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Zhang JJ, Cheng L, Qiao Q, Xiao XL, Lin SJ, He YF, Sha RL, Sha J, Ma Y, Zhang HL, Ye XR. Adenosine triphosphate-induced cell death in heart failure: Is there a link? World J Cardiol 2025; 17:105021. [PMID: 40308621 PMCID: PMC12038699 DOI: 10.4330/wjc.v17.i4.105021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/22/2025] [Accepted: 04/02/2025] [Indexed: 04/21/2025] Open
Abstract
Heart failure (HF) has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology. Adenosine triphosphate (ATP)-induced cell death represents a novel form of regulated cell deaths, marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation, identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis. Growing evidence suggests that ATP-induced cell death (AICD) is predominantly governed by various biological pathways, including energy metabolism, redox homeostasis and intracellular calcium equilibrium. Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may provide a foundation for the development of targeted therapies and novel treatment strategies. This review synthesizes current advancements in understanding the link between AICD and HF, while further elucidating its involvement in cardiac remodeling and HF progression.
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Affiliation(s)
- Jing-Jing Zhang
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Lu Cheng
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Qian Qiao
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Xue-Liang Xiao
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Shao-Jun Lin
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yue-Fang He
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Ren-Luo Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Jun Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yin Ma
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia.
| | - Xue-Rui Ye
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
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Bai J, Sun WB, Zheng WC, Wang XP, Bai Y. Carbon monoxide-releasing molecule-3 ameliorates traumatic brain injury-induced cardiac dysfunctions via inhibition of pyroptosis and apoptosis. Mol Cell Biochem 2025; 480:2501-2509. [PMID: 39377871 DOI: 10.1007/s11010-024-05130-w] [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: 08/16/2024] [Accepted: 09/29/2024] [Indexed: 10/09/2024]
Abstract
Traumatic brain injury (TBI) frequently results in cardiac dysfunction and impacts the quality of survivors' life. It has been reported that carbon monoxide-releasing molecule-3 (CORM-3) administration immediately after hemorrhagic shock and resuscitation (HSR) ameliorated the HSR‑induced cardiac dysfunctions. The purpose of this study was to determine whether the application of CORM-3 on TBI exerted therapeutic effects against TBI-induced cardiac dysfunctions. Rats were randomly divided into four groups (n = 12) including Sham, TBI, TBI/CORM-3 and TBI/inactive CORM-3 (iCORM-3) groups. TBI was established by a weight-drop model. The rats in the TBI/CORM-3 group and TBI/iCORM-3 group were intravenously injected with CORM-3 and iCORM-3 (4 mg/kg) following TBI, respectively. The time of death in the rats that did not survive within 24 h was recorded. 24 h post-trauma, the cardiac function, pathological change, serum troponin T and creatine kinase-MB (CK-MB) levels, pyroptosis, apoptosis and expressions of TUNEL staining, Gasdermin D (GSDMD), IL-1β, IL-18, ratio Bax/Bcl-2 were assessed by echocardiography, hematoxylin-eosin staining, chemiluminescence, immunofluorescence, and western blot assays, respectively. TBI-treated rats exhibited dramatically decreased ejection fraction and aggravated myocardial injury, increased mortality rate, elevated levels of serum troponin T and CK-MB, promoted cardiac pyroptosis and apoptosis, and upregulated expressions of cleaved caspase-3, GSDMD N-terminal fragments, IL-1β, IL-18, and ratio of Bax/Bcl-2, whereas CORM-3 partially reversed these changes. CORM-3 ameliorated TBI-induced cardiac injury and dysfunction. This mechanism may be responsible for the inhibition of pyroptosis and apoptosis in cardiomyocyte.
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Affiliation(s)
- Jing Bai
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China.
| | - Wen-Bo Sun
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China
| | - Wei-Chao Zheng
- Department of Anesthesiology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Xu-Peng Wang
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China
| | - Yang Bai
- Department of Anesthesiology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
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Mo B, Ding Y, Ji Q. NLRP3 inflammasome in cardiovascular diseases: an update. Front Immunol 2025; 16:1550226. [PMID: 40079000 PMCID: PMC11896874 DOI: 10.3389/fimmu.2025.1550226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/11/2025] [Indexed: 03/14/2025] Open
Abstract
Cardiovascular disease (CVD) continues to be the leading cause of mortality worldwide. The nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in numerous types of CVD. As part of innate immunity, the NLRP3 inflammasome plays a vital role, requiring priming and activation signals to trigger inflammation. The NLRP3 inflammasome leads both to the release of IL-1 family cytokines and to a distinct form of programmed cell death called pyroptosis. Inflammation related to CVD has been extensively investigated in relation to the NLRP3 inflammasome. In this review, we describe the pathways triggering NLRP3 priming and activation and discuss its pathogenic effects on CVD. This study also provides an overview of potential therapeutic approaches targeting the NLRP3 inflammasome.
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Affiliation(s)
- Binhai Mo
- People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yudi Ding
- First People’s Hospital of Nanning, Nanning, Guangxi, China
| | - Qingwei Ji
- People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
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4
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Liu Z, Li F, Li N, Chen Y, Chen Z. MicroRNAs as regulators of cardiac dysfunction in sepsis: pathogenesis and diagnostic potential. Front Cardiovasc Med 2025; 12:1517323. [PMID: 40041174 PMCID: PMC11876399 DOI: 10.3389/fcvm.2025.1517323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 01/29/2025] [Indexed: 03/06/2025] Open
Abstract
Introduction Sepsis, a life-threatening condition arising from an uncontrolled immune response to infection, can lead to organ dysfunction, with severe inflammation potentially causing multiple organ failures. Sepsis-induced cardiac dysfunction (SIMD) is a common and severe complication of sepsis, significantly increasing patient mortality. Understanding the pathogenesis of SIMD is crucial for improving treatment, and microRNAs (miRNAs) have emerged as important regulators in this process. Methods A comprehensive literature search was conducted in PubMed, Science Direct, and Embase databases up to September 2024. The search terms included ["miRNA" or "microRNA"] and ["Cardiac" or "Heart"] and ["Sepsis" or "Septic"], with the language limited to English. After initial filtering by the database search engine, Excel software was used to further screen references. Duplicate articles, those without abstracts or full texts, and review/meta-analyses or non-English articles were excluded. Finally, 106 relevant research articles were included for data extraction and analysis. Results The pathogenesis of SIMD is complex and involves mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis and pyroptosis, dysregulation of myocardial calcium homeostasis, myocardial inhibitory factors, autonomic nervous regulation disorders, hemodynamic changes, and myocardial structural alterations. miRNAs play diverse roles in SIMD. They are involved in regulating the above-mentioned pathological processes. Discussion Although significant progress has been made in understanding the role of miRNAs in SIMD, there are still challenges. Some studies on the pathogenesis of SIMD have limitations such as small sample sizes and failure to account for confounding factors. Research on miRNAs also faces issues like inconsistent measurement techniques and unclear miRNA-target gene relationships. Moreover, the translation of miRNA-based research into clinical applications is hindered by problems related to miRNA stability, delivery mechanisms, off-target effects, and long-term safety. In conclusion, miRNAs play a significant role in the pathogenesis of SIMD and have potential as diagnostic biomarkers. Further research is needed to overcome existing challenges and fully exploit the potential of miRNAs in the diagnosis and treatment of SIMD.
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Affiliation(s)
- Zhen Liu
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Feiyang Li
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ningcen Li
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yong Chen
- Department of Critical Care Medicine, Tianjin Hospital of ITCWM Nankai Hospital, Tianjin, China
| | - Zelin Chen
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Jin Y, Fleishman JS, Ma Y, Jing X, Guo Q, Shang W, Wang H. NLRP3 Inflammasome Targeting Offers a Novel Therapeutic Paradigm for Sepsis-Induced Myocardial Injury. Drug Des Devel Ther 2025; 19:1025-1041. [PMID: 39967903 PMCID: PMC11834678 DOI: 10.2147/dddt.s506537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/06/2025] [Indexed: 02/20/2025] Open
Abstract
Cardiac or myocardial dysfunction induced by sepsis, known as sepsis-induced cardiomyopathy or sepsis-induced myocardial injury (SIMI), is a common complication of sepsis and is associated with poor outcomes. However, the pathogenesis and molecular mechanisms underlying SIMI remain poorly understood, requiring further investigations. Emerging evidence has shown that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes contribute to SIMI. Compounds that inhibit NLRP3-associated pyroptosis may exert therapeutic effects against SIMI. In this review, we first outlined the principal elements of the NLRP3 signaling cascade and summarized the recent studies highlighting how NLRP3 activation contributes to the pathogenesis of SIMI. We outlined selective small-molecule modulators that function as NLRP3 inhibitors and delineated their mechanisms of action to attenuate SIMI. Finally, we discuss the major limitations of the current therapeutic paradigm and propose possible strategies to overcome them. This review highlights the pharmacological inhibition of SIMI as a promising therapeutic strategy.
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Affiliation(s)
- Yuzi Jin
- Department of Pediatrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110020, People’s Republic of China
| | - Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, 11439, USA
| | - Yudong Ma
- Department of Critical Care Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110020, People’s Republic of China
| | - Xiaoqing Jing
- Department of Pediatrics, Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Qin Guo
- Department of Pediatrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110020, People’s Republic of China
| | - Weiguang Shang
- Department of Pediatrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110020, People’s Republic of China
| | - Hongquan Wang
- Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, People’s Republic of China
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Wang W, Wang XM, Zhang HL, Zhao R, Wang Y, Zhang HL, Song ZJ. Molecular and metabolic landscape of adenosine triphosphate-induced cell death in cardiovascular disease. World J Cardiol 2024; 16:689-706. [PMID: 39734818 PMCID: PMC11669974 DOI: 10.4330/wjc.v16.i12.689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 10/04/2024] [Accepted: 11/01/2024] [Indexed: 11/26/2024] Open
Abstract
The maintenance of intracellular and extracellular adenosine triphosphate (ATP) levels plays a pivotal role in cardiac function. In recent years, burgeoning attention has been directed towards ATP-induced cell death (AICD), revealing it as a distinct cellular demise pathway triggered by heightened extracellular ATP concentrations, distinguishing it from other forms of cell death such as apoptosis and necrosis. AICD is increasingly acknowledged as a critical mechanism mediating the pathogenesis and progression of various cardiovascular maladies, encompassing myocardial ischemia-reperfusion injury, sepsis-induced cardiomyopathy, hypertrophic cardiomyopathy, arrhythmia, and diabetic cardiomyopathy. Consequently, a comprehensive understanding of the molecular and metabolic underpinnings of AICD in cardiac tissue holds promise for the prevention and amelioration of cardiovascular diseases. This review first elucidates the vital physiological roles of ATP in the cardiovascular system, subsequently delving into the intricate molecular mechanisms and metabolic signatures governing AICD. Furthermore, it addresses the potential therapeutic targets implicated in mitigating AICD for treating cardiovascular diseases, while also delineating the current constraints and future avenues for these innovative therapeutic targets, thereby furnishing novel insights and strategies for the prevention and management of cardiovascular disorders.
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Affiliation(s)
- Wei Wang
- College of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Xue-Mei Wang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 73000, Gansu Province, China
| | - Hao-Long Zhang
- University Sains Malaysia, Advanced Medical and Dental Institute, Penang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yong Wang
- Department of Pathology Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China.
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7
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Verra C, Paulmann MK, Wegener J, Marzani E, Ferreira Alves G, Collino M, Coldewey SM, Thiemermann C. Spleen tyrosine kinase: a novel pharmacological target for sepsis-induced cardiac dysfunction and multi-organ failure. Front Immunol 2024; 15:1447901. [PMID: 39559354 PMCID: PMC11570271 DOI: 10.3389/fimmu.2024.1447901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 10/14/2024] [Indexed: 11/20/2024] Open
Abstract
Sepsis is a systemic condition caused by a dysregulated host response to infection and often associated with excessive release of proinflammatory cytokines resulting in multi-organ failure (MOF), including cardiac dysfunction. Despite a number of effective supportive treatments (e.g. ventilation, dialysis), there are no specific interventions that prevent or reduce MOF in patients with sepsis. To identify possible intervention targets, we re-analyzed the publicly accessible Gene Expression Omnibus accession GSE131761 dataset, which revealed an increased expression of spleen tyrosine kinase (SYK) in the whole blood of septic patients compared to healthy volunteers. This result suggests a potential involvement of SYK in the pathophysiology of sepsis. Thus, we investigated the effects of the highly selective SYK inhibitor PRT062607 (15mg/kg; i.p.) on sepsis-induced cardiac dysfunction and MOF in a clinically-relevant, murine model of sepsis. PRT062607 or vehicle (saline) was administered to 10-weeks-old C57BL/6 mice at 1h after the onset of sepsis induced by cecal ligation and puncture (CLP). Antibiotics (imipenem/cilastatin; 2mg/kg; s.c.) and analgesic (buprenorphine; 0.05mg/kg; i.p.) were administered at 6h and 18h post-CLP. After 24h, cardiac function was assessed in vivo by echocardiography and, after termination of the experiments, serum and cardiac samples were collected to evaluate the effects of SYK inhibition on the systemic release of inflammatory mediators and the degree of organ injury and dysfunction. Our results show that treatment of CLP-mice with PRT062607 significantly reduces systolic and diastolic cardiac dysfunction, renal dysfunction and liver injury compared to CLP-mice treated with vehicle. In addition, the sepsis-induced systemic inflammation (measured as an increase in inflammatory cytokines and chemokines in the serum) and the cardiac activation of NF-kB (IKK) and the NLRP3 inflammasome were significantly reduced in CLP-mice treated with PRT062607. These results demonstrate, for the first time, that SYK inhibition 1h after the onset of sepsis reduces the systemic inflammation, cardiac dysfunction and MOF, suggesting a potential role of the activation of SYK in the pathophysiology of sepsis. Novel therapeutic strategies that inhibit SYK activity may be of benefit in patients with diseases associated with local or systemic inflammation including sepsis.
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Affiliation(s)
- Chiara Verra
- Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom
| | - Maria Kerstin Paulmann
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Jamila Wegener
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Enrica Marzani
- Department of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, Italy
| | | | - Massimo Collino
- Department of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, Italy
| | - Sina Maren Coldewey
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Christoph Thiemermann
- Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom
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8
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Payne FM, Dabb AR, Harrison JC, Sammut IA. Inhibitors of NLRP3 Inflammasome Formation: A Cardioprotective Role for the Gasotransmitters Carbon Monoxide, Nitric Oxide, and Hydrogen Sulphide in Acute Myocardial Infarction. Int J Mol Sci 2024; 25:9247. [PMID: 39273196 PMCID: PMC11395567 DOI: 10.3390/ijms25179247] [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: 07/26/2024] [Revised: 08/21/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024] Open
Abstract
Myocardial ischaemia reperfusion injury (IRI) occurring from acute coronary artery disease or cardiac surgical interventions such as bypass surgery can result in myocardial dysfunction, presenting as, myocardial "stunning", arrhythmias, infarction, and adverse cardiac remodelling, and may lead to both a systemic and a localised inflammatory response. This localised cardiac inflammatory response is regulated through the nucleotide-binding oligomerisation domain (NACHT), leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-3 (NLRP3) inflammasome, a multimeric structure whose components are present within both cardiomyocytes and in cardiac fibroblasts. The NLRP3 inflammasome is activated via numerous danger signals produced by IRI and is central to the resultant innate immune response. Inhibition of this inherent inflammatory response has been shown to protect the myocardium and stop the occurrence of the systemic inflammatory response syndrome following the re-establishment of cardiac circulation. Therapies to prevent NLRP3 inflammasome formation in the clinic are currently lacking, and therefore, new pharmacotherapies are required. This review will highlight the role of the NLRP3 inflammasome within the myocardium during IRI and will examine the therapeutic value of inflammasome inhibition with particular attention to carbon monoxide, nitric oxide, and hydrogen sulphide as potential pharmacological inhibitors of NLRP3 inflammasome activation.
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Affiliation(s)
- Fergus M Payne
- Department of Pharmacology and Toxicology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Alisha R Dabb
- Department of Pharmacology and Toxicology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Joanne C Harrison
- Department of Pharmacology and Toxicology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Ivan A Sammut
- Department of Pharmacology and Toxicology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
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9
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Liu HH, Zhang L, Yang F, Qian LL, Wang RX. The role and mechanism of heme oxygenase-1 in arrhythmias. J Mol Med (Berl) 2024; 102:1001-1007. [PMID: 38937302 DOI: 10.1007/s00109-024-02462-4] [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: 01/22/2024] [Revised: 06/11/2024] [Accepted: 06/18/2024] [Indexed: 06/29/2024]
Abstract
The global incidence and prevalence of arrhythmias are continuously increasing. However, the precise mechanisms of underlying arrhythmogenesis and the optimal measures for effective treatment remain incompletely understood. The inducible form of heme oxygenase, known as heme oxygenase-1 (HO-1), is recognized as a potent antioxidant molecule capable of exerting anti-inflammatory and anti-apoptotic effects. Recent research indicates that HO-1 plays a role in preventing arrhythmias by mitigating cardiac remodeling, including electrical remodeling, ion remodeling, and structural remodeling. This review aimed to consolidate current knowledge regarding the involvement of HO-1 in arrhythmias and elucidate its underlying mechanisms of action.
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Affiliation(s)
- Huan-Huan Liu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Lei Zhang
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Fan Yang
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Ling-Ling Qian
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China
| | - Ru-Xing Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China.
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China.
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10
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Roychowdhury S, Pant B, Cross E, Scheraga R, Vachharajani V. Effect of ethanol exposure on innate immune response in sepsis. J Leukoc Biol 2024; 115:1029-1041. [PMID: 38066660 PMCID: PMC11136611 DOI: 10.1093/jleuko/qiad156] [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: 05/10/2023] [Revised: 11/08/2023] [Accepted: 11/17/2023] [Indexed: 01/06/2024] Open
Abstract
Alcohol use disorder, reported by 1 in 8 critically ill patients, is a risk factor for death in sepsis patients. Sepsis, the leading cause of death, kills over 270,000 patients in the United States alone and remains without targeted therapy. Immune response in sepsis transitions from an early hyperinflammation to persistent inflammation and immunosuppression and multiple organ dysfunction during late sepsis. Innate immunity is the first line of defense against pathogen invasion. Ethanol exposure is known to impair innate and adaptive immune response and bacterial clearance in sepsis patients. Specifically, ethanol exposure is known to modulate every aspect of innate immune response with and without sepsis. Multiple molecular mechanisms are implicated in causing dysregulated immune response in ethanol exposure with sepsis, but targeted treatments have remained elusive. In this article, we outline the effects of ethanol exposure on various innate immune cell types in general and during sepsis.
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Affiliation(s)
- Sanjoy Roychowdhury
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Bishnu Pant
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Emily Cross
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Rachel Scheraga
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
- Department of Pulmonary and Critical Care Medicine, Integrated Hospital-Care Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195, United States
| | - Vidula Vachharajani
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
- Department of Pulmonary and Critical Care Medicine, Integrated Hospital-Care Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195, United States
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11
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Dong W, Liao R, Weng J, Du X, Chen J, Fang X, Liu W, Long T, You J, Wang W, Peng X. USF2 activates RhoB/ROCK pathway by transcriptional inhibition of miR-206 to promote pyroptosis in septic cardiomyocytes. Mol Cell Biochem 2024; 479:1093-1108. [PMID: 37347361 DOI: 10.1007/s11010-023-04781-5] [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: 04/07/2023] [Accepted: 06/03/2023] [Indexed: 06/23/2023]
Abstract
Septic cardiomyopathy (SCM) is one of the most serious complications of sepsis. The present study investigated the role and mechanism of upstream stimulatory factor 2 (USF2) in SCM. Serum samples were extracted from SCM patients and healthy individuals. A murine model of sepsis was induced by caecal ligation and puncture (CLP) surgery. Myocardial injury was examined by echocardiography and HE staining. ELISA assay evaluated myocardial markers (CK-MB, cTnI) and inflammatory cytokines (TNF-α, IL-1β, IL-18). Primary mouse cardiomyocytes were treated with lipopolysaccharide (LPS) to simulate sepsis in vitro. RT-qPCR and Western blot were used for analyzing gene and protein levels. CCK-8 assay assessed cell viability. NLRP3 was detected by immunofluorescence. ChIP, RIP and dual luciferase reporter assays were conducted to validate the molecular associations. USF2 was increased in serum from SCM patients, septic mice and primary cardiomyocytes. USF2 silencing improved the survival of septic mice and attenuated sepsis-induced myocardial pyroptosis and inflammation in vitro and in vivo. Mechanistically, USF2 could directly bind to the promoter of miR-206 to transcriptionally inhibit its expression. Moreover, RhoB was confirmed as a target of miR-206 and could promote ROCK activation and NLRP3 inflammasome formation. Moreover, overexpression of RhoB remarkably reversed the protection against LPS-induced inflammation and pyroptosis mediated by USF2 deletion or miR-206 overexpression in cardiomyocytes. The above findings elucidated that USF2 knockdown exerted a cardioprotective effect on sepsis by decreasing pyroptosis and inflammation via miR-206/RhoB/ROCK pathway, suggesting that USF2 may be a novel drug target in SCM.
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Affiliation(s)
- Wei Dong
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Ruichun Liao
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Junfei Weng
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Xingxiang Du
- Department of Emergency, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Jin Chen
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Xu Fang
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Wenyu Liu
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Tao Long
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Jiaxiang You
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Wensheng Wang
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Xiaoping Peng
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Waizheng Road, Donghu District, Nanchang, 330006, Jiangxi Province, People's Republic of China.
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Wu R, Xu J, Zeng H, Fan Y, Li H, Peng T, Xiao F. Golden bifid treatment regulates gut microbiota and serum metabolites to improve myocardial dysfunction in cecal ligation and puncture-induced sepsis mice. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167049. [PMID: 38301856 DOI: 10.1016/j.bbadis.2024.167049] [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: 07/27/2023] [Revised: 01/07/2024] [Accepted: 01/25/2024] [Indexed: 02/03/2024]
Abstract
Myocardial damage is a major consequence and a significant contributor to death in cases of sepsis, a severe infection characterized by a distinct inflammatory response and a potential threat to the patient's life. Recently, the effects of intestinal microbiota and serum metabolites on sepsis have garnered increasing attention. Herein, the effects of golden bifid treatment upon cecal ligation and puncture (CLP)-induced sepsis in mice as a model for myocardial dysfunction were explored. Our results demonstrated that golden bifid treatment partially improved myocardial dysfunction and apoptosis, cardiac inflammation and oxidative stress, and intestinal mucosal permeability and barrier dysfunction in CLP-induced sepsis mice. The intestinal microbiota diversity and abundance were also altered within sepsis mice and improved by golden bifid treatment. Mucispirillum schaedleri, Acinetobacter baumannii and Lactobacullus intestinalis were significantly correlated with heart damage markers, inflammatory factors, or oxidative stress indicators. Serum differential metabolite levels were also significantly correlated with these parameters. Altogether, golden bifid treatment might be an underlying approach for treating sepsis-induced myocardial dysfunction and highlight the underlying effect of intestinal microbiota and serum metabolites on the pathogenesis and treatment of sepsis-triggered myocardial dysfunction.
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Affiliation(s)
- Rui Wu
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Junmei Xu
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Hua Zeng
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yongmei Fan
- Department of Rehabilitation, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Hui Li
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Tian Peng
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Feng Xiao
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
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13
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Weber S, Sitte S, Voegele AL, Sologub L, Wilfer A, Rath T, Nägel A, Zundler S, Franchi L, Opipari AW, Sonnewald S, Reid S, Hartmann A, Eichhorn P, Handtrack C, Weber K, Grützmann R, Neufert C, Schellerer VS, Naschberger E, Ekici AB, Büttner C, Neurath MF, Atreya R. NLRP3 Inhibition Leads to Impaired Mucosal Fibroblast Function in Patients with Inflammatory Bowel Diseases. J Crohns Colitis 2024; 18:446-461. [PMID: 37748021 DOI: 10.1093/ecco-jcc/jjad164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 08/17/2023] [Accepted: 09/22/2023] [Indexed: 09/27/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel diseases (IBD) are characterized by mucosal inflammation and sequential fibrosis formation, but the exact role of the hyperactive NLRP3 inflammasome in these processes is unclear. Thus, we studied the expression and function of the NLRP3 inflammasome in the context of inflammation and fibrosis in IBD. METHODS We analysed intestinal NLRP3 expression in mucosal immune cells and fibroblasts from IBD patients and NLRP3-associated gene expression via single-cell RNA sequencing and microarray analyses. Furthermore, cytokine secretion of NLRP3 inhibitor treated blood and mucosal cells, as well as proliferation, collagen production, and cell death of NLRP3 inhibitor treated intestinal fibroblasts from IBD patients were studied. RESULTS We found increased NLRP3 expression in the inflamed mucosa of IBD patients and NLRP3 inhibition led to reduced IL-1β and IL-18 production in blood cells and diminished the bioactive form of mucosal IL-1β. Single cell analysis identified overlapping expression patterns of NLRP3 and IL-1β in classically activated intestinal macrophages and we also detected NLRP3 expression in CD163+ macrophages. In addition, NLRP3 expression was also found in intestinal fibroblasts from IBD patients. Inhibition of NLRP3 led to reduced proliferation of intestinal fibroblasts, which was associated with a marked decrease in production of collagen type I and type VI in IBD patients. Moreover, NLRP3 inhibition in intestinal fibroblasts induced autophagy, a cellular process involved in collagen degradation. CONCLUSIONS In the presented study, we demonstrate that inhibiting NLRP3 might pave the way for novel therapeutic approaches in IBD, especially to prevent the severe complication of intestinal fibrosis formation.
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Affiliation(s)
- Simone Weber
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Selina Sitte
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Anna-Lena Voegele
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Ludmilla Sologub
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Angelika Wilfer
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Timo Rath
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Andreas Nägel
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sebastian Zundler
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Luigi Franchi
- SVP, Translational Medicine, Odyssey Therapeutics, Michigan, USA
| | | | - Sophia Sonnewald
- Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Stephen Reid
- Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Arndt Hartmann
- Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Philip Eichhorn
- Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Claudia Handtrack
- Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Klaus Weber
- Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Robert Grützmann
- Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Clemens Neufert
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Vera S Schellerer
- Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Elisabeth Naschberger
- Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Arif B Ekici
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Büttner
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Raja Atreya
- First Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie [DZI], Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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Fan Y, Guan B, Xu J, Zhang H, Yi L, Yang Z. Role of toll-like receptor-mediated pyroptosis in sepsis-induced cardiomyopathy. Biomed Pharmacother 2023; 167:115493. [PMID: 37734261 DOI: 10.1016/j.biopha.2023.115493] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/08/2023] [Accepted: 09/12/2023] [Indexed: 09/23/2023] Open
Abstract
Sepsis, a life-threatening dysregulated status of the host response to infection, can cause multiorgan dysfunction and mortality. Sepsis places a heavy burden on the cardiovascular system due to the pathological imbalance of hyperinflammation and immune suppression. Myocardial injury and cardiac dysfunction caused by the aberrant host responses to pathogens can lead to cardiomyopathy, one of the most critical complications of sepsis. However, many questions about the specific mechanisms and characteristics of this complication remain to be answered. The causes of sepsis-induced cardiac dysfunction include abnormal cardiac perfusion, myocardial inhibitory substances, autonomic dysfunction, mitochondrial dysfunction, and calcium homeostasis dysregulation. The fight between the host and pathogens acts as the trigger for sepsis-induced cardiomyopathy. Pyroptosis, a form of programmed cell death, plays a critical role in the progress of sepsis. Toll-like receptors (TLRs) act as pattern recognition receptors and participate in innate immune pathways that recognize damage-associated molecular patterns as well as pathogen-associated molecular patterns to mediate pyroptosis. Notably, pyroptosis is tightly associated with cardiac dysfunction in sepsis and septic shock. In line with these observations, induction of TLR-mediated pyroptosis may be a promising therapeutic approach to treat sepsis-induced cardiomyopathy. This review focuses on the potential roles of TLR-mediated pyroptosis in sepsis-induced cardiomyopathy, to shed light on this promising therapeutic approach, thus helping to prevent and control septic shock caused by cardiovascular disorders and improve the prognosis of sepsis patients.
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Affiliation(s)
- Yixuan Fan
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Intensive Care Unit, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Baoyi Guan
- Department of Internal Medicine-Cardiovascular, The First Affiliated Hospital of Guangzhou University of Chinese Medicine
| | - Jianxing Xu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Intensive Care Unit, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - He Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China; National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Liang Yi
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Intensive Care Unit, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Zhixu Yang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Intensive Care Unit, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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15
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Wen Y, Liu Y, Liu W, Liu W, Dong J, Liu Q, Hao H, Ren H. Research progress on the activation mechanism of NLRP3 inflammasome in septic cardiomyopathy. Immun Inflamm Dis 2023; 11:e1039. [PMID: 37904696 PMCID: PMC10549821 DOI: 10.1002/iid3.1039] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 09/15/2023] [Accepted: 09/20/2023] [Indexed: 11/01/2023] Open
Abstract
Sepsis is an uncontrolled host response to infection, resulting in a clinical syndrome involving multiple organ dysfunctions. Cardiac damage is the most common organ damage in sepsis. Uncontrolled inflammatory response is an important mechanism in the pathogenesis of septic cardiomyopathy (SCM). NLRP3 inflammasome promotes inflammatory response by controlling the activation of caspase-1 and the release of pro-inflammatory cytokines interleukin IL-1β and IL-18. The role of NLRP3 inflammasome has received increasing attention, but its activation mechanism and regulation of inflammation in SCM remain to be investigated.
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Affiliation(s)
- Yuqi Wen
- Shandong University of Traditional Chinese MedicineJinanChina
| | - Yang Liu
- Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinanChina
| | - Weihong Liu
- Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinanChina
| | - Wenli Liu
- Shandong University of Traditional Chinese MedicineJinanChina
| | - Jinyan Dong
- Shandong University of Traditional Chinese MedicineJinanChina
| | - Qingkuo Liu
- Shandong University of Traditional Chinese MedicineJinanChina
| | - Hao Hao
- Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinanChina
| | - Hongsheng Ren
- Department of Intensive Care UnitShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
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16
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Verra C, Mohammad S, Alves GF, Porchietto E, Coldewey SM, Collino M, Thiemermann C. Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failure. Front Immunol 2023; 14:1223014. [PMID: 37781388 PMCID: PMC10536262 DOI: 10.3389/fimmu.2023.1223014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 08/07/2023] [Indexed: 10/03/2023] Open
Abstract
Sepsis is one of the major complications of surgery resulting in high morbidity and mortality, but there are no specific therapies for sepsis-induced organ dysfunction. Data obtained under Gene Expression Omnibus accession GSE131761 were re-analyzed and showed an increased gene expression of Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3) in the whole blood of post-operative septic patients. Based on these results, we hypothesized that JAK/STAT activation may contribute to the pathophysiology of septic shock and, hence, investigated the effects of baricitinib (JAK1/JAK2 inhibitor) on sepsis-induced cardiac dysfunction and multiple-organ failure (MOF). In a mouse model of post-trauma sepsis induced by midline laparotomy and cecal ligation and puncture (CLP), 10-week-old male (n=32) and female (n=32) C57BL/6 mice received baricitinib (1mg/kg; i.p.) or vehicle at 1h or 3h post-surgery. Cardiac function was assessed at 24h post-CLP by echocardiography in vivo, and the degree of MOF was analyzed by determination of biomarkers in the serum. The potential mechanism underlying both the cardiac dysfunction and the effect of baricitinib was analyzed by western blot analysis in the heart. Trauma and subsequent sepsis significantly depressed the cardiac function and induced multiple-organ failure, associated with an increase in the activation of JAK2/STAT3, NLRP3 inflammasome and NF- κβ pathways in the heart of both male and female animals. These pathways were inhibited by the administration of baricitinib post the onset of sepsis. Moreover, treatment with baricitinib at 1h or 3h post-CLP protected mice from sepsis-induced cardiac injury and multiple-organ failure. Thus, baricitinib may be repurposed for trauma-associated sepsis.
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Affiliation(s)
- Chiara Verra
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Shireen Mohammad
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | | | - Elisa Porchietto
- Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy
| | - Sina Maren Coldewey
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Massimo Collino
- Department of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, Italy
| | - Christoph Thiemermann
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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Sun F, Xu K, Zhou J, Zhang W, Duan G, Lei M. Allicin protects against LPS-induced cardiomyocyte injury by activating Nrf2-HO-1 and inhibiting NLRP3 pathways. BMC Cardiovasc Disord 2023; 23:410. [PMID: 37596540 PMCID: PMC10439633 DOI: 10.1186/s12872-023-03442-1] [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: 04/28/2023] [Accepted: 08/09/2023] [Indexed: 08/20/2023] Open
Abstract
BACKGROUND Allicin is a bioactive compound with potent antioxidative activity and plays a protective effect in myocardial damage and fibrosis. The role and mechanism of Allicin in septic cardiomyopathy are unclear. In this study, we investigated the effects and underlying mechanisms of Allicin on lipopolysaccharide (LPS) induced injury in H9c2 cardiomyocytes. METHODS H9c2 cardiomyocyte cells were pretreated with Allicin (0, 25, 50, and 100 µM) for 2 h, followed by incubation with LPS (10 µg/mL) for 24 h at 37 °C. Cell viability (cell counting kit-8 [CCK-8]), apoptosis (TUNEL staining), oxidative stress (malondialdehyde [MDA] and superoxide dismutase [SOD]), and cytokines release (Interleukin beta [IL-β], Interleukin 6 [IL-6], and tumor necrosis factor-alpha [TNF-α]) were determined. The mRNA and protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NLR family pyrin domain containing 3 (NLRP3) signaling pathway molecules were quantified by real-time quantitative PCR (RT-qPCR) and western blot, respectively. RESULTS Allicin had no effect on H9c2 cell viability but attenuated LPS-induced injury, with increased cell viability, reduction in inflammatory cytokines release, apoptosis, reduced MDA, and increased SOD (P < 0.05). Additionally, Allicin increased Nrf2 and cellular HO-1 expressions in LPS-treated H9c2 cells. Moreover, Allicin modulated the NLRP3 inflammasome, increased the cleaved caspase-1 (p10) protein, and attenuated the LPS-induced increase in NLRP3, pro-IL-1β, and IL-1β proteins. Silencing of Nrf2 by siRNA (siNrf2) significantly attenuated Allicin-induced increase in cell viability and HO-1 and decrease in NLRP3 protein in LPS-stimulated H9c2 cells. CONCLUSIONS Allicin protects cardiomyocytes against LPS‑induced injury through activation of Nrf2/HO-1 and inhibition of NLRP3 signaling pathways.
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Affiliation(s)
- Fangyuan Sun
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No.358, Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Kailiang Xu
- Department of Critical Care Medicine, The Seventh People's Hospital of Shanghai University of TCM, Shanghai, 200137, China
| | - Jiayi Zhou
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No.358, Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Wei Zhang
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No.358, Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Guihe Duan
- Department of Critical Care Medicine, The Shache County People's Hospital of Xinjiang Kashgar Prefecture, Xinjiang, 844710, China
| | - Ming Lei
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No.358, Datong Road, Pudong New Area, Shanghai, 200137, China.
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18
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Zhou W, Yu C, Long Y. Myo-inositol oxygenase (MIOX) accelerated inflammation in the model of infection-induced cardiac dysfunction by NLRP3 inflammasome. Immun Inflamm Dis 2023; 11:e829. [PMID: 37249295 PMCID: PMC10161780 DOI: 10.1002/iid3.829] [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: 08/14/2022] [Revised: 03/19/2023] [Accepted: 03/21/2023] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND Cardiac dysfunction is an important component of multiple organ failure caused by sepsis, and an important cause of high mortality in patients with sepsis. Herein, we attempted to determine whether myo-inositol oxygenase (MIOX) has proinflammation enzyme in infection-induced cardiac dysfunction (IICD) and its underlying mechanism. METHODS Patients with IICD were collected by our hospital. A mouse model of IICD was induced into male db/db mice by cecal ligation and puncture (CLP). All mice were injected with 20 μL of LV-MIOX or LV-control short hairpin RNA using a 0.5-mL insulin syringe. On the second day, all mice were induced by CLP. H9C2 cell was also induced with lipopolysaccharide and adenosine triphosphate. Quantitative analysis of messenger RNAs (mRNAs) and gene microarray hybridization was used to analyze the mRNA expression levels. Enzyme-linked immunosorbent assay, immunofluorescence, and Western blot analysis were used to analyze the protein expression levels. RESULTS The serum expressions of MIOX mRNA level in patients with IICD were upregulated compared to normal healthy volunteers. MIOX promoted inflammation levels in the in vitro model of IICD. Si-MIOX inhibited inflammation levels in the in vitro model of IICD. MIOX accelerated inflammation and cardiac dysfunction in infection-induced mice. MIOX interacted with NLR family pyrin domain containing 3 (NLRP3) protein to reduce the degradation of NLRP3. The inhibition of MIOX reversed the effects of NLRP3 in the in vitro model of cardiac dysfunction. CONCLUSIONS Taken together, these findings demonstrate that MIOX accelerates inflammation in the model of IICD, which may be, at least in part, attributable to NLRP3 activity by the suppression of NLRP3 degradation in IICD.
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Affiliation(s)
- Wenjun Zhou
- Department of Critical Care Medicine, Ruijin Hospital, Lu Wan BranchShanghai Jiaotong University School of MedicineShanghaiChina
| | - Congyi Yu
- Department of Critical Care Medicine, Ruijin Hospital, Lu Wan BranchShanghai Jiaotong University School of MedicineShanghaiChina
| | - Yiwen Long
- Department of Critical Care Medicine, Ruijin Hospital, Lu Wan BranchShanghai Jiaotong University School of MedicineShanghaiChina
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Yao H, Liu S, Zhang Z, Xiao Z, Li D, Yi Z, Huang Y, Zhou H, Yang Y, Zhang W. A bibliometric analysis of sepsis-induced myocardial dysfunction from 2002 to 2022. Front Cardiovasc Med 2023; 10:1076093. [PMID: 36793476 PMCID: PMC9922860 DOI: 10.3389/fcvm.2023.1076093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/09/2023] [Indexed: 01/31/2023] Open
Abstract
Background Sepsis-induced myocardial dysfunction (SIMD) has a significant contribution to sepsis-caused death in critically ill patients. In recent years, the number of published articles related to SIMD has increased rapidly. However, there was no literature that systematically analyzed and evaluated these documents. Thus, we aimed to lay a foundation for researchers to quickly understand the research hotspots, evolution processes and development trends in the SIMD field via a bibliometric analysis. Methods Articles related to SIMD were retrieved and extracted from the Web of Science Core Collection on July 19th, 2022. CiteSpace (version 6.1.R2) and VOSviewer (version 1.6.18) were used for performing visual analysis. Results A total of 1,076 articles were included. The number of SIMD-related articles published each year has increased significantly. These publications mainly came from 56 countries, led by China and the USA, and 461 institutions, but without stable and close cooperation. As authors, Li Chuanfu published the most articles, while Rudiger Alain had the most co-citations. Shock was the journal with the most studies, and Critical Care Medicine was the most commonly cited journal. All keywords were grouped into six clusters, some of which represented the current and developing research directions of SIMD as the molecular mechanisms. Conclusion Research on SIMD is flourishing. It is necessary to strengthen cooperation and exchanges between countries and institutions. The molecular mechanisms of SIMD, especially oxidative stress and regulated cell death, will be critical subjects in the future.
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Affiliation(s)
- Hanyi Yao
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China,Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shufang Liu
- Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhiyu Zhang
- Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zixi Xiao
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Dongping Li
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China,Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhangqing Yi
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China,Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yuyang Huang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Haojie Zhou
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yifeng Yang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China,Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Weizhi Zhang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China,Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Weizhi Zhang,
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20
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Tang N, Tian W, Ma GY, Xiao X, Zhou L, Li ZZ, Liu XX, Li CY, Wu KH, Liu W, Wang XY, Gao YY, Yang X, Qi J, Li D, Liu Y, Chen WS, Gao J, Li XQ, Cao W. TRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and Ca 2+ leakage. Nat Commun 2022; 13:7455. [PMID: 36460692 PMCID: PMC9718841 DOI: 10.1038/s41467-022-35242-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 11/23/2022] [Indexed: 12/04/2022] Open
Abstract
Intracellular Ca2+ dysregulation is a key marker in septic cardiac dysfunction; however, regulation of the classic Ca2+ regulatory modules cannot successfully abolish this symptom. Here we show that the knockout of transient receptor potential canonical (TRPC) channel isoforms TRPC1 and TRPC6 can ameliorate LPS-challenged heart failure and prolong survival in mice. The LPS-triggered Ca2+ release from the endoplasmic reticulum both in cardiomyocytes and macrophages is significantly inhibited by Trpc1 or Trpc6 knockout. Meanwhile, TRPC's molecular partner - calmodulin - is uncoupled during Trpc1 or Trpc6 deficiency and binds to TLR4's Pococurante site and atypical isoleucine-glutamine-like motif to block the inflammation cascade. Blocking the C-terminal CaM/IP3R binding domain in TRPC with chemical inhibitor could obstruct the Ca2+ leak and TLR4-mediated inflammation burst, demonstrating a cardioprotective effect in endotoxemia and polymicrobial sepsis. Our findings provide insight into the pathogenesis of endotoxemic cardiac dysfunction and suggest a novel approach for its treatment.
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Affiliation(s)
- Na Tang
- grid.144022.10000 0004 1760 4150Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi China ,grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
| | - Wen Tian
- grid.233520.50000 0004 1761 4404Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi China ,grid.233520.50000 0004 1761 4404Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi’an, Shaanxi China
| | - Guang-Yuan Ma
- grid.144022.10000 0004 1760 4150Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi China ,grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
| | - Xiong Xiao
- grid.233520.50000 0004 1761 4404Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi China ,grid.233520.50000 0004 1761 4404Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi’an, Shaanxi China
| | - Lei Zhou
- grid.144022.10000 0004 1760 4150Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi China ,grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
| | - Ze-Zhi Li
- grid.144022.10000 0004 1760 4150Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi China ,grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
| | - Xiao-Xiao Liu
- grid.233520.50000 0004 1761 4404Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi China ,grid.233520.50000 0004 1761 4404Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi’an, Shaanxi China
| | - Chong-Yao Li
- grid.412262.10000 0004 1761 5538Department of Pharmacy, Xi’an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, Shaanxi China
| | - Ke-Han Wu
- grid.144022.10000 0004 1760 4150Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi China ,grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
| | - Wenjuan Liu
- grid.144022.10000 0004 1760 4150Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi China
| | - Xue-Ying Wang
- grid.233520.50000 0004 1761 4404Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi China ,grid.233520.50000 0004 1761 4404Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi’an, Shaanxi China
| | - Yuan-Yuan Gao
- grid.233520.50000 0004 1761 4404Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi China ,grid.233520.50000 0004 1761 4404Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi’an, Shaanxi China
| | - Xin Yang
- grid.144022.10000 0004 1760 4150Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi China ,grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
| | - Jianzhao Qi
- grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
| | - Ding Li
- grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
| | - Yang Liu
- grid.233520.50000 0004 1761 4404Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi China
| | - Wen-Sheng Chen
- grid.233520.50000 0004 1761 4404Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi China ,Department of Cardiovascular Surgery, Xi’an Gaoxin Hospital, Xi’an, Shaanxi China
| | - Jinming Gao
- grid.144022.10000 0004 1760 4150Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi China ,grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
| | - Xiao-Qiang Li
- grid.233520.50000 0004 1761 4404Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi China ,grid.233520.50000 0004 1761 4404Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi’an, Shaanxi China
| | - Wei Cao
- grid.144022.10000 0004 1760 4150Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi China ,grid.144022.10000 0004 1760 4150Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi China
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21
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Mu Y, Li W, Yang X, Chen J, Weng Y. Partially Reduced MIL-100(Fe) as a CO Carrier for Sustained CO Release and Regulation of Macrophage Phenotypic Polarization. ACS Biomater Sci Eng 2022; 8:4777-4788. [PMID: 36256970 DOI: 10.1021/acsbiomaterials.2c00959] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Carbon monoxide (CO) is a bioactive molecule with high potential as it shows promising efficacy for regulating inflammation. Materials capable of storing and delivering CO are of great potential therapeutic value. Although CO-releasing molecules (CORMs) have been developed to deliver CO, the short CO duration of minutes to 2 h confines their practical use. In this study, partially reduced MIL-100(Fe) as a new CO-releasing nanoMOF was developed and used for sustained CO release and macrophage (MA) phenotypic polarization regulation. MIL-100(Fe) was synthesized and mildly annealed in vacuum for partial reduction. When the annealing temperature was lower than 250 °C, less Fe(II) present in MIL-100(Fe) and the subsequent CO adsorption and desorption profiles displayed typical features of physisorption. While it was annealed at 250 °C, it showed about 20% of Fe(III) was reduced, which resulted in chemisorption of CO due to the high coordination affinity of Fe(II) to CO. The loading amount of CO was increased, and the CO release was prolonged for about 24 h. Furthermore, the CO release from this nanoMOF could alter the lipopolysaccharide (LPS)-induced macrophage from M1 to the alternative M2 phenotype and promoted the growth of endothelial cells (ECs) by paracrine regulation of MA. It can be envisioned as a promising CO-releasing solid for biomedical application.
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Affiliation(s)
- Yixian Mu
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China
| | - Weijie Li
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China
| | - Xinlei Yang
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China
| | - Junying Chen
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China
| | - Yajun Weng
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China
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22
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Wen R, Liu YP, Tong XX, Zhang TN, Yang N. Molecular mechanisms and functions of pyroptosis in sepsis and sepsis-associated organ dysfunction. Front Cell Infect Microbiol 2022; 12:962139. [PMID: 35967871 PMCID: PMC9372372 DOI: 10.3389/fcimb.2022.962139] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/06/2022] [Indexed: 12/17/2022] Open
Abstract
Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death in intensive care units. The development of sepsis-associated organ dysfunction (SAOD) poses a threat to the survival of patients with sepsis. Unfortunately, the pathogenesis of sepsis and SAOD is complicated, multifactorial, and has not been completely clarified. Recently, numerous studies have demonstrated that pyroptosis, which is characterized by inflammasome and caspase activation and cell membrane pore formation, is involved in sepsis. Unlike apoptosis, pyroptosis is a pro-inflammatory form of programmed cell death that participates in the regulation of immunity and inflammation. Related studies have shown that in sepsis, moderate pyroptosis promotes the clearance of pathogens, whereas the excessive activation of pyroptosis leads to host immune response disorders and SAOD. Additionally, transcription factors, non-coding RNAs, epigenetic modifications and post-translational modifications can directly or indirectly regulate pyroptosis-related molecules. Pyroptosis also interacts with autophagy, apoptosis, NETosis, and necroptosis. This review summarizes the roles and regulatory mechanisms of pyroptosis in sepsis and SAOD. As our understanding of the functions of pyroptosis improves, the development of new diagnostic biomarkers and targeted therapies associated with pyroptosis to improve clinical outcomes appears promising in the future.
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Affiliation(s)
| | | | | | | | - Ni Yang
- *Correspondence: Tie-Ning Zhang, ; Ni Yang,
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23
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Li W, Shen X, Feng S, Liu Y, Zhao H, Zhou G, Sang M, Sun X, Jiao R, Liu F. BRD4 inhibition by JQ1 protects against LPS-induced cardiac dysfunction by inhibiting activation of NLRP3 inflammasomes. Mol Biol Rep 2022; 49:8197-8207. [PMID: 35854052 DOI: 10.1007/s11033-022-07377-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/15/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND JQ1, a BRD4 inhibitor, first identified its therapeutic role in cancer, has gradually demonstrated a protective effect on the heart in recent years; however, it is unclear whether JQ1 also plays a role in LPS-induced cardiac dysfunction. METHODS AND RESULTS A total of forty eight mice were randomly divided into control, LPS(7.5 mg/kg), and LPS + JQ1 (50 mg/kg). JQ1 was preprotected for 1 h, and LPS was stimulated for 12 h, mouse survival and cardiac function were observed, and histopathological, serum myocardial injury markers, and inflammatory indicators, and oxidative stress levels in heart tissue were examined. The experiment found that the cardiac BRD4 levels were upregulated and the heart severe damage in the LPS group compared with the control group. While compared with the LPS group, JQ1 preprotected increased survival rate and cardiac function, reducated cardiomypathological injury and CD45 infiltration, and reduced the release of LDH, CK-MB, IL-1, IL-18, reduced MDA generation, and increased SOD viability. In addition, JQ1 preprotected also upregulated SIRT1, and inhibited the expression of NLRP3, caspase-1p20, and GSDMD. Meanwhile, similar results were obtained in LPS-treated H9C2 cells, and further intervention with the SIRT1 inhibitor EX527 partially blocked the JQ1-mediated down regulation of NLRP3, caspase-1p20, and GSDMD. CONCLUSIONS We propose that JQ1 may improve LPS-induced cardiac dysfunction by inhibiting SIRT1-dependent activation of NLRP3 inflammasomes, which may be a promising strategy for treating sepsis cardiomyopathy.
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Affiliation(s)
- Wenjun Li
- Department of Cardiology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China
| | - XiuFeng Shen
- Department of Cardiology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China
| | - Shenglan Feng
- Department of Basic Medicine, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China
| | - Yue Liu
- Department of Pediatrics, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China
| | - Huiying Zhao
- Department of Cardiology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China
| | - Guohao Zhou
- Department of Cardiology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China
| | - Ming Sang
- Department of Basic Medicine, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China
| | - Xiaodong Sun
- Department of Basic Medicine, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China
| | - Rong Jiao
- Department of Pediatrics, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China.
| | - Fuyuan Liu
- Department of Cardiology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Hubei Province, Xiangyang, 441500, People's Republic of China.
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24
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Kwong AM, Luke PPW, Bhattacharjee RN. Carbon monoxide mechanism of protection against renal ischemia and reperfusion injury. Biochem Pharmacol 2022; 202:115156. [PMID: 35777450 DOI: 10.1016/j.bcp.2022.115156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 12/20/2022]
Abstract
Carbon monoxide is quickly moving past its historic label as a molecule once feared, to a therapeutic drug that modulates inflammation. The development of carbon monoxide releasing molecules and utilization of heme oxygenase-1 inducers have shown carbon monoxide to be a promising therapy in reducing renal ischemia and reperfusion injury and other inflammatory diseases. In this review, we will discuss the developments and application of carbon monoxide releasing molecules in renal ischemia and reperfusion injury, and transplantation. We will review the anti-inflammatory mechanisms of carbon monoxide in respect to mitigating apoptosis, suppressing dendritic cell maturation and signalling, inhibiting toll-like receptor activation, promoting anti-inflammatory responses, and the effects on renal vasculature.
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Affiliation(s)
- Aaron M Kwong
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Patrick P W Luke
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Surgery, London Health Sciences Centre, Canada; Matthew Mailing Centre for Translational Transplantation Studies, Canada.
| | - Rabindra N Bhattacharjee
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Surgery, London Health Sciences Centre, Canada; Matthew Mailing Centre for Translational Transplantation Studies, Canada.
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25
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Xia Z, Zhang C, Guo C, Song B, Hu W, Cui Y, Xue Y, Xia M, Xu D, Zhang S, Fang J. Nanoformulation of a carbon monoxide releasing molecule protects against cyclosporin A-induced nephrotoxicity and renal fibrosis via the suppression of the NLRP3 inflammasome mediated TGF-β/Smad pathway. Acta Biomater 2022; 144:42-53. [PMID: 35304324 DOI: 10.1016/j.actbio.2022.03.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 12/14/2022]
Abstract
Cyclosporin A (CsA) induced nephrotoxicity i.e., renal fibrosis is a critical clinical problem in renal transplant patients, in which chronic inflammatory response is the major cause. Previously, we developed a nano-drug delivery system for carbon monoxide (CO), a multi-functional gaseous molecule with a potent anti-inflammatory effect, i.e., SMA/CORM2, which showed therapeutic potential in several inflammatory disease models. Accordingly, in this study, we explored the potential and usefulness of SMA/CORM2 on CsA induced renal fibrosis. When mice were exposed to CsA for 4 weeks, severe injuries in the kidney as revealed by decreased kidney function and histological examination, and activation of NLRP3 inflammasome, as well as renal fibrosis along with the upregulation of transforming growth factor β (TGFβ)/Smad signaling molecule were observed, whereas SMA/CORM2 (1 mg/kg) treatment remarkably ameliorated the inflammatory injury and fibrosis in the kidney. CO is the major effector molecule of SMA/CORM2 which significantly suppressed the activation of NLRP3 inflammasome, and induced the downregulation of TGFβ/Smad signaling. Inhibition of NLRP3 inflammasome by its inhibitor MCC950 also similarly decreased TGFβ/Smad expression and subsequently improved kidney injury and renal fibrosis, suggesting SMA/CORM2 induced suppression of TGFβ/Smad signaling and renal signaling via an NLRP3 inflammasome-dependent pathway. Compared to native CORM2, SMA/CORM2 exhibited better therapeutic/preventive effects owing to its superior water-solubility and bioavailability. These findings strongly indicated the applicability of SMA/CORM2 as an enhanced permeability and retention (EPR) effect-based nanomedicine for CsA induced renal fibrosis as well as other inflammatory diseases. STATEMENT OF SIGNIFICANCE: Carbon monoxide (CO) is an important gaseous signaling molecule that plays a crucial role in the maintenance of homeostasis. Because of its versatile functions, it exhibits the potential as the target molecule for many diseases, including inflammatory diseases and cancer. The development of stable and disease-targeted delivery systems of CO is thus of interest and importance. Previously we developed a nano micellar CO donor SMA/CORM2 which shows superior bioavailability and therapeutic potential in many inflammatory disease models. We reported here, SMA/CORM2, through controlled release of CO, greatly ameliorated CsA-induced renal fibrosis via suppressing the NLRP3 inflammasome mediated TGF-β/Smad pathway. These findings suggest a new anti-inflammatory mechanism of CO, which also provides a new approach for controlling CsA-induced nephrotoxicity.
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26
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Zhu Z, Chambers S, Zeng Y, Bhatia M. Gases in Sepsis: Novel Mediators and Therapeutic Targets. Int J Mol Sci 2022; 23:3669. [PMID: 35409029 PMCID: PMC8998565 DOI: 10.3390/ijms23073669] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Sepsis, a potentially lethal condition resulting from failure to control the initial infection, is associated with a dysregulated host defense response to pathogens and their toxins. Sepsis remains a leading cause of morbidity, mortality and disability worldwide. The pathophysiology of sepsis is very complicated and is not yet fully understood. Worse still, the development of effective therapeutic agents is still an unmet need and a great challenge. Gases, including nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), are small-molecule biological mediators that are endogenously produced, mainly by enzyme-catalyzed reactions. Accumulating evidence suggests that these gaseous mediators are widely involved in the pathophysiology of sepsis. Many sepsis-associated alterations, such as the elimination of invasive pathogens, the resolution of disorganized inflammation and the preservation of the function of multiple organs and systems, are shaped by them. Increasing attention has been paid to developing therapeutic approaches targeting these molecules for sepsis/septic shock, taking advantage of the multiple actions played by NO, CO and H2S. Several preliminary studies have identified promising therapeutic strategies for gaseous-mediator-based treatments for sepsis. In this review article, we summarize the state-of-the-art knowledge on the pathophysiology of sepsis; the metabolism and physiological function of NO, CO and H2S; the crosstalk among these gaseous mediators; and their crucial effects on the development and progression of sepsis. In addition, we also briefly discuss the prospect of developing therapeutic interventions targeting these gaseous mediators for sepsis.
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Affiliation(s)
- Zhixing Zhu
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (Z.Z.); (S.C.)
- Department of Internal Medicine (Pulmonary and Critical Care Medicine), The Second Clinical Medical School of Fujian Medical University, Quanzhou 362002, China;
| | - Stephen Chambers
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (Z.Z.); (S.C.)
| | - Yiming Zeng
- Department of Internal Medicine (Pulmonary and Critical Care Medicine), The Second Clinical Medical School of Fujian Medical University, Quanzhou 362002, China;
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (Z.Z.); (S.C.)
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27
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Dai S, Ye B, Zhong L, Chen Y, Hong G, Zhao G, Su L, Lu Z. GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation. Front Cell Dev Biol 2021; 9:779432. [PMID: 34820388 PMCID: PMC8606561 DOI: 10.3389/fcell.2021.779432] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 10/22/2021] [Indexed: 01/06/2023] Open
Abstract
Myocardial dysfunction is a serious consequence of sepsis and contributes to high mortality. Currently, the molecular mechanism of myocardial dysfunction induced by sepsis remains unclear. In the present study, we investigated the role of gasdermin D (GSDMD) in cardiac dysfunction in septic mice and the underlying mechanism. C57BL/6 wild-type (WT) mice and age-matched Gsdmd-knockout (Gsdmd -/-) mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg) to mimic sepsis. The results showed that GSDMD-NT, the functional fragment of GSDMD, was upregulated in the heart tissue of septic WT mice induced by LPS, which was accompanied by decreased cardiac function and myocardial injury, as shown by decreased ejection fraction (EF) and fractional shortening (FS) and increased cardiac troponin I (cTnI), creatine kinase isoenzymes MB (CK-MB), and lactate dehydrogenase (LDH). Gsdmd -/- mice exhibited protection against LPS-induced myocardial dysfunction and had a higher survival rate. Gsdmd deficiency attenuated LPS-induced myocardial injury and cell death. Gsdmd deficiency prevented LPS-induced the increase of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum, as well as IL-1β and TNF-α mRNA levels in myocardium. In addition, LPS-mediated inflammatory cell infiltration into the myocardium was ameliorated and activation of NF-κB signaling pathway and the NOD-like receptor protein 3 (NLPR3) inflammasome were suppressed in Gsdmd -/- mice. Further research showed that in the myocardium of LPS-induced septic mice, GSDMD-NT enrichment in mitochondria led to mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, which further regulated the activation of the NLRP3 inflammasome. In summary, our data suggest that GSDMD plays a vital role in the pathophysiology of LPS-induced myocardial dysfunction and may be a crucial target for the prevention and treatment of sepsis-induced myocardial dysfunction.
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Affiliation(s)
- Shanshan Dai
- The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Bozhi Ye
- The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lingfeng Zhong
- The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanghao Chen
- The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guangliang Hong
- The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guangju Zhao
- The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lan Su
- The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhongqiu Lu
- The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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28
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Feng D, Guo L, Liu J, Song Y, Ma X, Hu H, Liu J, Hao E. DDX3X deficiency alleviates LPS-induced H9c2 cardiomyocytes pyroptosis by suppressing activation of NLRP3 inflammasome. Exp Ther Med 2021; 22:1389. [PMID: 34650637 PMCID: PMC8506920 DOI: 10.3892/etm.2021.10825] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022] Open
Abstract
Increasing evidence suggest that NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis may be the underlying pathological mechanism of sepsis-induced cardiomyopathy. DDX3X, an ATP-dependent RNA helicase, plays a vital role in the formation of the NLRP3 inflammasome by directly interacting with cytoplasmic NLRP3. However, whether DDX3X has a direct impact on lipopolysaccharide (LPS)-induced cardiomyocyte injury by regulating NLRP3 inflammasome assembly remains unclear. The present study aimed to investigate the role of DDX3X in the activation of the NLRP3 inflammasome and determine the molecular mechanism of DDX3X action in LPS-induced pyroptosis in H9c2 cardiomyocytes. H9c2 cardiomyocytes were treated with LPS to simulate sepsis in vitro. The results demonstrated that LPS stimulation upregulated DDX3X expression in H9c2 cardiomyocytes. Furthermore, Ddx3x knockdown significantly attenuated pyroptosis and cell injury in LPS-treated H9c2 cells by suppressing NLRP3 inflammasome activation. Taken together, these results suggest that DDX3X is involved in LPS-induced cardiomyocyte pyroptosis, and DDX3X deficiency mitigates cardiomyocyte damage induced by LPS treatment.
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Affiliation(s)
- Dandan Feng
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Liang Guo
- Department of Anesthesiology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Jing Liu
- Laboratory of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Yunxuan Song
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Jinan, Shandong 250014, P.R. China
| | - Xiuyuan Ma
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Haiyang Hu
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Ju Liu
- Laboratory of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Enkui Hao
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
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Molecular mechanism and therapeutic targeting of necrosis, apoptosis, pyroptosis, and autophagy in cardiovascular disease. Chin Med J (Engl) 2021; 134:2647-2655. [PMID: 34608069 PMCID: PMC8631411 DOI: 10.1097/cm9.0000000000001772] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
ABSTRACT Cell death occurs in various tissues and organs in the body. It is a physiological or pathological process that has different effects. It is of great significance in maintaining the morphological function of cells and clearing abnormal cells. Pyroptosis, apoptosis, and necrosis are all modes of cell death that have been studied extensively by many experts and scholars, including studies on their effects on the liver, kidney, the heart, other organs, and even the whole body. The heart, as the most important organ of the body, should be a particular focus. This review summarizes the mechanisms underlying the various cell death modes and the relationship between the various mechanisms and heart diseases. The current research status for heart therapy is discussed from the perspective of pathogenesis.
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30
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Sepsis-Induced Myocardial Dysfunction (SIMD): the Pathophysiological Mechanisms and Therapeutic Strategies Targeting Mitochondria. Inflammation 2021; 43:1184-1200. [PMID: 32333359 DOI: 10.1007/s10753-020-01233-w] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sepsis is a lethal syndrome with multiple organ failure caused by an inappropriate host response to infection. Cardiac dysfunction is one of the important complications of sepsis, termed sepsis-induced myocardial dysfunction (SIMD), which is characterized by systolic and diastolic dysfunction of both sides of the heart. Mechanisms that contribute to SIMD include an excessive inflammatory response, altered circulatory, microvascular status, nitric oxide (NO) synthesis impairment, endothelial dysfunction, disorders of calcium regulation, cardiac autophagy anomaly, autonomic nervous system dysregulation, metabolic reprogramming, and mitochondrial dysfunction. The role of mitochondrial dysfunction, which is characterized by structural abnormalities, increased oxidative stress, abnormal opening of the mitochondrial permeability transition pore (mPTP), mitochondrial uncoupling, and disordered quality control systems, has been gaining increasing attention as a central player in the pathophysiology of SIMD. The disruption of homeostasis within the organism induced by mitochondrial dysfunction may also be an important aspect of SIMD development. In addition, an emerging therapy strategy targeting mitochondria, namely, metabolic resuscitation, seems promising. The current review briefly introduces the mechanism of SIMD, highlights how mitochondrial dysfunction contributes to SIMD, and discusses the role of metabolic resuscitation in the treatment of SIMD.
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31
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Ryter SW. Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders. Int J Mol Sci 2021; 22:ijms22115509. [PMID: 34073678 PMCID: PMC8197128 DOI: 10.3390/ijms22115509] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 02/07/2023] Open
Abstract
The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases.
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32
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Du Y, Lu Z, Yang D, Wang D, Jiang L, Shen Y, Du Q, Yu W. MerTK inhibits the activation of the NLRP3 inflammasome after subarachnoid hemorrhage by inducing autophagy. Brain Res 2021; 1766:147525. [PMID: 34010608 DOI: 10.1016/j.brainres.2021.147525] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 05/03/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022]
Abstract
The NLR family pyrin domain-containing 3 (NLRP3) multiprotein complex is associated with neuroinflammation and poor prognosis after subarachnoid hemorrhage (SAH). Accumulating evidence shows that Mer tyrosine kinase (MerTK) alleviates inflammatory responses via a negative feedback mechanism. However, the contribution and function of MerTK in SAH remain to be determined. In this study, we explored the role of MerTK during microglial NLRP3 inflammasome activation and evaluated its contribution to the outcome of SAH in mice. Activating MerTK with growth arrest-specific 6 (Gas6) alleviated brain edema, neuronal degeneration and neurological deficits after SAH by regulating neuroinflammation. Gas6 did not change the mRNA levels of Nlrp3 or Casp1 but decreased the protein expression of NLRP3, cleaved caspase1 (p20), interleukin-1β and interleukin-18. Furthermore, Gas6 increased the expression of Beclin1, the ratio of LC3-II/LC3-I and the level of autophagic flux. Inhibiting autophagy with 3-MA reversed the inhibition of NLRP3 inflammasome activation and diminished the neuroprotective effects of Gas6. Thus, MerTK activation may exert protective effects by limiting neuroinflammation and promoting neurological recovery after SAH via autophagy induction.
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Affiliation(s)
- Yuanfeng Du
- Department of Neurosurgery, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, China; Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhangfan Lu
- The Fouth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Dingbo Yang
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ding Wang
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Li Jiang
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yongfeng Shen
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Quan Du
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Wenhua Yu
- Department of Neurosurgery, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, China; Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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33
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Zhou E, Gong S, Xia Q, Feng G. In Vivo Imaging and Tracking Carbon Monoxide-Releasing Molecule-3 with an NIR Fluorescent Probe. ACS Sens 2021; 6:1312-1320. [PMID: 33576235 DOI: 10.1021/acssensors.0c02624] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
As a water-soluble carbon monoxide-releasing molecule, CORM-3 is widely used as a CO donor to study CO in the life system. CORM-3 can also replace gaseous CO as a therapeutic drug molecule to reveal the physiological and pathological effects of CO in life. Therefore, it is of great importance to visualize and track CORM-3 in the life system. We develop herein a near-infrared (NIR) fluorescent probe CORM3-NIR that can detect CORM-3 both in living cells and in vivo effectively. The probe is based on the unique fluorescent QCy7 and uses a 4-nitrobenzyl group to trap CORM-3, and importantly, it shows good water solubility and responds rapidly, selectively, and sensitively to CORM-3, releasing QCy-7 and producing distinct colorimetric and significant NIR fluorescence change signals at 743 nm. The Stokes shift is up to 81 nm. The probe is also able to detect CORM-3 ratiometrically with fluorescence at 743 and 600 nm. Besides, with low cytotoxicity, the probe also shows good NIR fluorescence bioimaging ability for CORM-3 in live cells and mice, which indicates that CORM3-NIR is an effective probe for tracking and studying CORM-3 in the life system.
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Affiliation(s)
- Enbo Zhou
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University (CCNU), 152 Luoyu Road, Wuhan 430079, P. R. China
| | - Shengyi Gong
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University (CCNU), 152 Luoyu Road, Wuhan 430079, P. R. China
| | - Qingfeng Xia
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University (CCNU), 152 Luoyu Road, Wuhan 430079, P. R. China
| | - Guoqiang Feng
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University (CCNU), 152 Luoyu Road, Wuhan 430079, P. R. China
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34
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Zhang Y, Zhang S, Li B, Luo Y, Gong Y, Jin X, Zhang J, Zhou Y, Zhuo X, Wang Z, Zhao X, Han X, Gao Y, Yu H, Liang D, Zhao S, Sun D, Wang D, Xu W, Qu G, Bo W, Li D, Wu Y, Li Y. Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome. Cardiovasc Res 2021; 118:785-797. [PMID: 33757127 DOI: 10.1093/cvr/cvab114] [Citation(s) in RCA: 144] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/20/2021] [Indexed: 12/13/2022] Open
Abstract
AIMS Aging is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-related diseases. However, whether the aged-associated dysbiosis contributes to age-related AF is still unknown. Direct demonstration that the aged gut microbiota is sufficient to transmit the enhanced AF susceptibility in a young host via microbiota-intestinal barrier-atria axis has not yet been reported. This study aimed to determine whether gut microbiota dysbiosis affects age-related AF. METHODS AND RESULTS Herein, by using a fecal microbiota transplantation (FMT) rat model, we demonstrated that the high AF susceptibility of aged rats could be transmitted to a young host. Specially, we found the dramatically increased levels of circulating lipopolysaccharide (LPS) and glucose led to the up-regulated expression of NLR family pyrin domain containing 3 (NLRP3)-inflammasome, promoting the development of AF which depended on the enhanced atrial fibrosis in recipient host. Inhibition of inflammasome by a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, resulted in a lower atrial fibrosis and AF susceptibility. Then we conducted cross-sectional clinical studies to explore the effect of aging on the altering trends with glucose levels and circulating LPS among clinical individuals in two China hospitals. We found that both of serum LPS and glucose levels were progressively increased in elderly patients as compared with those young. Furthermore, the aging phenotype of circulating LPS and glucose levels, intestinal structure and atrial NLRP3-inflammasome of rats were also confirmed in clinical AF patients. Finally, aged rats colonized with youthful microbiota restored intestinal structure and atrial NLRP3-inflammasome activity, which suppressed the development of aged-related AF. CONCLUSIONS Collectively, these studies described a novel causal role of aberrant gut microbiota in the pathogenesis of age-related AF, which indicates that the microbiota-intestinal barrier-atrial NLRP3 inflammasome axis may be a rational molecular target for the treatment of aged-related arrhythmia disease. TRANSLATIONAL PERSPECTIVE The current study demonstrates that aged-associated microbiota dysbiosis promotes AF in part through a microbiota-gut-atria axis. Increased AF susceptibility due to enhanced atrial NLRP3-inflammasome activity by LPS and high glucose was found in an aged FMT rat model, and also confirmed within elderly clinical individuals. In a long-term FMT rat study, the AF susceptibility was ameliorated by treatment with youthful microbiota. The present findings can further increase our understanding of aged-related AF and address a promising therapeutic strategy that involves modulation of gut microbiota composition.
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Affiliation(s)
- Yun Zhang
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Song Zhang
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bolin Li
- Department of Cardiology, the First Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yingchun Luo
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongtai Gong
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuexin Jin
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jiawei Zhang
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yun Zhou
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaozhen Zhuo
- Department of Cardiology, the First Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Cardiology, Key Laboratory of Environment and Genes Related to Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zixi Wang
- Department of Cardiology, the First Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xinbo Zhao
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuejie Han
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunlong Gao
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hui Yu
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Desen Liang
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Harbin Medical University, Ministry of Education, Harbin, China
| | - Shiqi Zhao
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Danghui Sun
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dingyu Wang
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei Xu
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guangjin Qu
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wanlan Bo
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dan Li
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yue Wu
- Department of Cardiology, the First Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yue Li
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China.,The Cell Transplantation Key Laboratory of National Health Commission, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Harbin Medical University, Ministry of Education, Harbin, China.,Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin, China.,Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, China
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Su F, Shi M, Zhang J, Li Y, Tian J. Recombinant high‑mobility group box 1 induces cardiomyocyte hypertrophy by regulating the 14‑3‑3η, PI3K and nuclear factor of activated T cells signaling pathways. Mol Med Rep 2021; 23:214. [PMID: 33495819 PMCID: PMC7845624 DOI: 10.3892/mmr.2021.11853] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 09/07/2020] [Indexed: 01/20/2023] Open
Abstract
High-mobility group box 1 (HMGB1) is released by necrotic cells and serves an important role in cardiovascular pathology. However, the effects of HMGB1 in cardiomyocyte hypertrophy remain unclear. Therefore, the aim of the present study was to investigate the potential role of HMGB1 in cardiomyocyte hypertrophy and the underlying mechanisms of its action. Neonatal mouse cardiomyocytes (NMCs) were co-cultured with recombinant HMGB1 (rHMGB1). Wortmannin was used to inhibit PI3K activity in cardiomyocytes. Subsequently, atrial natriuretic peptide (ANP), 14-3-3 and phosphorylated-Akt (p-Akt) protein levels were detected using western blot analysis. In addition, nuclear factor of activated T cells 3 (NFAT3) protein levels were measured by western blot analysis and observed in NMCs under a confocal microscope. The results revealed that rHMGB1 increased ANP and p-Akt, and decreased 14-3-3η protein levels. Furthermore, wortmannin abrogated the effects of rHMGB1 on ANP, 14-3-3η and p-Akt protein levels. In addition, rHMGB1 induced nuclear translocation of NFAT3, which was also inhibited by wortmannin pretreatment. The results of this study suggest that rHMGB1 induces cardiac hypertrophy by regulating the 14-3-3η/PI3K/Akt/NFAT3 signaling pathway.
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Affiliation(s)
- Feifei Su
- Department of Cardiology, Air Force Medical Center, People's Liberation Army, Beijing 100142, P.R. China
| | - Miaoqian Shi
- Department of Cardiology, The Seventh Medical Centre of The People's Liberation Army General Hospital, Beijing 100700, P.R. China
| | - Jian Zhang
- Department of Cardiology, Beijing Chest Hospital Heart Center, Capital Medical University, Beijing 101149, P.R. China
| | - Yan Li
- Department of Cardiology, Tangdu Hospital Affiliated to The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Jianwei Tian
- Department of Cardiology, Air Force Medical Center, People's Liberation Army, Beijing 100142, P.R. China
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36
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Costa DL, Amaral EP, Andrade BB, Sher A. Modulation of Inflammation and Immune Responses by Heme Oxygenase-1: Implications for Infection with Intracellular Pathogens. Antioxidants (Basel) 2020; 9:antiox9121205. [PMID: 33266044 PMCID: PMC7761188 DOI: 10.3390/antiox9121205] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 02/07/2023] Open
Abstract
Heme oxygenase-1 (HO-1) catalyzes the degradation of heme molecules releasing equimolar amounts of biliverdin, iron and carbon monoxide. Its expression is induced in response to stress signals such as reactive oxygen species and inflammatory mediators with antioxidant, anti-inflammatory and immunosuppressive consequences for the host. Interestingly, several intracellular pathogens responsible for major human diseases have been shown to be powerful inducers of HO-1 expression in both host cells and in vivo. Studies have shown that this HO-1 response can be either host detrimental by impairing pathogen control or host beneficial by limiting infection induced inflammation and tissue pathology. These properties make HO-1 an attractive target for host-directed therapy (HDT) of the diseases in question, many of which have been difficult to control using conventional antibiotic approaches. Here we review the mechanisms by which HO-1 expression is induced and how the enzyme regulates inflammatory and immune responses during infection with a number of different intracellular bacterial and protozoan pathogens highlighting mechanistic commonalities and differences with the goal of identifying targets for disease intervention.
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Affiliation(s)
- Diego L. Costa
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto 14049-900, São Paulo, Brazil
- Correspondence: ; Tel.: +55-16-3315-3061
| | - Eduardo P. Amaral
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; (E.P.A.); (A.S.)
| | - Bruno B. Andrade
- Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa;
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Bahia, Brazil
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Bahia, Brazil
- Curso de Medicina, Faculdade de Tecnologia e Ciências (UniFTC), Salvador 41741-590, Bahia, Brazil
- Curso de Medicina, Universidade Salvador (UNIFACS), Laureate International Universities, Salvador 41770-235, Bahia, Brazil
- Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador 40290-000, Bahia, Brazil
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Alan Sher
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; (E.P.A.); (A.S.)
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Therapeutic Potential of Heme Oxygenase-1 and Carbon Monoxide in Acute Organ Injury, Critical Illness, and Inflammatory Disorders. Antioxidants (Basel) 2020; 9:antiox9111153. [PMID: 33228260 PMCID: PMC7699570 DOI: 10.3390/antiox9111153] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 10/29/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023] Open
Abstract
Heme oxygenase-1 (HO-1) is an inducible stress protein that catalyzes the oxidative conversion of heme to carbon monoxide (CO), iron, and biliverdin (BV), the latter of which is converted to bilirubin (BR) by biliverdin reductase. HO-1 has been implicated as a cytoprotectant in various models of acute organ injury and disease (i.e., lung, kidney, heart, liver). Thus, HO-1 may serve as a general therapeutic target in inflammatory diseases. HO-1 may function as a pleiotropic modulator of inflammatory signaling, via the removal of heme, and generation of its enzymatic degradation-products. Iron release from HO activity may exert pro-inflammatory effects unless sequestered, whereas BV/BR have well-established antioxidant properties. CO, derived from HO activity, has been identified as an endogenous mediator that can influence mitochondrial function and/or cellular signal transduction programs which culminate in the regulation of apoptosis, cellular proliferation, and inflammation. Much research has focused on the application of low concentration CO, whether administered in gaseous form by inhalation, or via the use of CO-releasing molecules (CORMs), for therapeutic benefit in disease. The development of novel CORMs for their translational potential remains an active area of investigation. Evidence has accumulated for therapeutic effects of both CO and CORMs in diseases associated with critical care, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS), mechanical ventilation-induced lung injury, pneumonias, and sepsis. The therapeutic benefits of CO may extend to other diseases involving aberrant inflammatory processes such as transplant-associated ischemia/reperfusion injury and chronic graft rejection, and metabolic diseases. Current and planned clinical trials explore the therapeutic benefit of CO in ARDS and other lung diseases.
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38
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Lan T, Tao A, Xu X, Kvietys P, Rui T. Peroxynitrite/PKR Axis Modulates the NLRP3 Inflammasome of Cardiac Fibroblasts. Front Immunol 2020; 11:558712. [PMID: 33101273 PMCID: PMC7545724 DOI: 10.3389/fimmu.2020.558712] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 08/18/2020] [Indexed: 02/05/2023] Open
Abstract
Sepsis/endotoxemia activates the NLRP3 inflammasome of macrophages leading to the maturation and release of IL-1β, an important mediator of the inflammatory response. Reactive oxygen species have been implicated in NLRP3 inflammasome activation. Further, our preliminary studies indicated that LPS challenge of cardiac fibroblasts could phosphorylate protein kinase R (PKR) on threonine 451 and increase message for pro-IL-1 β. Thus, the major aim of the present study was to address the role of PKR and the oxidant, peroxynitrite, in the two-tiered function of the NLRP3 inflammasome (priming and activation). Materials and Methods: Isolated murine fibroblasts were primed with LPS (1 μg/ml) for 6 h and subsequently activated by an ATP (3 mM) challenge for 30 min to induce optimum functioning of the inflammasome. Increased levels of NLRP3 and pro-IL-1β protein (Western) were used as readouts for inflammasome priming, while activation of caspase 1 (p20) (Western) and secretion of IL-1β (ELISA) were indicative of inflammasome activation. Results: Inhibition of PKR (PKR inhibitor or siRNA) prior to priming with LPS prevented the LPS-induced increase in NLRP3 and pro-IL-1β expression. Further, inhibition of PKR after priming, but before activation, did not affect NLRP3 or pro-IL-1β protein levels, but markedly reduced the activation of caspase 1 and secretion of mature IL-1β. In a similar fashion, a peroxynitrite decomposition catalyst (Fe-TPPS) prevented both the priming and activation of the NLRP3 inflammasome. Finally, pretreatment of the fibroblasts with Fe-TPPS prevented the LPS-induced PKR phosphorylation (T451). Conclusion: Our results indicate that peroxynitrite-/PKR pathway modulates priming and activation of NLRP3 inflammasome in LPS/ATP challenged cardiac fibroblasts.
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Affiliation(s)
- Ting Lan
- Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.,Critical Illness Research, Lawson Health Research Institute, London, ON, Canada.,Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Aibin Tao
- Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.,Critical Illness Research, Lawson Health Research Institute, London, ON, Canada
| | - Xuemei Xu
- Critical Illness Research, Lawson Health Research Institute, London, ON, Canada.,Critical Care Western, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Peter Kvietys
- Department of Physiological Sciences, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Tao Rui
- Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.,Critical Illness Research, Lawson Health Research Institute, London, ON, Canada.,Critical Care Western, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Departments of Medicine, Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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39
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Resveratrol Inhibits Ischemia-Induced Myocardial Senescence Signals and NLRP3 Inflammasome Activation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2647807. [PMID: 32908628 PMCID: PMC7468658 DOI: 10.1155/2020/2647807] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/26/2020] [Accepted: 07/23/2020] [Indexed: 01/01/2023]
Abstract
Aims The aim of this study was to investigate whether resveratrol (RSV) could ameliorate ischemia- and hypoxia-associated cardiomyocyte apoptosis and injury via inhibiting senescence signaling and inflammasome activation. Materials and Methods Mice were treated with RSV by gastric tube (320 mg/kg/day) or vehicle one week before left coronary artery ligation or sham surgery until the end of the experiments. After pressure–volume loop analysis, mouse hearts were harvested for histopathological (including PSR, TTC, TUNEL staining, immunohistochemistry, and immunofluorescence) and molecular analysis by western blotting and RT-PCR. In addition, neonatal rat cardiomyocytes (NRCMs), cardiac fibroblasts (CFs), and macrophages were isolated for in vitro experiments. Key Findings. RSV treatment decreased mortality and improved cardiac hemodynamics. RSV inhibited the expression of senescence markers (p53, p16, and p19), inflammasome markers (NLRP3 and Cas1 p20), and nuclear translocation of NF-κB, hence alleviating infarction area, fibrosis, and cell apoptosis. RSV also inhibited expression of interleukin- (IL-) 1β, IL-6, tumor necrosis factor-α, and IL-18 in vivo. In in vitro experiment, RSV prevented hypoxia-induced NRCM senescence and apoptosis. After inhibition of sirtuin 1 (Sirt1) by EX27, RSV failed to inhibit p53 acetylation and expression. Moreover, RSV could inhibit expression of NLRP3 and caspase 1 p20 in NRCMs, CFs, and macrophages, respectively, in in vitro experiments. Significance. Our findings revealed that RSV protected against ischemia-induced mouse heart injury in vivo and hypoxia-induced NRCM injury in vitro via regulating Sirt1/p53-mediated cell senescence and inhibiting NLRP3-mediated inflammasome activation.
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40
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Two Faces of Heme Catabolic Pathway in Newborns: A Potential Role of Bilirubin and Carbon Monoxide in Neonatal Inflammatory Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7140496. [PMID: 32908636 PMCID: PMC7450323 DOI: 10.1155/2020/7140496] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 07/27/2020] [Indexed: 12/18/2022]
Abstract
In an infant's body, all the systems undergo significant changes in order to adapt to the new, extrauterine environment and challenges which it poses. Fragile homeostasis can be easily disrupted as the defensive mechanisms are yet imperfect. The activity of antioxidant enzymes, i.e., superoxide dismutase, catalase, and glutathione peroxidase, is low; therefore, neonates are especially vulnerable to oxidative stress. Free radical burden significantly contributes to neonatal illnesses such as sepsis, retinopathy of premature, necrotizing enterocolitis, bronchopulmonary dysplasia, or leukomalacia. However, newborns have an important ally-an inducible heme oxygenase-1 (HO-1) which expression rises rapidly in response to stress stimuli. HO-1 activity leads to production of carbon monoxide (CO), free iron ion, and biliverdin; the latter is promptly reduced to bilirubin. Although CO and bilirubin used to be considered noxious by-products, new interesting properties of those compounds are being revealed. Bilirubin proved to be an efficient free radicals scavenger and modulator of immune responses. CO affects a vast range of processes such as vasodilatation, platelet aggregation, and inflammatory reactions. Recently, developed nanoparticles consisting of PEGylated bilirubin as well as several kinds of molecules releasing CO have been successfully tested on animal models of inflammatory diseases. This paper focuses on the role of heme metabolites and their potential utility in prevention and treatment of neonatal diseases.
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Nunes CDR, Barreto Arantes M, Menezes de Faria Pereira S, Leandro da Cruz L, de Souza Passos M, Pereira de Moraes L, Vieira IJC, Barros de Oliveira D. Plants as Sources of Anti-Inflammatory Agents. Molecules 2020; 25:E3726. [PMID: 32824133 PMCID: PMC7465135 DOI: 10.3390/molecules25163726] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/29/2020] [Accepted: 08/05/2020] [Indexed: 02/08/2023] Open
Abstract
Plants represent the main source of molecules for the development of new drugs, which intensifies the interest of transnational industries in searching for substances obtained from plant sources, especially since the vast majority of species have not yet been studied chemically or biologically, particularly concerning anti-inflammatory action. Anti-inflammatory drugs can interfere in the pathophysiological process of inflammation, to minimize tissue damage and provide greater comfort to the patient. Therefore, it is important to note that due to the existence of a large number of species available for research, the successful development of new naturally occurring anti-inflammatory drugs depends mainly on a multidisciplinary effort to find new molecules. Although many review articles have been published in this regard, the majority presented the subject from a limited regional perspective. Thus, the current article presents highlights from the published literature on plants as sources of anti-inflammatory agents.
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Affiliation(s)
- Clara dos Reis Nunes
- Laboratório de Tecnologia de Alimentos, Centro de Ciências e Tecnologias Agropecuárias, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ 28013-602, Brazil; (C.d.R.N.); (M.B.A.); (S.M.d.F.P.); (L.L.d.C.); (L.P.d.M.)
| | - Mariana Barreto Arantes
- Laboratório de Tecnologia de Alimentos, Centro de Ciências e Tecnologias Agropecuárias, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ 28013-602, Brazil; (C.d.R.N.); (M.B.A.); (S.M.d.F.P.); (L.L.d.C.); (L.P.d.M.)
| | - Silvia Menezes de Faria Pereira
- Laboratório de Tecnologia de Alimentos, Centro de Ciências e Tecnologias Agropecuárias, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ 28013-602, Brazil; (C.d.R.N.); (M.B.A.); (S.M.d.F.P.); (L.L.d.C.); (L.P.d.M.)
| | - Larissa Leandro da Cruz
- Laboratório de Tecnologia de Alimentos, Centro de Ciências e Tecnologias Agropecuárias, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ 28013-602, Brazil; (C.d.R.N.); (M.B.A.); (S.M.d.F.P.); (L.L.d.C.); (L.P.d.M.)
| | - Michel de Souza Passos
- Laboratório de Ciências Químicas, Centro de Ciências e Tecnologia, UniversidadeEstadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ 28013-602, Brazil; (M.d.S.P.); (I.J.C.V.)
| | - Luana Pereira de Moraes
- Laboratório de Tecnologia de Alimentos, Centro de Ciências e Tecnologias Agropecuárias, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ 28013-602, Brazil; (C.d.R.N.); (M.B.A.); (S.M.d.F.P.); (L.L.d.C.); (L.P.d.M.)
| | - Ivo José Curcino Vieira
- Laboratório de Ciências Químicas, Centro de Ciências e Tecnologia, UniversidadeEstadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ 28013-602, Brazil; (M.d.S.P.); (I.J.C.V.)
| | - Daniela Barros de Oliveira
- Laboratório de Tecnologia de Alimentos, Centro de Ciências e Tecnologias Agropecuárias, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ 28013-602, Brazil; (C.d.R.N.); (M.B.A.); (S.M.d.F.P.); (L.L.d.C.); (L.P.d.M.)
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Geng C, Wei J, Wu C. Yap-Hippo pathway regulates cerebral hypoxia-reoxygenation injury in neuroblastoma N2a cells via inhibiting ROCK1/F-actin/mitochondrial fission pathways. Acta Neurol Belg 2020; 120:879-892. [PMID: 29796942 DOI: 10.1007/s13760-018-0944-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 05/15/2018] [Indexed: 01/03/2023]
Abstract
Yes-associated protein (Yap), a regulator of cellular apoptosis, has been demonstrated to be involved in cerebral ischemia-reperfusion (IR) injury through poorly defined mechanisms. The present study aimed to explore the role of Yap in regulating cerebral IR injury in vitro, with a focus on mitochondrial fission and ROCK1/F-actin pathways. Our data demonstrated that Yap was actually downregulated in N2a cells after cerebral hypoxia-reoxygenation (HR) injury, and that lower expression of Yap was closely associated with increased cell death. However, the reintroduction of Yap was able to suppress the HR-mediated N2a cells death via blocking the mitochondria-related apoptotic signal. At the molecular levels, Yap overexpression sustained mitochondrial potential, normalized the mitochondrial respiratory function, reduced ROS overproduction, limited HtrA2/Omi release from mitochondria into the nucleus, and suppressed pro-apoptotic proteins activation. Subsequently, functional studies have further illustrated that HR-mediated mitochondrial apoptosis was highly regulated by mitochondrial fission, whereas Yap overexpression was able to attenuate HR-mediated mitochondrial fission and, thus, promote N2a cell survival in the context of HR injury. At last, we demonstrated that Yap handled mitochondrial fission via closing ROCK1/F-actin signaling pathways. Activation of ROCK1/F-actin pathways abrogated the protective role of Yap overexpression on mitochondrial homeostasis and N2a cell survival in the setting of HR injury. Altogether, our data identified Yap as the endogenous defender to relieve HR-mediated nerve damage via antagonizing ROCK1/F-actin/mitochondrial fission pathways.
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Affiliation(s)
- Chizi Geng
- Physician of Neurology Department, Beijing Luhe Hospital, Capital Medical University, Beijing, China.
| | - Jianchao Wei
- Director of Neurology Department, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Chengsi Wu
- Deputy Director of Eurology Department, Beijing Luhe Hospital, Capital Medical University, Beijing, China
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43
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Wang Y, Yu W, Shi C, Hu P. Crocetin Attenuates Sepsis-Induced Cardiac Dysfunction via Regulation of Inflammatory Response and Mitochondrial Function. Front Physiol 2020; 11:514. [PMID: 32581829 PMCID: PMC7295980 DOI: 10.3389/fphys.2020.00514] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 04/27/2020] [Indexed: 01/07/2023] Open
Abstract
Sepsis-induced systemic inflammation can induce cardiac dysfunction, which can result in heart failure and death. Recently, natural drugs/compounds have received increased attention as therapeutic agents to prevent sepsis-induced cardiac dysfunction. Crocetin (CRO) is a natural compound that has been shown to reduce inflammation and cytotoxicity in cardiac ischemia/reperfusion injury. However, the effects of CRO on sepsis-induced cardiac dysfunction have not been evaluated. In this study, we used lipopolysaccharide (LPS)-induced H9c2 cells as an in vitro model to mimic cardiac sepsis. Crocetin significantly alleviated LPS-induced cytotoxicity, cellular apoptosis, and oxidative stress through increased Bcl-2 activity and PI3K-Akt signaling and suppression of caspase 3 and caspase 9 activities. Furthermore, CRO dramatically decreased the mRNA levels of TNF-α, IL-1, IL-6, and IL-8 via suppression of p65/Keap1 signaling and activation of Nrf2/HO-1/NQO1 signaling. In addition, CRO protected mitochondrial respiration, free fatty acid β-oxidation, and mitochondrial morphology in LPS-induced H9c2 cells. This study showed that CRO attenuated LPS-induced cardiac dysfunction via regulation of the inflammatory response and mitochondrial function and potentially had an effect on sepsis-induced cardiac dysfunction.
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Affiliation(s)
- Yanpeng Wang
- Department of Emergency, Zhejiang Chinese Medicine and Western Medicine Integrated Hospital/Hangzhou Red Cross Hospital, Hangzhou, China
| | - Weiwei Yu
- Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Hangzhou, China
| | - Chenhui Shi
- The Second Clinical Medicine College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Pengfei Hu
- Department of Cardiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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44
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Zheng G, Zheng F, Luo Z, Ma H, Zheng D, Xiang G, Xu C, Zhou Y, Wu Y, Tian N, Wu Y, Zhang T, Ni W, Wang S, Xu H, Zhang X. CO-Releasing Molecule (CORM)-3 Ameliorates Spinal Cord-Blood Barrier Disruption Following Injury to the Spinal Cord. Front Pharmacol 2020; 11:761. [PMID: 32581781 PMCID: PMC7287126 DOI: 10.3389/fphar.2020.00761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 05/07/2020] [Indexed: 01/01/2023] Open
Abstract
Spinal cord injury (SCI) is a clinical tough neurological problem without efficient cure currently. Blood-spinal cord barrier (BSCB) interruption is not only a crucial pathological feature for SCI process but is a possible target for future SCI treatments; however, few treatments have been developed to intervene BSCB. In the present study, we intravenously injected CO-releasing molecule3 (CORM-3), a classical exogenous CO donor, to the rats experiencing SCI and assessed its protection on BSCB integrity in rats. Our results demonstrated that the exogenous increasing of CO by CORM-3 blocked the tight junction (TJ) protein degeneration and neutrophils infiltration, subsequently suppressed the BSCB damage and improved the motor recovery after SCI. And we certified that the CO-induced down-regulation of MMP-9 expression and activity in neutrophil might be associated with the NF-κB signaling. Taken together, our study indicates that CO-releasing molecule (CORM)-3 ameliorates BSCB after spinal cord injury.
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Affiliation(s)
- Gang Zheng
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China
| | - Fanghong Zheng
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Zucheng Luo
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China
| | - Haiwei Ma
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China
| | - Dongdong Zheng
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guangheng Xiang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China
| | - Cong Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China
| | - Yifei Zhou
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Yaosen Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Naifeng Tian
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Yan Wu
- Department of Orthopaedics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Wenzhou, China
| | - Tan Zhang
- Department of Orthopaedics, Shaoxing People's Hospital, Shaoxing, Wenzhou, China
| | - Wenfei Ni
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China
| | - Sheng Wang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Huazi Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Xiaolei Zhang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, China.,Department of Orthopaedics, Chinese Orthopaedic Regenerative Medicine Society, Hangzhou, China
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Wang B, Wu Y, Ge Z, Zhang X, Yan Y, Xie Y. NLRC5 deficiency ameliorates cardiac fibrosis in diabetic cardiomyopathy by regulating EndMT through Smad2/3 signaling pathway. Biochem Biophys Res Commun 2020; 528:545-553. [PMID: 32505342 DOI: 10.1016/j.bbrc.2020.05.151] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 05/20/2020] [Indexed: 02/07/2023]
Abstract
Diabetic cardiomyopathy (DCM) is one of the main causes of heart failure in patients with diabetes. Cardiac fibrosis caused by endothelial mesenchymal transformation (EndMT) plays an important role in the pathogenesis of DCM. NLRC5 is a recently discovered immune and inflammatory regulatory molecule in the NOD-like receptor family, and is involved in organ fibrosis. In this study, we found that the expression of NLRC5 was up-regulated in endothelial cells (ECs) and cardiac fibroblasts (CFs) in diabetes models both in vivo and in vitro. NLRC5 knockdown significantly inhibited high glucose-induced EndMT. In addition, NLRC5 deficiency inhibited the expression of phosphorylated Smad2/3 and the activation of EndMT-related transcription factors in ECs induced by high glucose. However, the effect of NLRC5 deficiency on CFs was not obvious. In summary, our results suggest that NLRC5 deficiency ameliorates cardiac fibrosis in DCM by inhibiting EndMT through Smad2/3 signaling pathway and related transcription factors. NLRC5 is likely to be a biomarker and therapeutic target of cardiac fibrosis in diabetic cardiomyopathy.
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Affiliation(s)
- Bo Wang
- Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yan Wu
- Department of Nutriology, Fudan University Shanghai Cancer Center, 270, Dong'An Road, Shanghai, 200032, China
| | - Zhuowang Ge
- Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Xuan Zhang
- Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yexiang Yan
- Department of Cardiology, Shanghai Tenth People's Hospital Chongming Branch, 66 Xiangyang East Road, Shanghai, 202157, China
| | - Yuquan Xie
- Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai, 200092, China.
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Wang H, Zhang S, Zhao H, Qin H, Zhang J, Dong J, Zhang H, Liu X, Zhao Z, Zhao Y, Shao M, Wu F, Zhang W. Carbon Monoxide Inhibits the Expression of Proteins Associated with Intestinal Mucosal Pyroptosis in a Rat Model of Sepsis Induced by Cecal Ligation and Puncture. Med Sci Monit 2020; 26:e920668. [PMID: 32351244 PMCID: PMC7207005 DOI: 10.12659/msm.920668] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 01/20/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Carbon monoxide (CO) has anti-inflammatory effects and protects the intestinal mucosal barrier in sepsis. Pyroptosis, or cell death associated with sepsis, is mediated by caspase-1 activation. This study aimed to investigate the role of CO on the expression of proteins associated with intestinal mucosal pyroptosis in a rat model of sepsis induced by cecal ligation and puncture (CLP). MATERIAL AND METHODS The rat model of sepsis was developed using CLP. Male Sprague-Dawley rats (n=120) were divided into six study groups: the sham group (n=20); the CLP group (n=20); the hemin group (treated with ferric chloride and heme) (n=20); the zinc protoporphyrin IX (ZnPPIX) group (n=20); the CO-releasing molecule 2 (CORM-2) group (n=20); and the inactive CORM-2 (iCORM-2) group (n=20). Hemin and CORM-2 were CO donors, and ZnPPIX was a CO inhibitor. In the six groups, the seven-day survival curves, the fluorescein isothiocyanate (FITC)-labeled dextran 4000 Da (FD-4) permeability assay, levels of intestinal pyroptosis proteins caspase-1, caspase-11, and gasdermin D (GSDMD) were measured by confocal fluorescence microscopy. Proinflammatory cytokines interleukin (IL)-18, IL-1ß, and high mobility group box protein 1 (HMGB1) were measured by Western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS CO reduced the mortality rate in rats with sepsis and reduced intestinal mucosal permeability and mucosal damage. CO also reduced the expression levels of IL-18, IL-1ß, and HMGB1, and reduced pyroptosis by preventing the cleavage of caspase-1 and caspase-11. CONCLUSIONS In a rat model of sepsis induced by CLP, CO had a protective role by inhibiting intestinal mucosal pyroptosis.
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Affiliation(s)
- Hongzhou Wang
- Department of Pathophysiology, Shihezi University School of Medicine and The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang, P.R. China
| | - Shunwen Zhang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Haijun Zhao
- The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, P.R. China
| | - Huiyuan Qin
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Jie Zhang
- The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, P.R. China
| | - Jiangtao Dong
- The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, P.R. China
| | - Hui Zhang
- Department of Pathophysiology, Shihezi University School of Medicine and The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang, P.R. China
| | - Xiaoling Liu
- Department of Pathophysiology, Shihezi University School of Medicine and The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang, P.R. China
| | - Zhengyong Zhao
- Department of Pathophysiology, Shihezi University School of Medicine and The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang, P.R. China
| | - Yanheng Zhao
- The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, P.R. China
| | - Meng Shao
- Department of Pathophysiology, Shihezi University School of Medicine and The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang, P.R. China
| | - Fang Wu
- Department of Pathophysiology, Shihezi University School of Medicine and The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang, P.R. China
| | - Wanjiang Zhang
- Department of Pathophysiology, Shihezi University School of Medicine and The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang, P.R. China
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CORM-2-Solid Lipid Nanoparticles Maintain Integrity of Blood-Spinal Cord Barrier After Spinal Cord Injury in Rats. Mol Neurobiol 2020; 57:2671-2689. [DOI: 10.1007/s12035-020-01914-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 03/30/2020] [Indexed: 12/21/2022]
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Guerci P, Ergin B, Kandil A, Ince Y, Heeman P, Hilty MP, Bakker J, Ince C. Resuscitation with PEGylated carboxyhemoglobin preserves renal cortical oxygenation and improves skeletal muscle microcirculatory flow during endotoxemia. Am J Physiol Renal Physiol 2020; 318:F1271-F1283. [PMID: 32281418 DOI: 10.1152/ajprenal.00513.2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
PEGylated carboxyhemoglobin (PEGHbCO), which has carbon monoxide-releasing properties and plasma expansion and oxygen-carrying properties, may improve both skeletal microcirculatory flow and renal cortical microcirculatory Po2 (CµPo2) and, subsequently, limit endotoxemia-induced acute kidney injury. Anesthetized, ventilated Wistar albino rats (n = 44) underwent endotoxemic shock. CµPo2 was measured in exposed kidneys using a phosphorescence-quenching method. Rats were randomly assigned to the following five groups: 1) unresuscitated lipopolysaccharide (LPS), 2) LPS + Ringer's acetate (RA), 3) LPS + RA + 0.5 µg·kg·-1min-1 norepinephrine (NE), 4) LPS + RA + 320 mg/kg PEGHbCO, and 5) LPS + RA + PEGHbCO + NE. The total volume was 30 mL/kg in each group. A time control animal group was used. Skeletal muscle microcirculation was assessed by handheld intravital microscopy. Kidney immunohistochemistry and myeloperoxidase-stained leukocytes in glomerular and peritubular areas were analyzed. Endotoxemia-induced histological damage was assessed. Plasma levels of IL-6, heme oxygenase-1, malondialdehyde, and syndecan-1 were assessed by ELISA. CµPo2 was higher in the LPS + RA + PEGHbCO-resuscitated group, at 35 ± 6mmHg compared with 21 ± 12 mmHg for the LPS+RA group [mean difference: -13.53, 95% confidence interval: (-26.35; -0.7156), P = 0.035]. The number of nonflowing, intermittent, or sluggish capillaries was smaller in groups infused with PEGHbCO compared with RA alone (P < 0.05), while the number of normally perfused vessels was greater (P < 0.05). The addition of NE did not further improve CµPo2 or microcirculatory parameters. Endotoxemia-induced kidney immunohistochemistry and histological alterations were not mitigated by PEGHbCO 1 h after resuscitation. Renal leukocyte infiltration and plasma levels of biomarkers were similar across groups. PEGHbCO enhanced CµPo2 while restoring skeletal muscle microcirculatory flow in previously nonflowing capillaries. PEGHbCO should be further evaluated as a resuscitation fluid in mid- to long-term models of sepsis-induced acute kidney injury.
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Affiliation(s)
- Philippe Guerci
- Department of Translational Physiology, Amsterdam University Medical Center Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Institut National de la Santé et de la Recherche Médicale U1116, University of Lorraine, Vandoeuvre-Les-Nancy, France.,Department of Anesthesiology and Critical Care Medicine, University Hospital of Nancy, Nancy, France
| | - Bülent Ergin
- Department of Translational Physiology, Amsterdam University Medical Center Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands
| | - Aslı Kandil
- Department of Biology, Faculty of Science, University of Istanbul, Istanbul, Turkey
| | - Yasin Ince
- Department of Translational Physiology, Amsterdam University Medical Center Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands
| | - Paul Heeman
- Department of Medical Technical Innovation & Development, Amsterdam University Medical Center Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Matthias Peter Hilty
- Department of Translational Physiology, Amsterdam University Medical Center Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jan Bakker
- Department of Intensive Care Medicine, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands.,Department of Pulmonology and Critical Care, Columbia University Medical Center, New York.,Department of Intensive Care, Pontifical Catholic University of Chile, Santiago, Chile
| | - Can Ince
- Department of Translational Physiology, Amsterdam University Medical Center Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands
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Abstract
There is abundant evidence that infectious sepsis both in humans and mice with polymicrobial sepsis results in robust activation of complement. Major complement activation products involved in sepsis include C5a anaphylatoxin and its receptors (C5aR1 and C5aR2) and, perhaps, the terminal complement activation product, C5b-9. These products (and others) also cause dysfunction of the innate immune system, with exaggerated early proinflammatory responses, followed by decline of the innate immune system, leading to immunosuppression and multiorgan dysfunction. Generation of C5a during sepsis also leads to activation of neutrophils and macrophages and ultimate appearance of extracellular histones, which have powerful proinflammatory and prothrombotic activities. The distal complement activation product, C5b-9, triggers intracellular Ca fluxes in epithelial and endothelial cells. Histones activate the NLRP3 inflammasome, products of which can damage cells. C5a also activates MAPKs and Akt signaling pathways in cardiomyocytes, causing buildup of [Ca]i, defective action potentials and substantial cell dysfunction, resulting in cardiac and other organ dysfunction. Cardiac dysfunction can be quantitated by ECHO-Doppler parameters. In vivo interventions that block these complement-dependent products responsible for organ dysfunction in sepsis reduce the intensity of sepsis. The obvious targets in sepsis are C5a and its receptors, histones, and perhaps the MAPK pathways. Blockade of C5 has been considered in sepsis, but the FDA-approved antibody (eculizumab) is known to compromise defenses against neisseria and pneumonococcal bacteria, and requires immunization before the mAb to C5 can be used clinically. Small molecular blocking agents for C5aRs are currently in development and may be therapeutically effective for treatment of sepsis.
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Zhang YF, Sun CC, Duan JX, Yang HH, Zhang CY, Xiong JB, Zhong WJ, Zu C, Guan XX, Jiang HL, Hammock BD, Hwang SH, Zhou Y, Guan CX. A COX-2/sEH dual inhibitor PTUPB ameliorates cecal ligation and puncture-induced sepsis in mice via anti-inflammation and anti-oxidative stress. Biomed Pharmacother 2020; 126:109907. [PMID: 32114358 DOI: 10.1016/j.biopha.2020.109907] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/31/2019] [Accepted: 12/31/2019] [Indexed: 12/14/2022] Open
Abstract
Arachidonic acid can be metabolized to prostaglandins and epoxyeicosatrienoic acids (EETs) by cyclooxygenase-2 (COX-2) and cytochrome P450 (CYP), respectively. While protective EETs are degraded by soluble epoxide hydrolase (sEH) very fast. We have reported that dual inhibition of COX-2 and sEH with specific inhibitor PTUPB shows anti-pulmonary fibrosis and renal protection. However, the effect of PTUPB on cecal ligation and puncture (CLP)-induced sepsis remains unclear. The current study aimed to investigate the protective effects of PTUPB against CLP-induced sepsis in mice and the underlying mechanisms. We found that COX-2 expressions were increased, while CYPs expressions were decreased in the liver, lung, and kidney of mice undergone CLP. PTUPB treatment significantly improved the survival rate, reduced the clinical scores and systemic inflammatory response, alleviated liver and kidney dysfunction, and ameliorated the multiple-organ injury of the mice with sepsis. Besides, PTUPB treatment reduced the expression of hypoxia-inducible factor-1α in the liver, lung, and kidney of septic mice. Importantly, we found that PTUPB treatment suppressed the activation of NLRP3 inflammasome in the liver and lung of septic mice. Meanwhile, we found that PTUPB attenuated the oxidative stress, which contributed to the activation of NLRP3 inflammasome. Altogether, our data, for the first time, demonstrate that dual inhibition of COX-2 and sEH with PTUPB ameliorates the multiple organ dysfunction in septic mice.
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Affiliation(s)
- Yan-Feng Zhang
- Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China
| | - Chen-Chen Sun
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Jia-Xi Duan
- Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China; Hunan Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
| | - Hui-Hui Yang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Chen-Yu Zhang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Jian-Bing Xiong
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Wen-Jing Zhong
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Cheng Zu
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Xin-Xin Guan
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Hui-Ling Jiang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Bruce D Hammock
- Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
| | - Sung Hee Hwang
- Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
| | - Yong Zhou
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China.
| | - Cha-Xiang Guan
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China.
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