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Gong G, Wan W, Zhang X, Chen X, Yin J. Management of ROS and Regulatory Cell Death in Myocardial Ischemia-Reperfusion Injury. Mol Biotechnol 2025; 67:1765-1783. [PMID: 38852121 DOI: 10.1007/s12033-024-01173-y] [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: 12/13/2023] [Accepted: 04/02/2024] [Indexed: 06/10/2024]
Abstract
Myocardial ischemia-reperfusion injury (MIRI) is fatal to patients, leading to cardiomyocyte death and myocardial remodeling. Reactive oxygen species (ROS) and oxidative stress play important roles in MIRI. There is a complex crosstalk between ROS and regulatory cell deaths (RCD) in cardiomyocytes, such as apoptosis, pyroptosis, autophagy, and ferroptosis. ROS is a double-edged sword. A reasonable level of ROS maintains the normal physiological activity of myocardial cells. However, during myocardial ischemia-reperfusion, excessive ROS generation accelerates myocardial damage through a variety of biological pathways. ROS regulates cardiomyocyte RCD through various molecular mechanisms. Targeting the removal of excess ROS has been considered an effective way to reverse myocardial damage. Many studies have applied antioxidant drugs or new advanced materials to reduce ROS levels to alleviate MIRI. Although the road from laboratory to clinic has been difficult, many scholars still persevere. This article reviews the molecular mechanisms of ROS inhibition to regulate cardiomyocyte RCD, with a view to providing new insights into prevention and treatment strategies for MIRI.
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Affiliation(s)
- Ge Gong
- Department of Geriatrics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 211002, China
| | - Wenhui Wan
- Department of Geriatrics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 211002, China
| | - Xinghu Zhang
- Department of Geriatrics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 211002, China
| | - Xiangxuan Chen
- Department of Cardiology, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, 211100, China.
| | - Jian Yin
- Department of Orthopedics, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, 211100, China.
- Department of Orthopedics, Jiangning Clinical Medical College of Jiangsu Medical Vocational College, Nanjing, 211100, China.
- Department of Orthopedics, Jiangning Clinical Medical College of Nanjing Medical University Kangda College, Nanjing, 211100, China.
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2
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Barik A, Bhoga D, Dhingra T, Karmarkar G, Ghosh B, Malik N, Parmar K, Datta A, Borah A, Bhattacharya P. Clemastine Reduces post-stroke Neurodegeneration by Alleviating Endoplasmic Reticulum stress-mediated Demyelination and Cognitive Impairment Through PERK/ATF4/CHOP Signaling Pathway. Neurochem Res 2025; 50:151. [PMID: 40274676 DOI: 10.1007/s11064-025-04403-0] [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: 01/30/2025] [Revised: 04/02/2025] [Accepted: 04/15/2025] [Indexed: 04/26/2025]
Abstract
The progressive brain damage following ischemic stroke is primarily due to oxidative stress and activation of inflammatory pathways. Post-stroke neurodegeneration can lead to the loss of neurons and glial cells, including oligodendrocytes, contributing to demyelination. Following ischemic stroke, reperfusion results in increased intracellular calcium, generation of free radicals, and inflammation culminating in accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen augmenting the ER stress. ER stress has been shown to aggravate post-stroke neurodegeneration by triggering neuronal apoptosis and also contributing towards demyelination of neurons. To address the limitations of current stroke therapies, repurposing of drugs as future adjunctive therapy may be promising. Clemastine, an antihistaminic drug, improves post stroke outcome as evident in the present study. Male Sprague Dawley (SD) rats were treated with clemastine following ischemic stroke. Harvested brain tissues were subjected to different biochemical assays, molecular assays, and histopathological analysis. Clemastine was able to reduce infarct size, alleviate oxidative stress, improve neuronal count, and functional outcomes. Clemastine downregulated genes and proteins responsible for ER stress, apoptosis and demyelination as shown by the western blot and qPCR results. Our study suggests that clemastine may alleviate endoplasmic reticulum stress-mediated demyelination by modulating PERK/ATF4/CHOP axis, and may be used as one of the adjunctive therapies for stroke in future.
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Affiliation(s)
- Anirban Barik
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Dipakkumar Bhoga
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Tannu Dhingra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Gautam Karmarkar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Bijoyani Ghosh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Nikita Malik
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Krupanshu Parmar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Aishika Datta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, 788011, Assam, India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India.
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Iurova EV, Rastorgueva EV, Beloborodov EA, Sugak DE, Pogodina ES, Fomin AN, Saenko YV. Peptide toxins targeting ion channels as cytoprotective agents in ischemia-reperfusion injury of epithelial cells. BIOMEDITSINSKAIA KHIMIIA 2025; 71:116-126. [PMID: 40326018 DOI: 10.18097/pbmcr1553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Abstract
Ischemia-reperfusion injury (IRI) is a complex process accompanying cessation of blood supply to an organ or tissue followed by subsequent restoration of blood circulation. The IRI is especially prominent in surgery and organ transplantation. One of the strategies for reducing organ and tissue damage during transplantation is regulation of intracellular ion concentrations. Maintenance of ion concentrations in the cell during damage development can be controlled by influencing voltage-dependent ion channels with certain types of compounds. We propose the peptide toxins tropic to calcium (omega-hexatoxin-Hv1a) and sodium (mu-agatoxin-Aa1a) voltage-dependent ion channels as potential agents reducing IRI. The toxins were obtained using solid-phase peptide synthesis. The IRI modeling for evaluation of the action of toxins was carried out on a culture of epithelial cells CHO-K1 during their incubation under conditions of hypoxia and nutrient deprivation followed by subsequent replenishment of the nutrient medium. The level of cell death, concentrations of calcium, sodium, potassium ions, and pH were recorded using a multimodal plate reader and fluorescent dyes. Experiments have shown that regardless of different mechanisms of action, both toxins reduced the development of CHO-K1 cell death by changing ion concentrations and maintaining the pH level.
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Affiliation(s)
- E V Iurova
- S.P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk, Russia
| | - E V Rastorgueva
- S.P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk, Russia
| | - E A Beloborodov
- S.P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk, Russia
| | - D E Sugak
- S.P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk, Russia
| | - E S Pogodina
- S.P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk, Russia
| | - A N Fomin
- S.P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk, Russia
| | - Y V Saenko
- S.P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk, Russia
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Ghanta SN, Kattamuri LPV, Odueke A, Mehta JL. Molecular Insights into Ischemia-Reperfusion Injury in Coronary Artery Disease: Mechanisms and Therapeutic Implications: A Comprehensive Review. Antioxidants (Basel) 2025; 14:213. [PMID: 40002399 PMCID: PMC11851988 DOI: 10.3390/antiox14020213] [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: 01/06/2025] [Revised: 02/05/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Coronary artery disease remains a leading cause of morbidity and mortality worldwide. Acute myocardial infarction results in ischemia-induced cellular dysfunction and death. While timely reperfusion limits myocardial damage, it paradoxically triggers ischemia-reperfusion injury (IRI), exacerbating tissue damage. IRI, first observed in the 1960s, is mediated by complex molecular pathways, including oxidative stress, calcium dysregulation, endothelial dysfunction, and inflammation. This review examines emerging therapeutic strategies targeting IRI, including ischemic preconditioning, postconditioning, pharmacological agents, and anti-inflammatory therapies. Preconditioning serves as an endogenous protection mechanism, while pharmacological postconditioning has become a more clinically feasible approach to target oxidative stress, inflammation, and apoptosis during reperfusion. Pharmacological agents, such as GSK-3β inhibitors, JNK inhibitors, and mesenchymal stem cell-derived exosomes, have shown promise in modulating molecular pathways, including Wnt/β-catenin and NF-κB, to reduce myocardial injury and enhance recovery. Combination therapies, integrating pharmacological agents with mechanical postconditioning, provide a synergistic approach to further protect tissue and mitigate damage. However, translating preclinical findings to clinical practice remains challenging due to discrepancies between animal models and human conditions, particularly with comorbidities such as diabetes and hypertension. Continued research is essential to refine these therapies, optimize clinical application, and address translational challenges to improve outcomes in IRI.
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Affiliation(s)
- Sai Nikhila Ghanta
- Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.N.G.); (A.O.)
| | - Lakshmi. P. V. Kattamuri
- Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA;
| | - Adetayo Odueke
- Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.N.G.); (A.O.)
| | - Jawahar L. Mehta
- Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.N.G.); (A.O.)
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Long M, Wang L, Kang L, Liu D, Long T, Ding H, Duan Y, He H, Xu B, Gu N. Prussian Blue Nanozyme Featuring Enhanced Superoxide Dismutase-like Activity for Myocardial Ischemia Reperfusion Injury Treatment. ACS NANO 2025; 19:4561-4581. [PMID: 39835774 DOI: 10.1021/acsnano.4c14445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
The blood flow, when restored clinically following a myocardial infarction (MI), disrupts the physiological and metabolic equilibrium of the ischemic myocardial area, resulting in secondary damage termed myocardial ischemia-reperfusion injury (MIRI). Reactive oxygen species (ROS) generation and inflammatory reactions stand as primary culprits behind MIRI. Current strategies focusing on ROS-scavenging and anti-inflammatory actions have limited remission of MIRI. Prussian blue nanozyme (PBNz) exhibits multiple enzyme-like activities including catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD), which are beneficial for ROS clearance and fighting inflammation. Herein, a formulation of PBNz coated with polydextrose-sorbitol carboxymethyl ether (PBNz@PSC) was developed to enhance its efficacy, biocompatibility, and safety for the treatment of MIRI. PBNz@PSC not only showed enhanced SOD-like activity due to its polysaccharide attributes but also could passively target the damaged myocardium through the enhanced permeability and retention (EPR) effect. Both in vitro and in vivo studies have validated their excellent biocompatibility, safety, ROS-scavenging ability, and capacity to drive macrophage polarization from M1 toward M2, thereby diminishing the levels of IL-1β, IL-6, and TNF-α to combat inflammation. Consequently, PBNz@PSC can reverse ischemia reperfusion-induced myocardial injury, reduce coronary microvascular obstruction (MVO), and improve myocardial remodeling and cardiac function. Moreover, PBNz@PSC showed more pronounced therapeutic effects for MIRI than a clinical drug, sulfotanshinone IIA sodium. Notably, our findings revealed the possible mechanism of PBNz@PSC in treating MIRI, which mediated AMPK activation. In conclusion, this study presents a pioneering strategy for addressing MIRI, promising improved ischemia-reperfusion outcomes.
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Affiliation(s)
- Mengmeng Long
- Jiangsu Key Laboratory for Biomaterials and Devices, School of Biomedical Sciences and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
| | - Lintao Wang
- Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, P. R. China
| | - Lina Kang
- Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, P. R. China
- Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine, Institute of Clinical Medicine, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210093, P. R. China
| | - Dongfang Liu
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210003, P. R. China
| | - Tingting Long
- Anqing Municipal Hospital, Anqing Medical Center of Anhui Medical University, AnQing 246003, P. R. China
| | - He Ding
- Jiangsu Key Laboratory for Biomaterials and Devices, School of Biomedical Sciences and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
| | - Yifan Duan
- Jiangsu Key Laboratory for Biomaterials and Devices, School of Biomedical Sciences and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
| | - Hongliang He
- Jiangsu Key Laboratory for Biomaterials and Devices, School of Biomedical Sciences and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
| | - Biao Xu
- Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, P. R. China
- Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine, Institute of Clinical Medicine, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210093, P. R. China
| | - Ning Gu
- Jiangsu Key Laboratory for Biomaterials and Devices, School of Biomedical Sciences and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
- Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine, Institute of Clinical Medicine, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210093, P. R. China
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Sanchez-Fernandez E, Guerra-Ojeda S, Suarez A, Serna E, Mauricio MD. Histone Deacetylase Inhibitors as a Promising Treatment Against Myocardial Infarction: A Systematic Review. J Clin Med 2024; 13:7797. [PMID: 39768722 PMCID: PMC11728224 DOI: 10.3390/jcm13247797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/16/2025] Open
Abstract
Background/Objectives: Acute myocardial infarction (AMI) is a critical medical condition that requires immediate attention to minimise heart damage and improve survival rates. Early identification and prompt treatment are essential to save the patient's life. Currently, the treatment strategy focuses on restoring blood flow to the myocardium as quickly as possible. However, reperfusion activates several cellular cascades that contribute to organ dysfunction, resulting in the ischaemia/reperfusion (I/R) injury. The search for treatments against AMI and I/R injury is urgent due to the shortage of effective treatments at present. In this regard, histone deacetylase (HDAC) inhibitors emerge as a promising treatment against myocardial infarction. The objective of this systematic review is to analyse the effects of HDAC inhibitors on ventricular function, cardiac remodelling and infarct size, among other parameters, focusing on the signalling pathways that may mediate these cardiovascular effects and protect against AMI. Methods: Original experimental studies examining the effects of HDAC inhibitors on AMI were included in the review using the PubMed and Scopus databases. Non-experimental papers were excluded. The SYRCLE RoB tool was used to assess risk of bias and the results were summarised in a table and presented in sections according to the type of HDAC inhibitor used. Results: A total of 18 studies were included, 10 of them using trichostatin A (TSA) as an HDAC inhibitor and concluding that the treatment improved ventricular function, reduced infarct size, and inhibited myocardial hypertrophy and remodelling after AMI. Other HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), valproic acid (VPA), mocetinostat, givinostat, entinostat, apicidin, and RGFP966, were also analysed, showing antioxidant and anti-inflammatory effects, an improvement in cardiac function and remodelling, and a decrease in apoptosis, among other effects. Conclusions: HDAC inhibitors constitute a significant promise for the treatment of AMI due to their diverse cardioprotective effects. However, high risk of selection, performance, and detection bias in the in vivo studies means that their application in the clinical setting is still a long way off and more research is needed to better understand their benefits and possible side effects.
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Affiliation(s)
- Eduardo Sanchez-Fernandez
- Department of Physiology, Universitat de Valencia, 46010 Valencia, Spain; (E.S.-F.); (S.G.-O.); (A.S.); (E.S.)
| | - Sol Guerra-Ojeda
- Department of Physiology, Universitat de Valencia, 46010 Valencia, Spain; (E.S.-F.); (S.G.-O.); (A.S.); (E.S.)
- Instituto Investigación Hospital Clínico-INCLIVA, 46010 Valencia, Spain
| | - Andrea Suarez
- Department of Physiology, Universitat de Valencia, 46010 Valencia, Spain; (E.S.-F.); (S.G.-O.); (A.S.); (E.S.)
- Instituto Investigación Hospital Clínico-INCLIVA, 46010 Valencia, Spain
| | - Eva Serna
- Department of Physiology, Universitat de Valencia, 46010 Valencia, Spain; (E.S.-F.); (S.G.-O.); (A.S.); (E.S.)
- Instituto Investigación Hospital Clínico-INCLIVA, 46010 Valencia, Spain
| | - Maria D. Mauricio
- Department of Physiology, Universitat de Valencia, 46010 Valencia, Spain; (E.S.-F.); (S.G.-O.); (A.S.); (E.S.)
- Instituto Investigación Hospital Clínico-INCLIVA, 46010 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBER-CV), 28029 Madrid, Spain
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Lu C, Gao C, Wei J, Dong D, Sun M. SIRT1-FOXOs signaling pathway: A potential target for attenuating cardiomyopathy. Cell Signal 2024; 124:111409. [PMID: 39277092 DOI: 10.1016/j.cellsig.2024.111409] [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: 06/12/2024] [Revised: 09/09/2024] [Accepted: 09/10/2024] [Indexed: 09/17/2024]
Abstract
Cardiomyopathy constitutes a global health burden. It refers to myocardial injury that causes alterations in cardiac structure and function, ultimately leading to heart failure. Currently, there is no definitive treatment for cardiomyopathy. This is because existing treatments primarily focus on drug interventions to attenuate symptoms rather than addressing the underlying causes of the disease. Notably, the cardiomyocyte loss is one of the key risk factors for cardiomyopathy. This loss can occur through various mechanisms such as metabolic disturbances, cardiac stress (e.g., oxidative stress), apoptosis as well as cell death resulting from disorders in autophagic flux, etc. Sirtuins (SIRTs) are categorized as class III histone deacetylases, with their enzyme activity primarily reliant on the substrate nicotinamide adenine dinucleotide (NAD (+)). Among them, Sirtuin 1 (SIRT1) is the most intensively studied in the cardiovascular system. Forkhead O transcription factors (FOXOs) are the downstream effectors of SIRT1. Several reports have shown that SIRT1 can form a signaling pathway with FOXOs in myocardial tissue, and this pathway plays a key regulatory role in cell loss. Thus, this review describes the basic mechanism of SIRT1-FOXOs in inhibiting cardiomyocyte loss and its favorable role in cardiomyopathy. Additionally, we summarized the SIRT1-FOXOs related regulation factor and prospects the SIRT1-FOXOs potential clinical application, which provide reference for the development of cardiomyopathy treatment.
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Affiliation(s)
- Changxu Lu
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Can Gao
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Jinwen Wei
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Dan Dong
- College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China.
| | - Mingli Sun
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China.
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8
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Rojas-Solé C, Pinilla-González V, Lillo-Moya J, González-Fernández T, Saso L, Rodrigo R. Integrated approach to reducing polypharmacy in older people: exploring the role of oxidative stress and antioxidant potential therapy. Redox Rep 2024; 29:2289740. [PMID: 38108325 PMCID: PMC10732214 DOI: 10.1080/13510002.2023.2289740] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2023] Open
Abstract
Increased life expectancy, attributed to improved access to healthcare and drug development, has led to an increase in multimorbidity, a key contributor to polypharmacy. Polypharmacy is characterised by its association with a variety of adverse events in the older persons. The mechanisms involved in the development of age-related chronic diseases are largely unknown; however, altered redox homeostasis due to ageing is one of the main theories. In this context, the present review explores the development and interaction between different age-related diseases, mainly linked by oxidative stress. In addition, drug interactions in the treatment of various diseases are described, emphasising that the holistic management of older people and their pathologies should prevail over the individual treatment of each condition.
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Affiliation(s)
- Catalina Rojas-Solé
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Víctor Pinilla-González
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - José Lillo-Moya
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Tommy González-Fernández
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Faculty of Pharmacy and Medicine, Sapienza University, Rome, Italy
| | - Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
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9
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Xiao Z, Li S, Wu X, Chen X, Yan D, He J. GATA-4 overexpressing BMSC-derived exosomes suppress H/R-induced cardiomyocyte ferroptosis. iScience 2024; 27:110784. [PMID: 39391723 PMCID: PMC11466636 DOI: 10.1016/j.isci.2024.110784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 07/01/2024] [Accepted: 08/19/2024] [Indexed: 10/12/2024] Open
Abstract
Bone marrow mesenchymal stem cell (BMSC)-derived exosomes overexpressing GATA-4 (Exosoe-GATA-4) can protect cardiac function. Mitochondrial permeability transition pore (mPTP) has a crucial role in ferroptosis. This study aimed to assess the mechanism of Exosoe-GATA-4 in myocardial ischemia/reperfusion (I/R) injury. Exos were successfully excreted, and 185 differential expression miRNAs were obtained using bioinformatics. The Exosoe-GATA-4 effectively suppressed hypoxia/reoxygenation (H/R)-induced cardiomyocytes' ferroptosis, while the effects were reversed by miR-330-3p inhibitor. miR-330-3p targeted negative regulated BAP1. The effects of miR-330-3p inhibitor were reversed by knock-down BAP1. Also, BAP1 reversed the effects of Exosoe-GATA-4 on H/R-induced cardiomyocytes' ferroptosis by downregulating SLC7A11. Mechanistically, BAP1 interacted with IP3R and increased cardiomyocytes' Ca2+ level, causing mPTP opening and mitochondrial dysfunction, promoting H/R-induced cardiomyocytes' ferroptosis. Moreover, hydrogen sulfide (H2S) content was increased and regulated the keap1/Nrf2 signaling pathway by Exosoe-GATA-4 treated. Exosoe-GATA-4 effectively suppresses H/R-induced cardiomyocytes' ferroptosis by upregulating miR-330-3p, which regulates the BAP1/SLC7A11/IP3R axis and inhibits mPTP opening.
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Affiliation(s)
- Zhiyuan Xiao
- Department of Medical Intensive Care Unit, the First People′s Hospital of Yunnan Province, No.157 Jinbi Road, Kunming, Yunnan 650032, China
| | - Si Li
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650500, P.R. China
| | - Xinxin Wu
- Yunnan University of Traditional Chinese Medicine, No.1076 Yuhua Road, Kunming, Yunnan 650500, China
| | - Xinhao Chen
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650500, P.R. China
| | - Dan Yan
- Department of Medical Intensive Care Unit, the First People′s Hospital of Yunnan Province, No.157 Jinbi Road, Kunming, Yunnan 650032, China
| | - Jigang He
- Department of Cardiovascular Surgery, the First People′s Hospital of Yunnan Province, No.157 Jinbi Road, Kunming, Yunnan 650032, China
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10
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Li S, Zhou Y, Li K, Liu L, Fang M, Gao H. Inhibition of circDGKZ ameliorates myocardial ischemia/reperfusion injury by targeting miR-345-5p/TLR4. ESC Heart Fail 2024; 11:2730-2741. [PMID: 38725137 PMCID: PMC11424286 DOI: 10.1002/ehf2.14809] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/25/2024] [Accepted: 04/01/2024] [Indexed: 09/27/2024] Open
Abstract
AIMS This study aims to explore the molecular mechanism of circular RNAs' (circRNAs) potential involvement in myocardial ischaemia-reperfusion injury (MIRI). METHODS AND RESULTS Differently expressed genes in myocardial infarction (MI) were identified by screening the GEO database. Serum was collected from MI patients and healthy volunteers (n = 5 for each group). AC16 cells were cultured and exposed to hypoxia/reperfusion (H/R) treatment for the cell experiments. Then candidate genes were validated in human serum and the H/R model. Quantitative real-time PCR and western blot were used to detect expression of key molecules such as circDGKZ, miR-345-5p, and Toll-like receptor 4 (TLR4), as well as pyroptosis markers such as NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), ASC, C-caspase1, interleukin (IL)-1β, and IL-18. CircDGKZ was positively correlated in human serum (P < 0.05) and in AC16 cells (P < 0.01). Knockdown of circDGKZ inhibited cardiomyocyte pyroptosis and the TLR4/nuclear factor kappa B (NF-κB) signalling pathway (all P < 0.05). A luciferase assay was used to detect the molecule interaction. MiR-345-5p was regulated by circDGKZ and regulated TLR4 in cardiomyocytes both through direct interaction (P < 0.01). The stability and distribution of circRNA or linear RNA were examined by subcellular localization and RNA decay assays. CircDGKZ was stably expressed in cardiomyocytes and mainly distributed in the cytoplasm (P < 0.01). Knockdown of circDGKZ also promoted the degradation of NLRP3 by inducing autophagy (P < 0.05). MIRI rat models were constructed (n = 5 for each group), and the cellular results were further confirmed in rat models (P < 0.05). CONCLUSIONS Knockdown of circDGKZ interrupted pyroptosis and induced autophagy of cardiomyocytes via regulating miR-345-5p/TLR4/NF-κB.
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Affiliation(s)
- Shiliang Li
- Division of Cardiothoracic and Vascular SurgeryTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubei ProvinceChina
| | - Yan Zhou
- Department of OtolaryngologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubei ProvinceChina
| | - KunSheng Li
- Department of Cardiovascular SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Lu Liu
- Department of PharmacyTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubei ProvinceChina
| | - Ming Fang
- Health Management CenterUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubei ProvinceChina
| | - Hongfeng Gao
- Department of Emergency MedicineWuhan Wuchang Hospital, Wuchang Hospital Affiliated to Wuhan University of Science and TechnologyNo. 116, Yangyuan StreetWuhan430000Hubei ProvinceChina
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11
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Deng H, Ding D, Ma Y, Zhang H, Wang N, Zhang C, Yang G. Nicotinamide Mononucleotide: Research Process in Cardiovascular Diseases. Int J Mol Sci 2024; 25:9526. [PMID: 39273473 PMCID: PMC11394709 DOI: 10.3390/ijms25179526] [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: 07/29/2024] [Revised: 08/21/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that plays a crucial role in diverse biological processes, including energy metabolism, gene expression, DNA repair, and mitochondrial function. An aberrant NAD+ level mediates the development of cardiovascular dysfunction and diseases. Both in vivo and in vitro studies have demonstrated that nicotinamide mononucleotide (NMN), as a NAD+ precursor, alleviates the development of cardiovascular diseases such as heart failure, atherosclerosis, and myocardial ischemia/reperfusion injury. Importantly, NMN has suggested pharmacological activities mostly through its involvement in NAD+ biosynthesis. Several clinical studies have been conducted to investigate the efficacy and safety of NMN supplementation, indicating its potential role in cardiovascular protection without significant adverse effects. In this review, we systematically summarize the impact of NMN as a nutraceutical and potential therapeutic drug on cardiovascular diseases and emphasize the correlation between NMN supplementation and cardiovascular protection.
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Affiliation(s)
- Haoyuan Deng
- Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Ding Ding
- School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Yu Ma
- Department of Health Toxicology, School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Hao Zhang
- School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Ningning Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Cong Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian 116044, China
| | - Guang Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian 116044, China
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12
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Hoebart C, Kiss A, Podesser BK, Tahir A, Fischer MJM, Heber S. Sensory Neurons Release Cardioprotective Factors in an In Vitro Ischemia Model. Biomedicines 2024; 12:1856. [PMID: 39200320 PMCID: PMC11351881 DOI: 10.3390/biomedicines12081856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/07/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Sensory neurons densely innervate the myocardium. The role of their sensing and response to acute and prolonged ischemia is largely unclear. In a cellular model of ischemia-reperfusion injury, the presence of sensory neurons increases cardiomyocyte survival. Here, after the exclusion of classical neurotransmitter release, and measurement of cytokine release, we modified the experiment from a direct co-culture of primary murine cardiomyocytes and sensory neurons to a transfer of the supernatant. Sensory neurons were exposed to ischemia and the resulting conditioned supernatant was transferred onto cardiomyocytes. This approach largely increased the tolerance of cardiomyocytes to ischemia and reperfusion. Towards the identification of the mechanism, it was demonstrated that after ten-fold dilution, the conditioned solution lost its protective effect. The effect remained after removal of extracellular vesicles by ultracentrifugation, and was not affected by exposure to protease activity, and fractionation pointed towards a hydrophilic agent. Solutions conditioned by HEK293t cells or 3T3 fibroblasts also increase cardiomyocyte survival, but to a lower degree. A metabolomic search identified 64 at least two-fold changed metabolites and lipids. Many of these could be identified and are involved in essential cellular functions. In the presented model for ischemia-reperfusion, sensory neurons secrete one or more cardioprotective substances that can improve cardiomyocyte survival.
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Affiliation(s)
- Clara Hoebart
- Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (C.H.); (S.H.)
| | - Attila Kiss
- Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090 Vienna, Austria; (A.K.); (B.K.P.)
| | - Bruno K. Podesser
- Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090 Vienna, Austria; (A.K.); (B.K.P.)
| | - Ammar Tahir
- Division of Pharmacognosy, University of Vienna, 1090 Vienna, Austria;
| | - Michael J. M. Fischer
- Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (C.H.); (S.H.)
| | - Stefan Heber
- Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (C.H.); (S.H.)
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13
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Zhang Q, Zhang L, Lin G, Luo F. The protective role of vagus nerve stimulation in ischemia-reperfusion injury. Heliyon 2024; 10:e30952. [PMID: 38770302 PMCID: PMC11103530 DOI: 10.1016/j.heliyon.2024.e30952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 05/02/2024] [Accepted: 05/08/2024] [Indexed: 05/22/2024] Open
Abstract
Ischemia-reperfusion injury (IRI) encompasses the damage resulting from the restoration of blood supply following tissue ischemia. This phenomenon commonly occurs in clinical scenarios such as hemorrhagic shock, severe trauma, organ transplantation, and thrombolytic therapy. Despite its prevalence, existing treatments exhibit limited efficacy against IRI. Vagus nerve stimulation (VNS) is a widely utilized technique for modulating the autonomic nervous system. Numerous studies have demonstrated that VNS significantly reduces IRI in various organs, including the heart, brain, and liver. This article reviews the pathological processes during IRI and summarizes the role and possible mechanisms of VNS in IRI of different organs. Furthermore, this review addresses the current challenges of VNS clinical applications, providing a novel perspective on IRI treatment.
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Affiliation(s)
- Qianqian Zhang
- Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Lei Zhang
- Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Guoqiang Lin
- Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Fanyan Luo
- Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
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14
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Wu J, Cui Y, Ding W, Zhang J, Wang L. The protective effect of Macrostemonoside T from Allium macrostemon Bunge against Isoproterenol-Induced myocardial injury via the PI3K/Akt/mTOR signaling pathway. Int Immunopharmacol 2024; 133:112086. [PMID: 38642441 DOI: 10.1016/j.intimp.2024.112086] [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: 02/27/2024] [Revised: 03/31/2024] [Accepted: 04/10/2024] [Indexed: 04/22/2024]
Abstract
Myocardial injury (MI) signifies a pathological aspect of cardiovascular diseases (CVDs) such as coronary artery disease, diabetic cardiomyopathy, and myocarditis. Macrostemonoside T (MST) has been isolated from Allium macrostemon Bunge (AMB), a key traditional Chinese medicine (TCM) used for treating chest stuffiness and pains. Although MST has demonstrated considerable antioxidant activity in vitro, its protective effect against MI remains unexplored. To investigate MST's effects in both in vivo and in vitro models of isoproterenol (ISO)-induced MI and elucidate its underlying molecular mechanisms. This study established an ISO-induced MI model in rats and assessed H9c2 cytotoxicity to examine MST's impact on MI. Various assays, including histopathological staining, TUNEL staining, immunohistochemical staining, DCFH-DA staining, JC-1 staining, ELISA technique, and Western blot (WB), were utilized to explore the potential molecular mechanisms of MI protection. In vivo experiments demonstrated that ISO caused myocardial fiber disorders, elevated cardiac enzyme levels, and apoptosis. However, pretreatment with MST significantly mitigated these detrimental changes. In vitro experiments revealed that MST boosted antioxidant enzyme levels and suppressed malondialdehyde (MDA) production in H9c2 cells. Concurrently, MST inhibited ISO-induced reactive oxygen species (ROS) production and mitigated the decline in mitochondrial membrane potential, thereby reducing the apoptosis rate. Moreover, pretreatment with MST elevated the expression levels of p-PI3K, p-Akt, and p-mTOR, indicating activation of the PI3K/Akt/mTOR signaling pathway and consequent protection against MI. MST attenuated ISO-induced MI in rats by impeding apoptosis through activation of the PI3K/Akt/mTOR signaling pathway. This study presents potential avenues for the development of precursor drugs for CVDs.
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Affiliation(s)
- Jianfa Wu
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Ying Cui
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Weixing Ding
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Jing Zhang
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
| | - Lulu Wang
- School of Medicine, Changchun Sci-Tech University, Changchun 130600, China.
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15
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Lysikova T, Tomascova A, Kovalska M, Lehotsky J, Leskova Majdova K, Kaplan P, Tatarkova Z. Dynamics in Redox-Active Molecules Following Ischemic Preconditioning in the Brain. Neurol Int 2024; 16:533-550. [PMID: 38804479 PMCID: PMC11130914 DOI: 10.3390/neurolint16030040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/28/2024] [Accepted: 05/06/2024] [Indexed: 05/29/2024] Open
Abstract
It is well known that the brain is quite vulnerable to oxidative stress, initiating neuronal loss after ischemia-reperfusion (IR) injury. A potent protective mechanism is ischemic preconditioning (IPC), where proteins are among the primary targets. This study explores redox-active proteins' role in preserving energy supply. Adult rats were divided into the control, IR, and IPC groups. Protein profiling was conducted to identify modified proteins and then verified through activity assays, immunoblot, and immunohistochemical analyses. IPC protected cortex mitochondria, as evidenced by a 2.26-fold increase in superoxide dismutase (SOD) activity. Additionally, stable core subunits of respiratory chain complexes ensured sufficient energy production, supported by a 16.6% increase in ATP synthase activity. In hippocampal cells, IPC led to the downregulation of energy-related dehydrogenases, while a significantly higher level of peroxiredoxin 6 (PRX6) was observed. Notably, IPC significantly enhanced glutathione reductase activity to provide sufficient glutathione to maintain PRX6 function. Astrocytes may mobilize PRX6 to protect neurons during initial ischemic events, by decreased PRX6 positivity in astrocytes, accompanied by an increase in neurons following both IR injury and IPC. Maintained redox signaling via astrocyte-neuron communication triggers IPC's protective state. The partnership among PRX6, SOD, and glutathione reductase appears essential in safeguarding and stabilizing the hippocampus.
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Affiliation(s)
- Terezia Lysikova
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia; (T.L.); (A.T.); (J.L.); (K.L.M.); (P.K.)
| | - Anna Tomascova
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia; (T.L.); (A.T.); (J.L.); (K.L.M.); (P.K.)
| | - Maria Kovalska
- Department of Histology and Embryology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Jan Lehotsky
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia; (T.L.); (A.T.); (J.L.); (K.L.M.); (P.K.)
| | - Katarina Leskova Majdova
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia; (T.L.); (A.T.); (J.L.); (K.L.M.); (P.K.)
| | - Peter Kaplan
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia; (T.L.); (A.T.); (J.L.); (K.L.M.); (P.K.)
| | - Zuzana Tatarkova
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia; (T.L.); (A.T.); (J.L.); (K.L.M.); (P.K.)
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16
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Li T, Li Y, Zeng Y, Zhou X, Zhang S, Ren Y. Construction of preclinical evidence for propofol in the treatment of reperfusion injury after acute myocardial infarction: A systematic review and meta-analysis. Biomed Pharmacother 2024; 174:116629. [PMID: 38640712 DOI: 10.1016/j.biopha.2024.116629] [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: 01/17/2024] [Revised: 04/04/2024] [Accepted: 04/17/2024] [Indexed: 04/21/2024] Open
Abstract
Propofol, a commonly used intravenous anesthetic, has demonstrated potential in protecting against myocardial ischemia/reperfusion injury (MIRI) based on preclinical animal studies. However, the clinical benefits of propofol in this context are subject to debate. We conducted a systematic search across eight databases to identify all relevant animal studies investigating the preventive effects of propofol on MIRI until October 30, 2023. We assessed the methodological quality of the included studies using SYRCLE's bias risk tool. Statistical analysis was performed using STATA 15.1. The primary outcome measures analyzed in this study were myocardial infarct size (IS) and myocardial injury biomarkers. This study presents a comprehensive analysis of 48 relevant animal studies investigating propofol's preventive effects on MIRI. Propofol administration demonstrated a reduction in myocardial IS and decreased levels of myocardial injury biomarkers (CK-MB, LDH, cTnI). Moreover, propofol improved myocardial function parameters (+dp/dtmax, -dP/dtmax, LVEF, LVFS), exhibited favorable effects on inflammatory markers (IL-6, TNF-α) and oxidative stress markers (SOD, MDA), and reduced myocardial cell apoptotic index (AI). These findings suggest propofol exerts cardioprotective effects by reducing myocardial injury, decreasing infarct size, and improving heart function. However, the absence of animal models that accurately represent comorbidities such as aging and hypertension, as well as inconsistent administration methods that align with clinical practice, may hinder its clinical translation. Further robust investigations are required to validate these findings, elucidate the underlying mechanisms of propofol, and facilitate its potential translation into clinical practice.
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Affiliation(s)
- Tao Li
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanwei Li
- Cardiology Department, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiwei Zeng
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xin Zhou
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Su Zhang
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yulan Ren
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China; School of Chinese Classics, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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17
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Oskuye ZZ, Mehri K, Mokhtari B, Bafadam S, Nemati S, Badalzadeh R. Cardioprotective effect of antioxidant combination therapy: A highlight on MitoQ plus alpha-lipoic acid beneficial impact on myocardial ischemia-reperfusion injury in aged rats. Heliyon 2024; 10:e28158. [PMID: 38524576 PMCID: PMC10957437 DOI: 10.1016/j.heliyon.2024.e28158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 03/26/2024] Open
Abstract
Objective (s): Considering the poor prognosis of ischemic heart disease and the diminished effectiveness of cardioprotective interventions in the elderly, it becomes necessary to investigate the interaction of aging with protection during myocardial ischemia/reperfusion injury (IRI). This study was conducted to assess the impact of mitoquinone (MitoQ) and alpha-lipoic acid (ALA) preconditioning on cardioprotection following IRI in aged rats. Methods Fifty aged male Wistar rats (22-24 months old) were divided into five groups including Sham, IR, and treatment groups receiving ALA and/or MitoQ. Treatment groups were received 100 mg/kg/day ALA by oral gavage and/or 10 mg/kg/day MitoQ by intraperitoneal injection for 14 consecutive days. An in vivo model of myocardial IRI was established through ligation of coronary artery for 30 min and it's reopening for 24 h. The left ventricles were removed at the end of reperfusion to assess oxidative stress indicators, mitochondrial function, and expression of mitochondrial dynamic genes. Myocardial infarct size (IS), hemodynamic parameters, and serum lactate dehydrogenase (LDH) level were also measured. Results Combination of MitoQ and ALA reduced oxidative stress, LDH level, and IS in aged hearts subjected to IRI. It also enhanced mitochondrial function and upregulated Mfn1, Mfn2, and Foxo1 and downregulated Drp1 and Fis1 gene expression. Co-administration of MitoQ and ALA partially restored IRI-induced hemodynamic changes to normal state. In all measured parameters, the effect of combined treatment was greater than monotherapies. Conclusion The combination therapy of MitoQ and ALA demonstrated considerable therapeutic potential in protecting the aging heart against IRI by improving oxidative stress, mitochondrial function, and dynamics in aged rats.
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Affiliation(s)
- Zohreh Zavvari Oskuye
- Drug Applied Research Center, Tabriz University of Medical Sciences, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Iran
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
| | - Keyvan Mehri
- Student Research Committee, Tabriz University of Medical Sciences, Iran
| | - Behnaz Mokhtari
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Iran
| | - Soleyman Bafadam
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Iran
| | - Samira Nemati
- Physiology Research Center, Semnan University of Medical Sciences, Iran
| | - Reza Badalzadeh
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Iran
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18
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Patanè GT, Putaggio S, Tellone E, Barreca D, Ficarra S, Maffei C, Calderaro A, Laganà G. Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds. Int J Mol Sci 2023; 24:17279. [PMID: 38139106 PMCID: PMC10744228 DOI: 10.3390/ijms242417279] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/01/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Ferroptosis is a form of cell death that is distinguished from other types of death for its peculiar characteristics of death regulated by iron accumulation, increase in ROS, and lipid peroxidation. In the past few years, experimental evidence has correlated ferroptosis with various pathological processes including neurodegenerative and cardiovascular diseases. Ferroptosis also is involved in several types of cancer because it has been shown to induce tumor cell death. In particular, the pharmacological induction of ferroptosis, contributing to the inhibition of the proliferative process, provides new ideas for the pharmacological treatment of cancer. Emerging evidence suggests that certain mechanisms including the Xc- system, GPx4, and iron chelators play a key role in the regulation of ferroptosis and can be used to block the progression of many diseases. This review summarizes current knowledge on the mechanism of ferroptosis and the latest advances in its multiple regulatory pathways, underlining ferroptosis' involvement in the diseases. Finally, we focused on several types of ferroptosis inducers and inhibitors, evaluating their impact on the cell death principal targets to provide new perspectives in the treatment of the diseases and a potential pharmacological development of new clinical therapies.
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Affiliation(s)
| | - Stefano Putaggio
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy; (G.T.P.); (D.B.); (S.F.); (C.M.); (A.C.); (G.L.)
| | - Ester Tellone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy; (G.T.P.); (D.B.); (S.F.); (C.M.); (A.C.); (G.L.)
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19
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Stephan D, Blatt S, Riedel J, Mohnke K, Ruemmler R, Ziebart A, Al-Nawas B, Kämmerer PW, Thiem DGE. The Impact of Transfer-Related Ischemia on Free Flap Metabolism and Electrolyte Homeostasis-A New In Vivo Experimental Approach in Pigs. J Clin Med 2023; 12:6625. [PMID: 37892763 PMCID: PMC10607031 DOI: 10.3390/jcm12206625] [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: 09/17/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Free flap tissue transfer represents the gold standard for extensive defect reconstruction, although malperfusion due to thrombosis remains the leading risk factor for flap failure. Recent studies indicate an increased immune response and platelet activation in connection with pathologic coagulation. The underlying cellular and molecular mechanisms remain poorly understood, however. The presented study, therefore, aims to investigate if transfer-related ischemia alters intra-flap metabolism and electrolyte concentrations compared to central venous blood after free flap transfer in pigs to establish a novel experimental model. Free transfer of a myocutaneous gracilis flap to the axillary region was conducted in five juvenile male pigs. The flap artery was anastomosed to the axillary artery, and intra-flap venous blood was drained and transfused using a rubber-elastic fixed intravenous catheter. Blood gas analysis was performed to assess the effect of transfer time-induced ischemia on intra-flap electrolyte levels, acid-base balance, and hemoglobin concentrations compared to central venous blood. Time to flap reperfusion was 52 ± 10 min on average, resulting in a continuous pH drop (acidosis) in the flaps' venous blood compared to the central venous system (p = 0.037). Potassium (p = 0.016), sodium (p = 0.003), and chloride (p = 0.007) concentrations were significantly increased, whereas bicarbonate (p = 0.016) and calcium (p = 0.008) significantly decreased within the flap. These observations demonstrate the induction of anaerobic glycolysis and electrolyte displacement resulting in acidosis and hence significant tissue damage already after a short ischemic period, thereby validating the novel animal model for investigating intra-flap metabolism and offering opportunities for exploring various (immuno-) thrombo-hemostatic issues in transplantation surgery.
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Affiliation(s)
- Daniel Stephan
- Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University Medical Centre, Johannes Gutenberg University Mainz, Augustusplatz 2, 55131 Mainz, Germany; (S.B.); (B.A.-N.); (P.W.K.); (D.G.E.T.)
| | - Sebastian Blatt
- Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University Medical Centre, Johannes Gutenberg University Mainz, Augustusplatz 2, 55131 Mainz, Germany; (S.B.); (B.A.-N.); (P.W.K.); (D.G.E.T.)
| | - Julian Riedel
- Department of Anaesthesiology, University Medical Centre, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (J.R.); (K.M.); (R.R.); (A.Z.)
| | - Katja Mohnke
- Department of Anaesthesiology, University Medical Centre, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (J.R.); (K.M.); (R.R.); (A.Z.)
| | - Robert Ruemmler
- Department of Anaesthesiology, University Medical Centre, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (J.R.); (K.M.); (R.R.); (A.Z.)
| | - Alexander Ziebart
- Department of Anaesthesiology, University Medical Centre, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (J.R.); (K.M.); (R.R.); (A.Z.)
| | - Bilal Al-Nawas
- Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University Medical Centre, Johannes Gutenberg University Mainz, Augustusplatz 2, 55131 Mainz, Germany; (S.B.); (B.A.-N.); (P.W.K.); (D.G.E.T.)
| | - Peer W. Kämmerer
- Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University Medical Centre, Johannes Gutenberg University Mainz, Augustusplatz 2, 55131 Mainz, Germany; (S.B.); (B.A.-N.); (P.W.K.); (D.G.E.T.)
| | - Daniel G. E. Thiem
- Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University Medical Centre, Johannes Gutenberg University Mainz, Augustusplatz 2, 55131 Mainz, Germany; (S.B.); (B.A.-N.); (P.W.K.); (D.G.E.T.)
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20
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Ouhaddi Y, Dalisson B, Rastinfard A, Gilardino M, Watters K, Job D, Azizi-Mehr P, Merle G, Lasagabaster AV, Barralet J. Necrosis reduction efficacy of subdermal biomaterial mediated oxygen delivery in ischemic skin flaps. BIOMATERIALS ADVANCES 2023; 153:213519. [PMID: 37392519 DOI: 10.1016/j.bioadv.2023.213519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/24/2023] [Accepted: 06/10/2023] [Indexed: 07/03/2023]
Abstract
Inadequate tissue blood supply as may be found in a wound or a poorly vascularised graft, can result in tissue ischemia and necrosis. As revascularization is a slow process relative to the proliferation of bacteria and the onset of tissue necrosis, extensive tissue damage and loss can occur before healing is underway. Necrosis can develop rapidly, and treatment options are limited such that loss of tissue following necrosis onset is considered unavoidable and irreversible. Oxygen delivery from biomaterials exploiting aqueous decomposition of peroxy-compounds has shown some potential in overcoming the supply limitations by creating oxygen concentration gradients higher than can be attained physiologically or by air saturated solutions. We sought to test whether subdermal oxygen delivery from a material composite that was buffered and contained a catalyst, to reduce hydrogen peroxide release, could ameliorate necrosis in a 9 × 2 cm flap in a rat model that reliably underwent 40 % necrosis if untreated. Blood flow in this flap reduced from near normal to essentially zero, along its 9 cm length and subdermal perforator vessel anastomosis was physically prevented by placement of a polymer sheet. In the middle, low blood flow region of the flap, treatment significantly reduced necrosis based on measurements from photographs and histological micrographs. No change was observed in blood vessel density but significant differences in HIF1-α, inducible nitric oxide synthase and liver arginase were observed with oxygen delivery.
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Affiliation(s)
- Yassine Ouhaddi
- Division of Orthopaedics, Department of Surgery, Faculty of Medicine and Health Sciences, Montreal General Hospital, Montreal, QC H3G 1A4, Canada
| | - Benjamin Dalisson
- Faculty of Dentistry, McGill University, 2001 McGill College Avenue, Montreal, QC, H3A 1G1, Canada
| | - Arghavan Rastinfard
- Division of Orthopaedics, Department of Surgery, Faculty of Medicine and Health Sciences, Montreal General Hospital, Montreal, QC H3G 1A4, Canada
| | - Mirko Gilardino
- Division of Pastic and Reconstructive Surgery, Department of Surgery, Montreal General Hospital, Montreal, QC H3G 1A4, Canada
| | - Kevin Watters
- Department of Pathology, Glen Site, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada
| | - Dario Job
- Division of Orthopaedics, Department of Surgery, Faculty of Medicine and Health Sciences, Montreal General Hospital, Montreal, QC H3G 1A4, Canada
| | - Parsa Azizi-Mehr
- Division of Orthopaedics, Department of Surgery, Faculty of Medicine and Health Sciences, Montreal General Hospital, Montreal, QC H3G 1A4, Canada
| | - Geraldine Merle
- Division of Orthopaedics, Department of Surgery, Faculty of Medicine and Health Sciences, Montreal General Hospital, Montreal, QC H3G 1A4, Canada
| | - Arturo Vela Lasagabaster
- Division of Pastic and Reconstructive Surgery, Department of Surgery, Montreal General Hospital, Montreal, QC H3G 1A4, Canada
| | - Jake Barralet
- Division of Orthopaedics, Department of Surgery, Faculty of Medicine and Health Sciences, Montreal General Hospital, Montreal, QC H3G 1A4, Canada; Faculty of Dentistry, McGill University, 2001 McGill College Avenue, Montreal, QC, H3A 1G1, Canada.
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21
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Pooth JS, Liu Y, Petzold R, Scherer C, Benning L, Kreibich M, Czerny M, Beyersdorf F, Benk C, Trummer G, Brixius SJ. Effects of Prolonged Serum Calcium Suppression during Extracorporeal Cardiopulmonary Resuscitation in Pigs. Biomedicines 2023; 11:2612. [PMID: 37892986 PMCID: PMC10604109 DOI: 10.3390/biomedicines11102612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 09/18/2023] [Accepted: 09/22/2023] [Indexed: 10/29/2023] Open
Abstract
Controlled reperfusion by monitoring the blood pressure, blood flow, and specific blood parameters during extracorporeal reperfusion after cardiac arrest has the potential to limit ischemia-reperfusion injury. The intracellular calcium overload as part of the ischemia-reperfusion injury provides the possibility for the injury to be counteracted by the early suppression of serum calcium with the aim of improving survival and the neurological outcome. We investigated the effects of prolonged serum calcium suppression via sodium citrate during extracorporeal resuscitation using the CARL protocol (CARL-controlled automated reperfusion of the whole body) compared to a single-dose approach in a porcine model after prolonged cardiac arrest. A control group (N = 10) was resuscitated after a 20 min cardiac arrest, initially lowering the intravascular calcium with the help of a single dose of sodium citrate as part of the priming solution. Animals in the intervention group (N = 13) received additional sodium citrate for the first 15 min of reperfusion. In the control group, 9/10 (90.0%) animals survived until day 7 and 7/13 (53.8%) survived in the intervention group (p = 0.09). A favorable neurological outcome on day 7 after the cardiac arrest was observed in all the surviving animals using a species-specific neurological deficit score. The coronary perfusion pressure was significantly lower with a tendency towards more cardiac arrhythmias in the intervention group. In conclusion, a prolonged reduction in serum calcium levels over the first 15 min of reperfusion after prolonged cardiac arrest tended to be unfavorable regarding survival and hemodynamic variables compared to a single-dose approach in this animal model.
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Affiliation(s)
- Jan-Steffen Pooth
- Department of Emergency Medicine, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (J.-S.P.); (R.P.); (L.B.)
| | - Yechi Liu
- Department of Cardiovascular Surgery, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (Y.L.); (C.S.); (M.K.); (M.C.); (F.B.); (C.B.); (G.T.)
| | - Ralf Petzold
- Department of Emergency Medicine, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (J.-S.P.); (R.P.); (L.B.)
| | - Christian Scherer
- Department of Cardiovascular Surgery, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (Y.L.); (C.S.); (M.K.); (M.C.); (F.B.); (C.B.); (G.T.)
| | - Leo Benning
- Department of Emergency Medicine, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (J.-S.P.); (R.P.); (L.B.)
| | - Maximilian Kreibich
- Department of Cardiovascular Surgery, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (Y.L.); (C.S.); (M.K.); (M.C.); (F.B.); (C.B.); (G.T.)
| | - Martin Czerny
- Department of Cardiovascular Surgery, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (Y.L.); (C.S.); (M.K.); (M.C.); (F.B.); (C.B.); (G.T.)
| | - Friedhelm Beyersdorf
- Department of Cardiovascular Surgery, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (Y.L.); (C.S.); (M.K.); (M.C.); (F.B.); (C.B.); (G.T.)
| | - Christoph Benk
- Department of Cardiovascular Surgery, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (Y.L.); (C.S.); (M.K.); (M.C.); (F.B.); (C.B.); (G.T.)
| | - Georg Trummer
- Department of Cardiovascular Surgery, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (Y.L.); (C.S.); (M.K.); (M.C.); (F.B.); (C.B.); (G.T.)
| | - Sam Joé Brixius
- Department of Cardiovascular Surgery, Faculty of Medicine, University Medical Centre Freiburg, University of Freiburg, 79106 Freiburg, Germany; (Y.L.); (C.S.); (M.K.); (M.C.); (F.B.); (C.B.); (G.T.)
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22
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Liu Y, Gong JS, Marshall G, Su C, Shi JS, Xu ZH. Technology and functional insights into the nicotinamide mononucleotide for human health. Appl Microbiol Biotechnol 2023:10.1007/s00253-023-12612-2. [PMID: 37347262 DOI: 10.1007/s00253-023-12612-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/23/2023]
Abstract
Nicotinamide mononucleotide (NMN), a naturally occurring biologically active nucleotide, mainly functions via mediating the biosynthesis of NAD+. In recent years, its excellent pharmacological activities including anti-aging, treating neurodegenerative diseases, and protecting the heart have attracted increasing attention from scholars and entrepreneurs for production of a wide range of formulations, including functional food ingredients, health care products, active pharmaceuticals, and pharmaceutical intermediates. Presently, the synthesis methods of NMN mainly include two categories: chemical synthesis and biosynthesis. With the development of biocatalyst engineering and synthetic biology strategies, bio-preparation has proven to be efficient, economical, and sustainable methods. This review summarizes the chemical synthesis and biosynthetic pathways of NMN and provides an in-depth investigation on the mining and modification of enzyme resources during NMN biosynthesis, as well as the screening of hosts and optimization of chassis cells via metabolic engineering, which provide effective strategies for efficient production of NMN. In addition, an overview of the significant physiological functions and activities of NMN is elaborated. Finally, future research on technical approaches to further enhance NMN synthesis and strengthen clinical studies of NMN are prospected, which would lay the foundation for further promoting the application of NMN in nutrition, healthy food, and medicine in the future. KEY POINTS: • NMN supplementation effectively increases the level of NAD+. • The chemical and biological synthesis of NMN are comprehensively reviewed. • The impact of NMN on the treatment of various diseases is summarized.
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Affiliation(s)
- Ye Liu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, People's Republic of China
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, School of Biotechnology, Jiangnan University, Wuxi, 214122, People's Republic of China
- Yixing Institute of Food and Biotechnology Co., Ltd., Yixing, 214200, People's Republic of China
| | - Jin-Song Gong
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, People's Republic of China.
| | - George Marshall
- Seragon Biosciences, Inc., 400 Spectrum Center Drive, 16th Floor, Irvine, CA, 92618, USA
| | - Chang Su
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, People's Republic of China
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, School of Biotechnology, Jiangnan University, Wuxi, 214122, People's Republic of China
| | - Jin-Song Shi
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, People's Republic of China
| | - Zheng-Hong Xu
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, School of Biotechnology, Jiangnan University, Wuxi, 214122, People's Republic of China
- Yixing Institute of Food and Biotechnology Co., Ltd., Yixing, 214200, People's Republic of China
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23
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Ohla J, Wiciński M, Słupski M, Zabrzyński J, Malinowski B. Cyclic AMP but Not Calmodulin as a Potential Wasoconstrictor in Simulated Reperfusion. Int J Mol Sci 2023; 24:10355. [PMID: 37373502 DOI: 10.3390/ijms241210355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
The phenomena of ischemia and reperfusion are associated with the pathological background of cardiovascular diseases. Ischemia is initiated by ischemia reperfusion injury (IRI), which involves disruption of intracellular signaling pathways and causes cell death. The aim of this study was to assess the reactivity of vascular smooth muscle cells in the conditions of induced ischemia and reperfusion, and to determine the mechanisms leading to contractility disorders. This study was conducted using classical pharmacometric methods on an isolated model of the rat caudal artery. The experiment consisted of the analysis of the final and initial perfusate pressure measurements after induction of arterial contraction with phenylephrine in the presence of forskolin and A7 hydrochloride, two ligands modifying the contractility of vascular smooth muscle cells (VSMC). The pharmacometric analysis showed that in simulated reperfusion, cyclic nucleotides have a vasoconstrictive effect, and calmodulin has a vasodilating effect. The responsiveness of vascular smooth muscle cells to the vasopressor effects of α1-adrenomimetics during reperfusion may change uncontrollably, and the effects of secondary messengers may be counter physiological. Further studies are needed to evaluate the function of other second messengers on VSMCs in the process of ischemia and reperfusion.
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Affiliation(s)
- Jakub Ohla
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-090 Bydgoszcz, Poland
| | - Michał Wiciński
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-090 Bydgoszcz, Poland
| | - Maciej Słupski
- Department of Hepatobiliary and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-090 Bydgoszcz, Poland
| | - Jan Zabrzyński
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-090 Bydgoszcz, Poland
| | - Bartosz Malinowski
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-090 Bydgoszcz, Poland
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24
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Husková Z, Kikerlová S, Miklovič M, Kala P, Papoušek F, Neckář J. Inappropriate activation of the renin-angiotensin system improves cardiac tolerance to ischemia/reperfusion injury in rats with late angiotensin II-dependent hypertension. Front Physiol 2023; 14:1151308. [PMID: 37389123 PMCID: PMC10301744 DOI: 10.3389/fphys.2023.1151308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 06/05/2023] [Indexed: 07/01/2023] Open
Abstract
The aim of the study was to clarify the role of the interplay between hypertension and the renin-angiotensin system (RAS) in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. We hypothesized that in the late phase of hypertension with already developed signs of end-organ damage, inappropriate RAS activation could impair cardiac tolerance to I/R injury. Experiments were performed in male Cyp1a1-Ren-2 transgenic rats with inducible hypertension. The early phase of ANG II-dependent hypertension was induced by 5 days and the late phase by the 13 days dietary indole-3-carbinol (I3C) administration. Noninduced rats served as controls. Echocardiography and pressure-volume analysis were performed, angiotensins' levels were measured and cardiac tolerance to ischemia/reperfusion injury was studied. The infarct size was significantly reduced (by 50%) in 13 days I3C-induced hypertensive rats with marked cardiac hypertrophy, this reduction was abolished by losartan treatment. In the late phase of hypertension there are indications of a failing heart, mainly in reduced preload recruitable stroke work (PRSW), but only nonsignificant trends in worsening of some other parameters, showing that the myocardium is in a compensated phase. The influence of the RAS depends on the balance between the vasoconstrictive and the opposed vasodilatory axis. In the initial stage of hypertension, the vasodilatory axis of the RAS prevails, and with the development of hypertension the vasoconstrictive axis of the RAS becomes stronger. We observed a clear effect of AT1 receptor blockade on maximum pressure in left ventricle, cardiac hypertrophy and ANG II levels. In conclusion, we confirmed improved cardiac tolerance to I/R injury in hypertensive hypertrophied rats and showed that, in the late phase of hypertension, the myocardium is in a compensated phase.
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Affiliation(s)
- Zuzana Husková
- Center of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Soňa Kikerlová
- Center of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Matúš Miklovič
- Center of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
- Department of Pathophysiology, 2nd Faculty of Medicine, Charles University, Prague, Czechia
| | - Petr Kala
- Center of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
- Department of Cardiology, 2nd Medical Faculty, Charles University and University Hospital Motol, Prague, Czechia
| | - František Papoušek
- Laboratory of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia
| | - Jan Neckář
- Center of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
- Laboratory of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic (ASCR), Prague, Czechia
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25
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Cao Y, Redd MA, Fang C, Mizikovsky D, Li X, Macdonald PS, King GF, Palpant NJ. New Drug Targets and Preclinical Modelling Recommendations for Treating Acute Myocardial Infarction. Heart Lung Circ 2023:S1443-9506(23)00139-7. [PMID: 37230806 DOI: 10.1016/j.hlc.2022.12.015] [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: 09/05/2022] [Revised: 11/28/2022] [Accepted: 12/15/2022] [Indexed: 05/27/2023]
Abstract
Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide and the primary underlying risk factor for heart failure. Despite decades of research and clinical trials, there are no drugs currently available to prevent organ damage from acute ischaemic injuries of the heart. In order to address the increasing global burden of heart failure, drug, gene, and cell-based regeneration technologies are advancing into clinical testing. In this review we highlight the burden of disease associated with AMI and the therapeutic landscape based on market analyses. New studies revealing the role of acid-sensitive cardiac ion channels and other proton-gated ion channels in cardiac ischaemia are providing renewed interest in pre- and post-conditioning agents with novel mechanisms of action that may also have implications for gene- and cell-based therapeutics. Furthermore, we present guidelines that couple new cell technologies and data resources with traditional animal modelling pipelines to help de-risk drug candidates aimed at treating AMI. We propose that improved preclinical pipelines and increased investment in drug target identification for AMI is critical to stem the increasing global health burden of heart failure.
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Affiliation(s)
- Yuanzhao Cao
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia
| | - Meredith A Redd
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia
| | - Chen Fang
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia
| | - Dalia Mizikovsky
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia
| | - Xichun Li
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia
| | - Peter S Macdonald
- Cardiopulmonary Transplant Unit, St Vincent's Hospital, Sydney, NSW, Australia
| | - Glenn F King
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Qld, Australia
| | - Nathan J Palpant
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia.
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26
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Jones IC, Dass CR. Roles of pigment epithelium-derived factor in cardiomyocytes: implications for use as a cardioprotective therapeutic. J Pharm Pharmacol 2023:7146108. [PMID: 37104852 DOI: 10.1093/jpp/rgad037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 04/12/2023] [Indexed: 04/29/2023]
Abstract
OBJECTIVES Cardiovascular diseases are the leading cause of death worldwide, with patients having limited options for treatment. Pigment epithelium-derived factor (PEDF) is an endogenous multifunctional protein with several mechanisms of action. Recently, PEDF has emerged as a potential cardioprotective agent in response to myocardial infarction. However, PEDF is also associated with pro-apoptotic effects, complicating its role in cardioprotection. This review summarises and compares knowledge of PEDF's activity in cardiomyocytes with other cell types and draws links between them. Following this, the review offers a novel perspective of PEDF's therapeutic potential and recommends future directions to understand the clinical potential of PEDF better. KEY FINDINGS PEDF's mechanisms as a pro-apoptotic and pro-survival protein are not well understood, despite PEDF's implication in several physiological and pathological activities. However, recent evidence suggests that PEDF may have significant cardioprotective properties mediated by key regulators dependent on cell type and context. CONCLUSIONS While PEDF's cardioprotective activity shares some key regulators with its apoptotic activity, cellular context and molecular features likely allow manipulation of PEDF's cellular activity, highlighting the importance of further investigation into its activities and its potential to be applied as a therapeutic to mitigate damage from a range of cardiac pathologies.
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Affiliation(s)
- Isobel C Jones
- Curtin Medical School, Curtin University, Bentley, Australia
- Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia
| | - Crispin R Dass
- Curtin Medical School, Curtin University, Bentley, Australia
- Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia
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27
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Mandel IA, Podoksenov YK, Mikheev SL, Suhodolo IV, Svirko YS, Shipulin VM, Ivanova AV, Yavorovskiy AG, Yaroshetskiy AI. Endothelial Function and Hypoxic–Hyperoxic Preconditioning in Coronary Surgery with a Cardiopulmonary Bypass: Randomized Clinical Trial. Biomedicines 2023; 11:biomedicines11041044. [PMID: 37189663 DOI: 10.3390/biomedicines11041044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 03/31/2023] Open
Abstract
A hypoxic–hyperoxic preconditioning (HHP) may be associated with cardioprotection by reducing endothelial damage and a beneficial effect on postoperative outcome in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Patients (n = 120) were randomly assigned to an HHP and a control group. A safe, inhaled oxygen fraction for the hypoxic preconditioning phase (10–14% oxygen for 10 min) was determined by measuring the anaerobic threshold. At the hyperoxic phase, a 75–80% oxygen fraction was used for 30 min. The cumulative frequency of postoperative complications was 14 (23.3%) in the HHP vs. 23 (41.1%), p = 0.041. The nitrate decreased after surgery by up to 20% in the HHP group and up to 38% in the control group. Endothelin-1 and nitric oxide metabolites were stable in HHP but remained low for more than 24 h in the control group. The endothelial damage markers appeared to be predictors of postoperative complications. The HHP with individual parameters based on the anaerobic threshold is a safe procedure, and it can reduce the frequency of postoperative complications. The endothelial damage markers appeared to be predictors of postoperative complications.
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28
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Wagner MJ, Hatami S, Freed DH. Thoracic organ machine perfusion: A review of concepts with a focus on reconditioning therapies. FRONTIERS IN TRANSPLANTATION 2023; 2:1060992. [PMID: 38993918 PMCID: PMC11235380 DOI: 10.3389/frtra.2023.1060992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 02/06/2023] [Indexed: 07/13/2024]
Abstract
Thoracic organ transplantation, including lung, heart, and heart-lung transplants are highly regarded as gold standard treatments for patients suffering from heart failure or chronic end stage lung conditions. The relatively high prevalence of conditions necessitating thoracic organ transplants combined with the lack of available organs has resulted in many either dying or becoming too ill to receive a transplant while on the waiting list. There is a dire need to increase both the number of organs available and the utilization of such organs. Improved preservation techniques beyond static storage have shown great potential to lengthen the current period of viability of thoracic organs while outside the body, promising better utilization rates, increased donation distance, and improved matching of donors to recipients. Ex-situ organ perfusion (ESOP) can also make some novel therapeutic strategies viable, and the combination of the ESOP platform with such reconditioning therapies endeavors to better improve functional preservation of organs in addition to making more organs viable for transplantation. Given the abundance of clinical and pre-clinical studies surrounding reconditioning of thoracic organs in combination with ESOP, we summarize in this review important concepts and research regarding thoracic organ machine perfusion in combination with reconditioning therapies.
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Affiliation(s)
| | - Sanaz Hatami
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Darren H Freed
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Department of Physiology, University of Alberta, Edmonton, AB, Canada
- Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada
- Alberta Transplant Institute, Edmonton, AB, Canada
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29
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Zhao N, Gao Y, Jia H, Jiang X. Anti-apoptosis effect of traditional Chinese medicine in the treatment of cerebral ischemia-reperfusion injury. Apoptosis 2023; 28:702-729. [PMID: 36892639 DOI: 10.1007/s10495-023-01824-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2023] [Indexed: 03/10/2023]
Abstract
Cerebral ischemia, one of the leading causes of neurological dysfunction of brain cells, muscle dysfunction, and death, brings great harm and challenges to individual health, families, and society. Blood flow disruption causes decreased glucose and oxygen, insufficient to maintain normal brain tissue metabolism, resulting in intracellular calcium overload, oxidative stress, neurotoxicity of excitatory amino acids, and inflammation, ultimately leading to neuronal cell necrosis, apoptosis, or neurological abnormalities. This paper summarizes the specific mechanism of cell injury that apoptosis triggered by reperfusion after cerebral ischemia, the related proteins involved in apoptosis, and the experimental progress of herbal medicine treatment through searching, analyzing, and summarizing the PubMed and Web Of Science databases, which includes active ingredients of herbal medicine, prescriptions, Chinese patent medicines, and herbal extracts, providing a new target or new strategy for drug treatment, and providing a reference for future experimental directions and using them to develop suitable small molecule drugs for clinical application. With the research of anti-apoptosis as the core, it is important to find highly effective, low toxicity, safe and cheap compounds from natural plants and animals with abundant resources to prevent and treat Cerebral ischemia/reperfusion (I/R) injury (CIR) and solve human suffering. In addition, understanding and summarizing the apoptotic mechanism of cerebral ischemia-reperfusion injury, the microscopic mechanism of CIR treatment, and the cellular pathways involved will help to develop new drugs.
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Affiliation(s)
- Nan Zhao
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Yuhe Gao
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Hongtao Jia
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Xicheng Jiang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China.
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30
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Pre-Treatment of Transplant Donors with Hydrogen Sulfide to Protect against Warm and Cold Ischemia-Reperfusion Injury in Kidney and Other Transplantable Solid Organs. Int J Mol Sci 2023; 24:ijms24043518. [PMID: 36834928 PMCID: PMC9963309 DOI: 10.3390/ijms24043518] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/01/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Ischemia-reperfusion injury (IRI), a pathological condition resulting from prolonged cessation and subsequent restoration of blood flow to a tissue, is an inevitable consequence of solid organ transplantation. Current organ preservation strategies, such as static cold storage (SCS), are aimed at reducing IRI. However, prolonged SCS exacerbates IRI. Recent research has examined pre-treatment approaches to more effectively attenuate IRI. Hydrogen sulfide (H2S), the third established member of a family of gaseous signaling molecules, has been shown to target the pathophysiology of IRI and thus appears to be a viable candidate that can overcome the transplant surgeon's enemy. This review discusses pre-treatment of renal grafts and other transplantable organs with H2S to mitigate transplantation-induced IRI in animal models of transplantation. In addition, ethical principles of pre-treatment and potential applications of H2S pre-treatment in the prevention of other IRI-associated conditions are discussed.
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Eastin TM, Dye JA, Pillai P, Lopez-Gonzalez MA, Huang L, Zhang JH, Boling WW. Delayed revascularization in acute ischemic stroke patients. Front Pharmacol 2023; 14:1124263. [PMID: 36843940 PMCID: PMC9945110 DOI: 10.3389/fphar.2023.1124263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Stroke shares a significant burden of global mortality and disability. A significant decline in the quality of life is attributed to the so-called post-stroke cognitive impairment including mild to severe cognitive alterations, dementia, and functional disability. Currently, only two clinical interventions including pharmacological and mechanical thrombolysis are advised for successful revascularization of the occluded vessel. However, their therapeutic effect is limited to the acute phase of stroke onset only. This often results in the exclusion of a significant number of patients who are unable to reach within the therapeutic window. Advances in neuroimaging technologies have allowed better assessment of salvageable penumbra and occluded vessel status. Improvement in diagnostic tools and the advent of intravascular interventional devices such as stent retrievers have expanded the potential revascularization window. Clinical studies have demonstrated positive outcomes of delayed revascularization beyond the recommended therapeutic window. This review will discuss the current understanding of ischemic stroke, the latest revascularization doctrine, and evidence from clinical studies regarding effective delayed revascularization in ischemic stroke.
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Affiliation(s)
- T. Marc Eastin
- Department of Neurological Surgery, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Justin A. Dye
- Department of Neurological Surgery, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Promod Pillai
- Department of Neurological Surgery, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Miguel A. Lopez-Gonzalez
- Department of Neurological Surgery, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Lei Huang
- Department of Neurological Surgery, Loma Linda University Medical Center, Loma Linda, CA, United States,Department of Pharmacology and Physiology, Loma Linda University, Loma Linda, CA, United States
| | - John H. Zhang
- Department of Neurological Surgery, Loma Linda University Medical Center, Loma Linda, CA, United States,Department of Pharmacology and Physiology, Loma Linda University, Loma Linda, CA, United States,Department of Neurology, Loma Linda University Medical Center, Loma Linda, CA, United States,Department of Anesthesiology, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Warren W. Boling
- Department of Neurological Surgery, Loma Linda University Medical Center, Loma Linda, CA, United States,*Correspondence: Warren W. Boling,
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Kadowaki S, Siraj MA, Chen W, Wang J, Parker M, Nagy A, Steve Fan C, Runeckles K, Li J, Kobayashi J, Haller C, Husain M, Honjo O. Cardioprotective Actions of a Glucagon-like Peptide-1 Receptor Agonist on Hearts Donated After Circulatory Death. J Am Heart Assoc 2023; 12:e027163. [PMID: 36695313 PMCID: PMC9973624 DOI: 10.1161/jaha.122.027163] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Background Heart transplantation with a donation after circulatory death (DCD) heart is complicated by substantial organ ischemia and ischemia-reperfusion injury. Exenatide, a glucagon-like peptide-1 receptor agonist, manifests protection against cardiac ischemia-reperfusion injury in other settings. Here we evaluate the effects of exenatide on DCD hearts in juvenile pigs. Methods and Results DCD hearts with 15-minutes of global warm ischemia after circulatory arrest were reperfused ex vivo and switched to working mode. Treatment with concentration 5-nmol exenatide was given during reperfusion. DCD hearts treated with exenatide showed higher myocardial oxygen consumption (exenatide [n=7] versus controls [n=7], over 60-120 minutes of reperfusion, P<0.001) and lower cardiac troponin-I release (27.94±11.17 versus 42.25±11.80 mmol/L, P=0.04) during reperfusion compared with controls. In working mode, exenatide-treated hearts showed better diastolic function (dp/dt min: -3644±620 versus -2193±610 mm Hg/s, P<0.001; Tau: 15.62±1.78 versus 24.59±7.35 milliseconds, P=0.02; lateral e' velocity: 11.27 ± 1.46 versus 7.19±2.96, P=0.01), as well as lower venous lactate levels (3.17±0.75 versus 5.17±1.44 mmol/L, P=0.01) compared with controls. Higher levels of activated endothelial nitric oxide synthase (phosphorylated to total endothelial nitric oxide synthase levels: 2.71±1.16 versus 1.37±0.35, P=0.02) with less histological evidence of endothelial damage (von Willebrand factor expression: 0.024±0.007 versus 0.331±0.302, pixel/μm, P=0.04) was also observed with exenatide treatment versus controls. Conclusions Acute treatment of DCD hearts with exenatide limits myocardial and endothelial injury and improves donor cardiac function.
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Affiliation(s)
- Sachiko Kadowaki
- Division of Cardiovascular SurgeryThe Hospital for Sick ChildrenTorontoOntarioCanada,Department of SurgeryUniversity of TorontoTorontoOntarioCanada
| | - M. Ahsan Siraj
- Department of Medicine, Ted Rogers Centre for Heart Research, Peter Munk Cardiac CentreUniversity of TorontoTorontoOntarioCanada
| | - Weiden Chen
- Division of Cardiovascular SurgeryThe Hospital for Sick ChildrenTorontoOntarioCanada,Department of SurgeryUniversity of TorontoTorontoOntarioCanada,Department of Cardiac SurgeryGuangzhou Women and Children’s Medical CenterGuangzhouChina
| | - Jian Wang
- Division of Perfusion ServicesThe Hospital for Sick ChildrenTorontoOntarioCanada
| | - Marlee Parker
- Division of Perfusion ServicesThe Hospital for Sick ChildrenTorontoOntarioCanada
| | - Anita Nagy
- Division of PathologyThe Hospital for Sick ChildrenTorontoOntarioCanada
| | - Chun‐Po Steve Fan
- Ted Rogers Centre for Heart Research, Peter Munk Cardiac Centre, Labatt Family Heart CentreUniversity Health Network, The Hospital for Sick ChildrenTorontoOntarioCanada
| | - Kyle Runeckles
- Ted Rogers Centre for Heart Research, Peter Munk Cardiac Centre, Labatt Family Heart CentreUniversity Health Network, The Hospital for Sick ChildrenTorontoOntarioCanada
| | - Jing Li
- Division of Cardiovascular SurgeryThe Hospital for Sick ChildrenTorontoOntarioCanada,Department of SurgeryUniversity of TorontoTorontoOntarioCanada
| | - Junko Kobayashi
- Division of Cardiovascular SurgeryThe Hospital for Sick ChildrenTorontoOntarioCanada,Department of SurgeryUniversity of TorontoTorontoOntarioCanada,Department of Cardiovascular SurgeryOkayama University HospitalOkayamaJapan,Department of Cardiovascular SurgeryFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityOkayamaJapan
| | - Christoph Haller
- Division of Cardiovascular SurgeryThe Hospital for Sick ChildrenTorontoOntarioCanada,Department of SurgeryUniversity of TorontoTorontoOntarioCanada
| | - Mansoor Husain
- Department of Medicine, Ted Rogers Centre for Heart Research, Peter Munk Cardiac CentreUniversity of TorontoTorontoOntarioCanada
| | - Osami Honjo
- Division of Cardiovascular SurgeryThe Hospital for Sick ChildrenTorontoOntarioCanada,Department of SurgeryUniversity of TorontoTorontoOntarioCanada
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Madder ( Rubia cordifolia L.) Alleviates Myocardial Ischemia-Reperfusion Injury by Protecting Endothelial Cells from Apoptosis and Inflammation. Mediators Inflamm 2023; 2023:5015039. [PMID: 36875688 PMCID: PMC9981279 DOI: 10.1155/2023/5015039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 02/25/2023] Open
Abstract
Objective Ischemia-reperfusion injury often occurs in organ transplantation, coronary heart disease, ischemic heart disease, and other diseases, which greatly reduces clinical efficacy. This study examined the effectiveness of madder as a medicine to treat ischemia-reperfusion injury. Methods The efficacy of madder was evaluated by measuring myocardial infarction size, coronary outflow volume, myocardial contraction rate, activation of inflammatory factors, autophagy factors, apoptosis factors, and related pathway genes in mice. Results The results indicated that treatment with madder can effectively reduce the area of myocardial infarction and restore arterial blood flow velocity and myocardial contractility in mice. Additionally, madder treatment inhibited the expression of inflammatory factors, autophagy factors, and apoptosis factors in mice and reduced the degree of myocardial cell injury. Studies have also shown that madder treatment can alleviate myocardial ischemia-reperfusion injury in mice and inhibit the occurrence of inflammatory response by inhibiting the activity of the NF-κB pathway. Conclusion The results showed that madder was effective against ischemia-reperfusion injury, thus showing potential as a clinical drug for treating ischemia-reperfusion injury.
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Xiong Y, Jian J, Yu H, Wu J, Mao H, Feng R, Wang L, Jian Y, Liu X. Cyanidin-3-O-glucoside plays a protective role against renal ischemia/ reperfusion injury via the JAK/STAT pathway. Acta Cir Bras 2023; 38:e381023. [PMID: 37132754 PMCID: PMC10158851 DOI: 10.1590/acb381023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 01/05/2023] [Indexed: 05/04/2023] Open
Abstract
PURPOSE To investigate the role of cyanidin-3-O-glucoside (C3G) in renal ischemia/reperfusion (I/R) injury and the potential mechanisms. METHODS Mouse models were established by clamping the left renal vessels, and in vitro cellular models were established by hypoxic reoxygenation. RESULTS Renal dysfunction and tissue structural damage were significantly higher in the I/R group. After treatment with different concentrations of C3G, the levels of renal dysfunction and tissue structural damage decreased at different levels. And its protective effect was most pronounced at 200 mg/kg. The use of C3G reduced apoptosis as well as the expression of endoplasmic reticulum stress (ERS)-related proteins. Hypoxia/reoxygenation (H/R)-induced apoptosis and ERS are dependent on oxidative stress in vitro. In addition, both AG490 and C3G inhibited the activation of JAK/STAT pathway and attenuated oxidative stress, ischemia-induced apoptosis and ERS. CONCLUSIONS The results demonstrated that C3G blocked renal apoptosis and ERS protein expression by preventing reactive oxygen species (ROS) production after I/R via the JAK/STAT pathway, suggesting that C3G may be a potential therapeutic agent for renal I/R injury.
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Affiliation(s)
- Yufeng Xiong
- Renmin Hospital of Wuhan University - Department of Urology - Wuhan (Hubei), China
- Renmin Hospital of Wuhan University - Institute of Urologic Disease - Wuhan (Hubei), China
| | - Jun Jian
- Renmin Hospital of Wuhan University - Department of Urology - Wuhan (Hubei), China
- Renmin Hospital of Wuhan University - Institute of Urologic Disease - Wuhan (Hubei), China
| | - Honglin Yu
- University of Science and Technology of China, The First Affiliated Hospital - Department of Radiology - Hefei (Anhui), China
| | - Jiejun Wu
- Renmin Hospital of Wuhan University - Department of Urology - Wuhan (Hubei), China
- Renmin Hospital of Wuhan University - Institute of Urologic Disease - Wuhan (Hubei), China
| | - Hu Mao
- Renmin Hospital of Wuhan University - Department of Urology - Wuhan (Hubei), China
- Renmin Hospital of Wuhan University - Institute of Urologic Disease - Wuhan (Hubei), China
| | - Ruikang Feng
- Renmin Hospital of Wuhan University - Department of Urology - Wuhan (Hubei), China
- Renmin Hospital of Wuhan University - Institute of Urologic Disease - Wuhan (Hubei), China
| | - Lei Wang
- Renmin Hospital of Wuhan University - Department of Urology - Wuhan (Hubei), China
- Renmin Hospital of Wuhan University - Institute of Urologic Disease - Wuhan (Hubei), China
| | - Yonghong Jian
- Renmin Hospital of Wuhan University - Department of Nephrology - Wuhan (Hubei), China
| | - Xiuheng Liu
- Renmin Hospital of Wuhan University - Department of Urology - Wuhan (Hubei), China
- Renmin Hospital of Wuhan University - Institute of Urologic Disease - Wuhan (Hubei), China
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Song W, Qiu N. MiR-495-3p depletion contributes to myocardial ischemia/reperfusion injury in cardiomyocytes by targeting TNC. Regen Ther 2022; 21:380-388. [PMID: 36161101 PMCID: PMC9478495 DOI: 10.1016/j.reth.2022.08.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 08/08/2022] [Accepted: 08/25/2022] [Indexed: 11/24/2022] Open
Abstract
Background Tenascin-C (TNC) has been found to abnormally express in myocardial ischemia/reperfusion injury (MI/RI), but its effect on cardiomyocytes apoptosis is unknown and is worthy of investigation. Methods H9C2 cells were given hypoxia/reoxygenation (H/R) treatment to obtain the replica of MI/RI in vitro. The effect of H/R on viability, apoptosis and inflammation was studied by CCK-8 assay, flow cytometry, mitochondrial membrane potential (MMP) and Ca2+ measurements as well as enzyme linked immunosorbent assay. We applied bioinformatics analysis and luciferase reporter assay to screened and validated TNC-targeting miR-495-3p which was then mechanistically investigated by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. With the assistance of cell transfection, rescue assays were conducted. Results H9C2 cells showed diminished viability, accelerated apoptosis, elevated tumour necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), and TNC overexpression in response to H/R induction, while silencing of TNC partially reversed the effect of H/R treatment on the H9C2 cells. TNC silencing reduced Ca2+ level and enhanced MMP level in the H/R-stimulated cells. MiR-495-3p targeted TNC and showed a low expression in the H/R-stimulated cells. The expression of TNC was negatively regulated by miR-495-3p. Inhibition of miR-495-3p repressed viability and MMP level, and facilitated apoptosis and levels of Ca2+, TNF-α and IL-1β in the H/R-stimulated cells. The effect of TNC silencing and miR-495-3p depletion on H/R-induced cardiomyocyte injury was mutually reversed in vitro. Conclusion MiR-495-3p targeted TNC to regulate the apoptosis and inflammation of cardiomyocytes in H/R induction, which was associated with Ca2+ overload.
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Affiliation(s)
- Wei Song
- Department of Cardiology, Taizhou Central Hospital (Taizhou University Hospital), 999 Donghai Avenue, Jiaojiang District, Taizhou, Zhejiang Province, China
| | - Naiyan Qiu
- Department of Cardiology, The Fifth People's Hospital of Jinan, No. 24297 Jingshi Road, Huaiyin District, Jinan, Shandong Province, 250021, China
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Ji MJ, Son KH, Hong JH. Addition of oh8dG to Cardioplegia Attenuated Myocardial Oxidative Injury through the Inhibition of Sodium Bicarbonate Cotransporter Activity. Antioxidants (Basel) 2022; 11:antiox11091641. [PMID: 36139714 PMCID: PMC9495749 DOI: 10.3390/antiox11091641] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/28/2022] Open
Abstract
The biomarker 8-hydroxy-2′-deoxyguanosine (oh8dG) is derived from oxidized nucleic acids or products of oxidant-mediated DNA damage. Enhanced sodium bicarbonate cotransporter (NBC) activity is caused by reactive oxygen species (ROS) production in ventricular myocytes. Thus, we hypothesized that cardioplegia-solution-mediated ROS generation may be involved in the regulation of NBC activity in cardiomyocytes and that oh8dG treatment may modulate ROS and associated NBC activity. Langendorff-free cardioplegia-arrested cardiac strips and cardiomyocytes were isolated to determine the NBC activity and effects of oh8dG on oxidative-stress-mediated cardiac damage markers. We first determined the histidine-tryptophan-ketoglutarate (HTK) solution mediated NBC activity in cardiac strips and cells. The oh8dG treatment attenuated NBC activity in the electroneutral or electrogenic form of NBC. Additionally, exposure to HTK solution induced ROS, whereas co-administration of oh8dG attenuated ROS-mediated NBC activity, reduced ROS levels, and decreased the expression of apoptotic markers and fibrosis-associated proteins in cardiac cells. The oh8dG-administrated cardiac tissues were also protected from enhanced HTK-induced damage markers, heat shock protein 60 and polyADP-ribose. Our results show that oh8dG has a protective role against myocardial oxidative damage and provides a useful treatment strategy for restoring cardiac function.
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Affiliation(s)
- Min Jeong Ji
- Department of Health Sciences and Technology, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Korea
| | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea
- Correspondence: (K.H.S.); (J.H.H.); Tel.: +82-32-899-6682 (J.H.H.)
| | - Jeong Hee Hong
- Department of Health Sciences and Technology, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Korea
- Correspondence: (K.H.S.); (J.H.H.); Tel.: +82-32-899-6682 (J.H.H.)
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Zhu D, Jia C, Cai T, Li J, Feng X, Chen N, Zhao C, Wang Y, Cao Y, Cao Y. Ruan Jian Qing Mai Recipe Inhibits the Inflammatory Response in Acute Lower Limb Ischemic Mice through the JAK2/STAT3 Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:2481022. [PMID: 36034959 PMCID: PMC9410777 DOI: 10.1155/2022/2481022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 07/21/2022] [Indexed: 11/17/2022]
Abstract
Ruan jian qing mai recipe (RJQM) is an empirical prescription for treating arteriosclerosis obliterans (ASO). However, the mechanism of RJQM recipe-mediated ASO attenuation has not yet been elucidated. Therefore, this study aimed to explore the mechanism by which the RJQM recipe relieves ASO in a mouse model of lower limb ischemia, which was established by ligating and breaking the femoral artery of the left lower limb. The surgical groups were divided into the ischemic group, beraprost sodium group, low-dose RJQM group, medium-dose RJQM group, and high-dose RJQM group. Normal mice were set as the control group. The blood flow of the lower limb was examined on days 7 and 14. At the end of animal procedures, blood samples were collected, and the rectus femoris of the left lower limb were harvested. Results revealed that mice in the ischemic group demonstrated low blood flow. Additionally, hematoxylin and eosin, and Masson staining results showed that inflammation of the rectus femoris was obvious in the ischemia group, and the level of fibrosis was increased. Blood flow was recovered in all treatment groups compared to the ischemic group, and the inflammatory infiltration and fibrosis of the rectus femoris were relieved after RJQM treatment. The serum levels of interleukin (IL)-17A and IL-21 were decreased, and the expression of JAK2/STAT3 proteins was inhibited in all RJQM treatment groups compared to the ischemia group. Furthermore, the improvement of IL-17A, IL-21, and rectus femoris fibrosis was more obvious with increasing treatment time. In conclusion, RJQM can effectively alleviate ASO and promote the recovery of lower limb blood flow by regulating the JAK2/STAT3 signaling pathway to reduce the inflammatory response.
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Affiliation(s)
- Di Zhu
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
- Institute of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Chenglin Jia
- Institute of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Tongkai Cai
- PLA Naval Medical University, Shanghai 200433, China
| | - Jiacheng Li
- Institute of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Xia Feng
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
- Institute of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Nan Chen
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Institute of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Cheng Zhao
- Department of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
- Institute of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Yuzhen Wang
- Department of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
- Institute of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Yongbing Cao
- Institute of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Yemin Cao
- Department of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
- Institute of Vascular Diseases, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
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Koju N, Qin ZH, Sheng R. Reduced nicotinamide adenine dinucleotide phosphate in redox balance and diseases: a friend or foe? Acta Pharmacol Sin 2022; 43:1889-1904. [PMID: 35017669 PMCID: PMC9343382 DOI: 10.1038/s41401-021-00838-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 12/03/2021] [Accepted: 12/03/2021] [Indexed: 12/20/2022]
Abstract
The nicotinamide adenine dinucleotide (NAD+/NADH) and nicotinamide adenine dinucleotide phosphate (NADP+/NADPH) redox couples function as cofactors or/and substrates for numerous enzymes to retain cellular redox balance and energy metabolism. Thus, maintaining cellular NADH and NADPH balance is critical for sustaining cellular homeostasis. The sources of NADPH generation might determine its biological effects. Newly-recognized biosynthetic enzymes and genetically encoded biosensors help us better understand how cells maintain biosynthesis and distribution of compartmentalized NAD(H) and NADP(H) pools. It is essential but challenging to distinguish how cells sustain redox couple pools to perform their integral functions and escape redox stress. However, it is still obscure whether NADPH is detrimental or beneficial as either deficiency or excess in cellular NADPH levels disturbs cellular redox state and metabolic homeostasis leading to redox stress, energy stress, and eventually, to the disease state. Additional study of the pathways and regulatory mechanisms of NADPH generation in different compartments, and the means by which NADPH plays a role in various diseases, will provide innovative insights into its roles in human health and may find a value of NADPH for the treatment of certain diseases including aging, Alzheimer's disease, Parkinson's disease, cardiovascular diseases, ischemic stroke, diabetes, obesity, cancer, etc.
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Affiliation(s)
- Nirmala Koju
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences of Soochow University, Suzhou, 215123, China
| | - Zheng-Hong Qin
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences of Soochow University, Suzhou, 215123, China.
| | - Rui Sheng
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences of Soochow University, Suzhou, 215123, China.
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Ortona S, Barisione C, Ferrari PF, Palombo D, Pratesi G. PCSK9 and Other Metabolic Targets to Counteract Ischemia/Reperfusion Injury in Acute Myocardial Infarction and Visceral Vascular Surgery. J Clin Med 2022; 11:jcm11133638. [PMID: 35806921 PMCID: PMC9267902 DOI: 10.3390/jcm11133638] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 12/13/2022] Open
Abstract
Ischemia/reperfusion (I/R) injury complicates both unpredictable events (myocardial infarction and stroke) as well as surgically-induced ones when transient clampage of major vessels is needed. Although the main cause of damage is attributed to mitochondrial dysfunction and oxidative stress, the use of antioxidant compounds for protection gave poor results when challenged in clinics. More recently, there is an assumption that, in humans, profound metabolic changes may prevail in driving I/R injury. In the present work, we narrowed the field of search to I/R injury in the heart/brain/kidney axis in acute myocardial infarction, major vascular surgery, and to the current practice of protection in both settings; then, to help the definition of novel strategies to be translated clinically, the most promising metabolic targets with their modulatory compounds—when available—and new preclinical strategies against I/R injury are described. The consideration arisen from the broad range of studies we have reviewed will help to define novel therapeutic approaches to ensure mitochondrial protection, when I/R events are predictable, and to cope with I/R injury, when it occurs unexpectedly.
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Affiliation(s)
- Silvia Ortona
- Vascular and Endovascular Surgery Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; (S.O.); (D.P.); (G.P.)
| | - Chiara Barisione
- Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
- Correspondence: ; Tel.: +39-010-555-7881
| | - Pier Francesco Ferrari
- Department of Civil, Chemical and Environmental Engineering, University of Genoa, Via Opera Pia, 15, 16145 Genoa, Italy;
| | - Domenico Palombo
- Vascular and Endovascular Surgery Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; (S.O.); (D.P.); (G.P.)
- Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
- Research Center for Biologically Inspired Engineering in Vascular Medicine and Longevity, University of Genoa, Via Montallegro, 1, 16145 Genoa, Italy
| | - Giovanni Pratesi
- Vascular and Endovascular Surgery Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; (S.O.); (D.P.); (G.P.)
- Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
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Role of Oxidative Stress in Cardiac Dysfunction and Subcellular Defects Due to Ischemia-Reperfusion Injury. Biomedicines 2022; 10:biomedicines10071473. [PMID: 35884777 PMCID: PMC9313001 DOI: 10.3390/biomedicines10071473] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/17/2022] Open
Abstract
Ischemia-reperfusion (I/R) injury is well-known to be associated with impaired cardiac function, massive arrhythmias, marked alterations in cardiac metabolism and irreversible ultrastructural changes in the heart. Two major mechanisms namely oxidative stress and intracellular Ca2+-overload are considered to explain I/R-induced injury to the heart. However, it is becoming apparent that oxidative stress is the most critical pathogenic factor because it produces myocardial abnormalities directly or indirectly for the occurrence of cardiac damage. Furthermore, I/R injury has been shown to generate oxidative stress by promoting the formation of different reactive oxygen species due to defects in mitochondrial function and depressions in both endogenous antioxidant levels as well as regulatory antioxidative defense systems. It has also been demonstrated to adversely affect a wide variety of metabolic pathways and targets in cardiomyocytes, various resident structures in myocardial interstitium, as well as circulating neutrophils and leukocytes. These I/R-induced alterations in addition to myocardial inflammation may cause cell death, fibrosis, inflammation, Ca2+-handling abnormalities, activation of proteases and phospholipases, as well as subcellular remodeling and depletion of energy stores in the heart. Analysis of results from isolated hearts perfused with or without some antioxidant treatments before subjecting to I/R injury has indicated that cardiac dysfunction is associated with the development of oxidative stress, intracellular Ca2+-overload and protease activation. In addition, changes in the sarcolemma and sarcoplasmic reticulum Ca2+-handling, mitochondrial oxidative phosphorylation as well as myofibrillar Ca2+-ATPase activities in I/R hearts were attenuated by pretreatment with antioxidants. The I/R-induced alterations in cardiac function were simulated upon perfusing the hearts with oxyradical generating system or oxidant. These observations support the view that oxidative stress may be intimately involved in inducing intracellular Ca2+-overload, protease activation, subcellular remodeling, and cardiac dysfunction as a consequence of I/R injury to the heart.
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Roesel MJ, Sharma NS, Schroeter A, Matsunaga T, Xiao Y, Zhou H, Tullius SG. Primary Graft Dysfunction: The Role of Aging in Lung Ischemia-Reperfusion Injury. Front Immunol 2022; 13:891564. [PMID: 35686120 PMCID: PMC9170999 DOI: 10.3389/fimmu.2022.891564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/21/2022] [Indexed: 01/14/2023] Open
Abstract
Transplant centers around the world have been using extended criteria donors to remedy the ongoing demand for lung transplantation. With a rapidly aging population, older donors are increasingly considered. Donor age, at the same time has been linked to higher rates of lung ischemia reperfusion injury (IRI). This process of acute, sterile inflammation occurring upon reperfusion is a key driver of primary graft dysfunction (PGD) leading to inferior short- and long-term survival. Understanding and improving the condition of older lungs is thus critical to optimize outcomes. Notably, ex vivo lung perfusion (EVLP) seems to have the potential of reconditioning ischemic lungs through ex-vivo perfusing and ventilation. Here, we aim to delineate mechanisms driving lung IRI and review both experimental and clinical data on the effects of aging in augmenting the consequences of IRI and PGD in lung transplantation.
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Affiliation(s)
- Maximilian J Roesel
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.,Institute of Medical Immunology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Nirmal S Sharma
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, United States.,Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Andreas Schroeter
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.,Regenerative Medicine and Experimental Surgery, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Tomohisa Matsunaga
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.,Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Yao Xiao
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Hao Zhou
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Stefan G Tullius
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
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Siracusa R, Voltarelli VA, Trovato Salinaro A, Modafferi S, Cuzzocrea S, Calabrese EJ, Di Paola R, Otterbein LE, Calabrese V. NO, CO and H 2S: A Trinacrium of Bioactive Gases in the Brain. Biochem Pharmacol 2022; 202:115122. [PMID: 35679892 DOI: 10.1016/j.bcp.2022.115122] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 11/02/2022]
Abstract
Oxygen and carbon dioxide are time honored gases that have direct bearing on almost all life forms, but over the past thirty years, and in large part due to the Nobel Prize Award in Medicine for the elucidation of nitric oxide (NO) as a bioactive gas, the research and medical communities now recognize other gases as critical for survival. In addition to NO, hydrogen sulfide (H2S) and carbon monoxide (CO) have emerged as a triumvirate or Trinacrium of gases with analogous importance and that serve important homeostatic functions. Perhaps, one of the most intriguing aspects of these gases is the functional interaction between them, which is intimately linked by the enzyme systems that produce them. Despite the need to better understand NO, H2S and CO biology, the notion that these are environmental pollutants remains ever present. For this reason, incorporating the concept of hormesis becomes imperative and must be included in discussions when considering developing new therapeutics that involve these gases. While there is now an enormous literature base for each of these gasotransmitters, we provide here an overview of their respective physiologic roles in the brain.
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Affiliation(s)
- Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Messina, 98166, Italy
| | - Vanessa A Voltarelli
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA
| | - Angela Trovato Salinaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Sergio Modafferi
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Messina, 98166, Italy
| | - Edward J Calabrese
- Department of Environmental Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA 01003, USA
| | - Rosanna Di Paola
- Department of Veterinary Science, University of Messina, 98168, Messina, Italy
| | - Leo E Otterbein
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA.
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
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Song L, Mu L, Wang H. MicroRNA-489-3p aggravates neuronal apoptosis and oxidative stress after cerebral ischemia-reperfusion injury. Bioengineered 2022; 13:14047-14056. [PMID: 35730531 PMCID: PMC9342425 DOI: 10.1080/21655979.2022.2062534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Cerebral ischemia-reperfusion injury (CIRI) mostly occurs in the treatment stage of ischemic diseases and aggravate brain tissue damage. Although studies have demonstrated that miR-489-3p is closely related to CIRI, the effects of miR-489-3p on neural function in CIRI have not been directly studied. The transient middle cerebral artery occlusion (tMCAO) model was established by suture method, and the corresponding plasmids that interfered with the expression of miR-489-3p or Sirtuin1 (SIRT1) were injected into the model mice, and the behavioral changes of the mice were observed. Then the concentration of serum neuronal injury markers and oxidative stress indices were examined. Next, the pathological conditions, neuronal loss and apoptosis of brain tissue were observed by hematoxylin-eosin staining, Nissl staining, and Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining. Finally, the hemoglobin content and cerebral edema in the mouse brain were determined. In addition, the expression levels of miR-489-3p and SIRT1 were detected by reverse transcription quantitative polymerase chain reaction or Western blot, and the targeting relationship between miR-489-3p and SIRT1 was verified by bioinformatics analysis and luciferase reporter assay. The experimental results found that in tMCAO mice, miR-489-3p in brain tissue was up-regulated and SIRT1 was down-regulated. Down-regulating miR-489-3p or up-regulating SIRT1 ameliorated behavioral dysfunction, neuronal damage and apoptosis, oxidative stress and brain histopathology. miR-489-3p targeted the regulation of SIRT1 expression, and down-regulating SIRT1 can reverse the protective effect of silenced miR-489-3p on brain injury. Taken together, by targeting SIRT1, elevated miR-489-3p aggravates CIRI-induced neuronal apoptosis and oxidative stress.
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Affiliation(s)
- LiGuo Song
- Department of Neurosurgery, The First People's Hospital of Mudanjiang, Mudanjiang City, Heilongjiang Province, China
| | - LuYan Mu
- Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Haerbin, Heilongjiang Province, China
| | - HongLiang Wang
- Department of Neurology, The Sixth People's Hospital of Nantong City, Nantong City, Jiangsu Province, China
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Wang L, Liu Y, Zhang X, Ye Y, Xiong X, Zhang S, Gu L, Jian Z, Wang H. Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cerebral Ischemia/Reperfusion Injury. Front Cell Neurosci 2022; 16:864426. [PMID: 35602556 PMCID: PMC9114642 DOI: 10.3389/fncel.2022.864426] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/07/2022] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke is an acute cerebrovascular disease characterized by sudden interruption of blood flow in a certain part of the brain, leading to serious disability and death. At present, treatment methods for ischemic stroke are limited to thrombolysis or thrombus removal, but the treatment window is very narrow. However, recovery of cerebral blood circulation further causes cerebral ischemia/reperfusion injury (CIRI). The endoplasmic reticulum (ER) plays an important role in protein secretion, membrane protein folding, transportation, and maintenance of intracellular calcium homeostasis. Endoplasmic reticulum stress (ERS) plays a crucial role in cerebral ischemia pathophysiology. Mild ERS helps improve cell tolerance and restore cell homeostasis; however, excessive or long-term ERS causes apoptotic pathway activation. Specifically, the protein kinase R-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways are significantly activated following initiation of the unfolded protein response (UPR). CIRI-induced apoptosis leads to nerve cell death, which ultimately aggravates neurological deficits in patients. Therefore, it is necessary and important to comprehensively explore the mechanism of ERS in CIRI to identify methods for preserving brain cells and neuronal function after ischemia.
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Affiliation(s)
- Lei Wang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan Liu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xu Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yingze Ye
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shudi Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhihong Jian
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
- Zhihong Jian,
| | - Hongfa Wang
- Rehabilitation Medicine Center, Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
- *Correspondence: Hongfa Wang,
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Antioxidant Cardioprotection against Reperfusion Injury: Potential Therapeutic Roles of Resveratrol and Quercetin. Molecules 2022; 27:molecules27082564. [PMID: 35458766 PMCID: PMC9027566 DOI: 10.3390/molecules27082564] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/06/2022] [Accepted: 04/12/2022] [Indexed: 12/14/2022] Open
Abstract
Ischemia-reperfusion myocardial damage is a paradoxical tissue injury occurring during percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) patients. Although this damage could account for up to 50% of the final infarct size, there has been no available pharmacological treatment until now. Oxidative stress contributes to the underlying production mechanism, exerting the most marked injury during the early onset of reperfusion. So far, antioxidants have been shown to protect the AMI patients undergoing PCI to mitigate these detrimental effects; however, no clinical trials to date have shown any significant infarct size reduction. Therefore, it is worthwhile to consider multitarget antioxidant therapies targeting multifactorial AMI. Indeed, this clinical setting involves injurious effects derived from oxygen deprivation, intracellular pH changes and increased concentration of cytosolic Ca2+ and reactive oxygen species, among others. Thus, we will review a brief overview of the pathological cascades involved in ischemia-reperfusion injury and the potential therapeutic effects based on preclinical studies involving a combination of antioxidants, with particular reference to resveratrol and quercetin, which could contribute to cardioprotection against ischemia-reperfusion injury in myocardial tissue. We will also highlight the upcoming perspectives of these antioxidants for designing future studies.
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Sobot NM, Sobot TS, Jeremic JN, Bolevich SB, Bolevich SS, Mitrovic SL, Fisenko VP, Inic SG, Samanovic ADM, Rankovic MR, Srejovic IM, Zivkovic VI, Jakovljevic VL. Minocycline as heart conditioning agent in experimental type 2 diabetes mellitus - an antibacterial drug in heart protection. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:429-444. [PMID: 35113200 DOI: 10.1007/s00210-021-02179-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/05/2021] [Indexed: 11/25/2022]
Abstract
Cardiovascular diseases, and among them certainly myocardial infarction, remain leading cause of death worldwide. Diabetes increases risk of occurrence as well as adverse outcome of myocardial infarction. Conditioning maneuvers are the most attractive method for alleviating both the consequences of ischemia and reperfusion. Minocycline is a tetracycline derivative which exerts antioxidant, anti-inflammatory, and anti-apoptotic effects. The aim of this study was to assess the protective ability of preconditioning and postconditioning of isolated hearts from healthy and rats with experimentally induced type 2 diabetes with minocycline on functional recovery and redox status after ischemia and reperfusion. The hearts from healthy and diabetic rats were excised and retrogradely perfused according to the Langendorff technique. Using sensor in the left ventricle, the cardiodynamic parameters were recorded and in the samples of the coronary venous effluent oxidative stress biomarkers were analyzed. Minocycline was injected directly into the coronary vessels, in preconditioning 5 min before global ischemia, and in postconditioning during the first 5 min of reperfusion. Results of this study clearly show beneficial effects of minocycline applied both before ischemia and in the first minutes of reperfusion fashion in both healthy and diabetic rat hearts. The most prominent protective effect regarding oxidative stress is related to the decreased production of superoxide anion radical due postconditioning with minocycline in diabetic hearts. Cardiodynamic parameters were significantly improved in minocycline conditioned groups. Superoxide anion radical stands out as the most susceptible to changes induced by minocycline.
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Affiliation(s)
- Nikola M Sobot
- Clinic for Cardiac Surgery, University Clinical Centre of the Republic of Srpska, Dvanaest beba st. bb, 78000, Banja Luka, Bosnia and Herzegovina
| | - Tanja S Sobot
- Department of Physiology, University of Banja Luka, Save Mrkalja st. 14, 78000, Banja Luka, Bosnia and Herzegovina
| | - Jovana N Jeremic
- Department of Pharmacy, University of Kragujevac, Svetozara Markovica st. 69, 34000, Kragujevac, Serbia
| | - Sergey B Bolevich
- Department of Human Pathology, I.M. Sechenov First Moscow State Medical University (Sechenov University, Trubetskaya st. 8, Moscow, 119991, Russia
| | - Stefani S Bolevich
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University (Sechenov University, Trubetskaya st. 8, Moscow, 119991, Russia
- Department of Pharmacology, I.M. Sechenov First Moscow State Medical University (Sechenov University, Trubetskaya st. 8, Moscow, 119991, Russia
| | - Slobodanka Lj Mitrovic
- Department of Pathology, University of Kragujevac, Svetozara Markovica st. 69, 34000, Kragujevac, Serbia
| | - Vladimir P Fisenko
- Department of Pharmacology, I.M. Sechenov First Moscow State Medical University (Sechenov University, Trubetskaya st. 8, Moscow, 119991, Russia
| | - Sofija G Inic
- University of Pristina With Temporary Headquarters in Kosovksa Mitrovica Anri Dinana St. Bb, 38220, Kosovska Mitrovica, Serbia
| | | | - Marina R Rankovic
- Department of Physiology, University of Kragujevac, Svetozara Markovica st. 69, 34000, Kragujevac, Serbia
| | - Ivan M Srejovic
- Department of Physiology, University of Kragujevac, Svetozara Markovica st. 69, 34000, Kragujevac, Serbia
| | - Vladimir I Zivkovic
- Department of Physiology, University of Kragujevac, Svetozara Markovica st. 69, 34000, Kragujevac, Serbia
| | - Vladimir Lj Jakovljevic
- Department of Human Pathology, I.M. Sechenov First Moscow State Medical University (Sechenov University, Trubetskaya st. 8, Moscow, 119991, Russia.
- Department of Physiology, University of Kragujevac, Svetozara Markovica st. 69, 34000, Kragujevac, Serbia.
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An Overview of the Molecular Mechanisms Associated with Myocardial Ischemic Injury: State of the Art and Translational Perspectives. Cells 2022; 11:cells11071165. [PMID: 35406729 PMCID: PMC8998015 DOI: 10.3390/cells11071165] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease is the leading cause of death in western countries. Among cardiovascular diseases, myocardial infarction represents a life-threatening condition predisposing to the development of heart failure. In recent decades, much effort has been invested in studying the molecular mechanisms underlying the development and progression of ischemia/reperfusion (I/R) injury and post-ischemic cardiac remodeling. These mechanisms include metabolic alterations, ROS overproduction, inflammation, autophagy deregulation and mitochondrial dysfunction. This review article discusses the most recent evidence regarding the molecular basis of myocardial ischemic injury and the new potential therapeutic interventions for boosting cardioprotection and attenuating cardiac remodeling.
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Modification of Ischemia/Reperfusion-Induced Alterations in Subcellular Organelles by Ischemic Preconditioning. Int J Mol Sci 2022; 23:ijms23073425. [PMID: 35408783 PMCID: PMC8998910 DOI: 10.3390/ijms23073425] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 02/07/2023] Open
Abstract
It is now well established that ischemia/reperfusion (I/R) injury is associated with the compromised recovery of cardiac contractile function. Such an adverse effect of I/R injury in the heart is attributed to the development of oxidative stress and intracellular Ca2+-overload, which are known to induce remodeling of subcellular organelles such as sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils. However, repeated episodes of brief periods of ischemia followed by reperfusion or ischemic preconditioning (IP) have been shown to improve cardiac function and exert cardioprotective actions against the adverse effects of prolonged I/R injury. This protective action of IP in attenuating myocardial damage and subcellular remodeling is likely to be due to marked reductions in the occurrence of oxidative stress and intracellular Ca2+-overload in cardiomyocytes. In addition, the beneficial actions of IP have been attributed to the depression of proteolytic activities and inflammatory levels of cytokines as well as the activation of the nuclear factor erythroid factor 2-mediated signal transduction pathway. Accordingly, this review is intended to describe some of the changes in subcellular organelles, which are induced in cardiomyocytes by I/R for the occurrence of oxidative stress and intracellular Ca2+-overload and highlight some of the mechanisms for explaining the cardioprotective effects of IP.
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Hatami S, Hefler J, Freed DH. Inflammation and Oxidative Stress in the Context of Extracorporeal Cardiac and Pulmonary Support. Front Immunol 2022; 13:831930. [PMID: 35309362 PMCID: PMC8931031 DOI: 10.3389/fimmu.2022.831930] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Extracorporeal circulation (ECC) systems, including cardiopulmonary bypass, and extracorporeal membrane oxygenation have been an irreplaceable part of the cardiothoracic surgeries, and treatment of critically ill patients with respiratory and/or cardiac failure for more than half a century. During the recent decades, the concept of extracorporeal circulation has been extended to isolated machine perfusion of the donor organ including thoracic organs (ex-situ organ perfusion, ESOP) as a method for dynamic, semi-physiologic preservation, and potential improvement of the donor organs. The extracorporeal life support systems (ECLS) have been lifesaving and facilitating complex cardiothoracic surgeries, and the ESOP technology has the potential to increase the number of the transplantable donor organs, and to improve the outcomes of transplantation. However, these artificial circulation systems in general have been associated with activation of the inflammatory and oxidative stress responses in patients and/or in the exposed tissues and organs. The activation of these responses can negatively affect patient outcomes in ECLS, and may as well jeopardize the reliability of the organ viability assessment, and the outcomes of thoracic organ preservation and transplantation in ESOP. Both ECLS and ESOP consist of artificial circuit materials and components, which play a key role in the induction of these responses. However, while ECLS can lead to systemic inflammatory and oxidative stress responses negatively affecting various organs/systems of the body, in ESOP, the absence of the organs that play an important role in oxidant scavenging/antioxidative replenishment of the body, such as liver, may make the perfused organ more susceptible to inflammation and oxidative stress during extracorporeal circulation. In the present manuscript, we will review the activation of the inflammatory and oxidative stress responses during ECLP and ESOP, mechanisms involved, clinical implications, and the interventions for attenuating these responses in ECC.
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Affiliation(s)
- Sanaz Hatami
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Canadian National Transplant Research Program, Edmonton, AB, Canada
| | - Joshua Hefler
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Darren H. Freed
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Canadian National Transplant Research Program, Edmonton, AB, Canada
- Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada
- Alberta Transplant Institute, Edmonton, AB, Canada
- Department of Physiology, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Darren H. Freed,
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50
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Mehta AA, Patel P, Thakur VR, Beladiya JV. Effect of soya phosphatidylcholine and possible underlying mechanism on ischemia/reperfusion injury in isolated perfused rat heart: an experimental and computational study. Can J Physiol Pharmacol 2022; 100:252-258. [PMID: 34990309 DOI: 10.1139/cjpp-2021-0056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study was designed to assess the effect of soya phosphatidylcholine (SPC) against ischemia/reperfusion (I/R) injury and the possible underlying mechanism using experimental and computational studies. I/R injury was induced by global ischemia for 30 min followed by reperfusion for 120 min. The perfusion of the SPC was performed for 10 min before inducing global ischemia. In the mechanistic study, the involvement of specific cellular pathways was identified using various inhibitors such as ATP-dependent potassium channel (KATP) inhibitor (glibenclamide), protein kinase C (PKC) inhibitor (chelerythrine), non-selective nitric oxide synthase inhibitor (L-NAME), and endothelium remover (Triton X-100). The computational study of various ligands was performed on toll-like receptor 4 (TLR4) protein using AutoDock version 4.0. SPC (100 μM) significantly decreased the levels of cardiac damage markers and %infarction compared with the vehicle control (VC). Furthermore, cardiodynamics (indices of left ventricular contraction (dp/dtmax), indices of left ventricular relaxation (dp/dtmin), coronary flow, and antioxidant enzyme levels were significantly improved as compared with VC. This protective effect was attenuated by glibenclamide, chelerythrine, and Triton X-100, but it was not attenuated by L-NAME. The computational study showed a significant bonding affinity of SPC to the TLR4-MD2 complex. Thus, SPC reduced myocardial I/R injury in isolated perfused rat hearts, which might be governed by the KATP channel, PKC, endothelium response, and TLR4-MyD88 signaling pathway.
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Affiliation(s)
- Anita A Mehta
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
| | - Purav Patel
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
| | - Vandana R Thakur
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
| | - Jayesh V Beladiya
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
- Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India
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