compound that appears to selectively inhibit HDAC6 activity, dramatically increased eNOS expression in several different endothelial cell lines, as determined by both immunoblotting and NO production assays. Mechanistically, we found that these effects were not mediated by tubacin's inhibitory effect on HDAC6 activity, but rather were due to its ability to stabilize eNOS mRNA transcripts. Consistent with these findings, tubacin also inhibited proinflammatory cytokine-induced degradation of eNOS transcripts and impairment of endothelium-dependent relaxation in the mouse aorta. Furthermore, we found that tubacin-induced up-regulation in eNOS expression in vivo is associated with improved endothelial function in diabetic db/db mice and with a marked attenuation of ischemic brain injury in a murine stroke model. Our findings indicate that tubacin exhibits potent eNOS-inducing effects and suggest that this compound might be useful for the prevention or management of endothelial dysfunction-associated cardiovascular diseases.
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Affiliation(s)
- Jihui Chen
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.,Department of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China
| | - Jian Zhang
- Department of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China
| | - Noor F Shaik
- Cardeza Center for Vascular Biology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Bing Yi
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Xin Wei
- Department of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China
| | - Xiao-Feng Yang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19107
| | - Ulhas P Naik
- Cardeza Center for Vascular Biology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Ross Summer
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Guijun Yan
- Reproductive Medicine Center, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210023, China
| | - Xinyun Xu
- Department of General Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Jianxin Sun
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
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