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Hanson MG, Ambre R, Joshi R, Amidon JD, Snow JB, Lawless VC, Worrell BT. Visible Light Triggerable CO Releasing Micelles. J Am Chem Soc 2024; 146:35029-35034. [PMID: 39663914 DOI: 10.1021/jacs.4c13872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
Carbon monoxide (CO), along with nitric oxide and hydrogen sulfide, is one of a trinity of known gasotransmitters, or endogenously produced gaseous molecules that signal and regulate a panoply of physiological functions. CO releasing molecules (CORMs) are chemical tools that enable the study and application of this ephemeral gas, that, ideally, release CO on-demand when externally stimulated. Surveying the available triggers, photolysis is potentially advantageous: It is contactless and grants practitioners unparalleled spatial and temporal control. However, current phototriggered CORMs are capricious and do not meet current needs. Presented here is a highly efficient platform for the visible light triggered release of CO gas. This platform is built on a unique CO containing functionality, the cyclopropenone, which undergoes facile decarbonylation through visible light (470 nm) mediated photoredox catalysis. Due to the exothermic strain-release that occurs upon formation of CO, this photoreaction is rapid, quantitative, and has tunable release rates. To render this photo-CORM water-soluble, deliverable, and to keep reactants in proximity, necessary components were polymerized into block copolymers that self-assemble into CO releasing micelles (CORMIs). This platform was compared directly to other state-of-the-art CORMs, showing significantly improved CO production efficiency, lower toxicity, tunable release rates, and consistent efficacy in ex vivo and in vitro settings.
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Affiliation(s)
- Mckenna G Hanson
- Department of Chemistry & Biochemistry, University of Denver, Denver, Colorado 80210, United States
| | - Ram Ambre
- Department of Chemistry & Biochemistry, University of Denver, Denver, Colorado 80210, United States
| | - Riya Joshi
- Department of Chemistry & Biochemistry, University of Denver, Denver, Colorado 80210, United States
| | - Jeffrey D Amidon
- Department of Chemistry & Biochemistry, University of Denver, Denver, Colorado 80210, United States
| | - Jackson B Snow
- Department of Chemistry & Biochemistry, University of Denver, Denver, Colorado 80210, United States
| | - Vivian C Lawless
- Department of Chemistry & Biochemistry, University of Denver, Denver, Colorado 80210, United States
| | - Brady T Worrell
- Department of Chemistry & Biochemistry, University of Denver, Denver, Colorado 80210, United States
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Alves de Souza RW, Voltarelli V, Gallo D, Shankar S, Tift MS, Young M, Gomperts E, Gomperts A, Otterbein LE. Beneficial Effects of Oral Carbon Monoxide on Doxorubicin-Induced Cardiotoxicity. J Am Heart Assoc 2024; 13:e032067. [PMID: 38700010 PMCID: PMC11179858 DOI: 10.1161/jaha.123.032067] [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: 08/03/2023] [Accepted: 12/21/2023] [Indexed: 05/05/2024]
Abstract
BACKGROUND Doxorubicin and other anthracyclines are crucial cancer treatment drugs. However, they are associated with significant cardiotoxicity, severely affecting patient care and limiting dosage and usage. Previous studies have shown that low carbon monoxide (CO) concentrations protect against doxorubicin toxicity. However, traditional methods of CO delivery pose complex challenges for daily administration, such as dosing and toxicity. To address these challenges, we developed a novel oral liquid drug product containing CO (HBI-002) that can be easily self-administered by patients with cancer undergoing doxorubicin treatment, resulting in CO being delivered through the upper gastrointestinal tract. METHODS AND RESULTS HBI-002 was tested in a murine model of doxorubicin cardiotoxicity in the presence and absence of lung or breast cancer. The mice received HBI-002 twice daily before doxorubicin administration and experienced increased carboxyhemoglobin levels from a baseline of ≈1% to 7%. Heart tissue from mice treated with HBI-002 had a 6.3-fold increase in CO concentrations and higher expression of the cytoprotective enzyme heme oxygenase-1 compared with placebo control. In both acute and chronic doxorubicin toxicity scenarios, HBI-002 protected the heart from cardiotoxic effects, including limiting tissue damage and cardiac dysfunction and improving survival. In addition, HBI-002 did not compromise the efficacy of doxorubicin in reducing tumor volume, but rather enhanced the sensitivity of breast 4T1 cancer cells to doxorubicin while simultaneously protecting cardiac function. CONCLUSIONS These findings strongly support using HBI-002 as a cardioprotective agent that maintains the therapeutic benefits of doxorubicin cancer treatment while mitigating cardiac damage.
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Affiliation(s)
| | - Vanessa Voltarelli
- Department of SurgeryBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonMAUSA
| | - David Gallo
- Department of SurgeryBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonMAUSA
| | - Sidharth Shankar
- Department of SurgeryBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonMAUSA
| | - Michael S. Tift
- Department of Biology and Marine BiologyUniversity of North Carolina WilmingtonWilmingtonNCUSA
| | - Mark Young
- Hillhurst Biopharmaceuticals, lncMontroseCAUSA
| | | | | | - Leo E. Otterbein
- Department of SurgeryBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonMAUSA
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3
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Antibacterial gas therapy: Strategies, advances, and prospects. Bioact Mater 2023; 23:129-155. [DOI: 10.1016/j.bioactmat.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/20/2022] [Accepted: 10/05/2022] [Indexed: 11/13/2022] Open
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Yuan Z, De La Cruz LK, Yang X, Wang B. Carbon Monoxide Signaling: Examining Its Engagement with Various Molecular Targets in the Context of Binding Affinity, Concentration, and Biologic Response. Pharmacol Rev 2022; 74:823-873. [PMID: 35738683 PMCID: PMC9553107 DOI: 10.1124/pharmrev.121.000564] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Carbon monoxide (CO) has been firmly established as an endogenous signaling molecule with a variety of pathophysiological and pharmacological functions, including immunomodulation, organ protection, and circadian clock regulation, among many others. In terms of its molecular mechanism(s) of action, CO is known to bind to a large number of hemoproteins with at least 25 identified targets, including hemoglobin, myoglobin, neuroglobin, cytochrome c oxidase, cytochrome P450, soluble guanylyl cyclase, myeloperoxidase, and some ion channels with dissociation constant values spanning the range of sub-nM to high μM. Although CO's binding affinity with a large number of targets has been extensively studied and firmly established, there is a pressing need to incorporate such binding information into the analysis of CO's biologic response in the context of affinity and dosage. Especially important is to understand the reservoir role of hemoglobin in CO storage, transport, distribution, and transfer. We critically review the literature and inject a sense of quantitative assessment into our analyses of the various relationships among binding affinity, CO concentration, target occupancy level, and anticipated pharmacological actions. We hope that this review presents a picture of the overall landscape of CO's engagement with various targets, stimulates additional research, and helps to move the CO field in the direction of examining individual targets in the context of all of the targets and the concentration of available CO. We believe that such work will help the further understanding of the relationship of CO concentration and its pathophysiological functions and the eventual development of CO-based therapeutics. SIGNIFICANCE STATEMENT: The further development of carbon monoxide (CO) as a therapeutic agent will significantly rely on the understanding of CO's engagement with therapeutically relevant targets of varying affinity. This review critically examines the literature by quantitatively analyzing the intricate relationships among targets, target affinity for CO, CO level, and the affinity state of carboxyhemoglobin and provide a holistic approach to examining the molecular mechanism(s) of action for CO.
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Affiliation(s)
- Zhengnan Yuan
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Ladie Kimberly De La Cruz
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Xiaoxiao Yang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Binghe Wang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
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Gianni S, Valsecchi C, Berra L. Therapeutic Gases and Inhaled Anesthetics as Adjunctive Therapies in Critically Ill Patients. Semin Respir Crit Care Med 2022; 43:440-452. [PMID: 35533689 DOI: 10.1055/s-0042-1747966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The administration of exogenous oxygen to support adequate gas exchange is the cornerstone of respiratory care. In the past few years, other gaseous molecules have been introduced in clinical practice to treat the wide variety of physiological derangement seen in critical care patients.Inhaled nitric oxide (NO) is used for its unique selective pulmonary vasodilator effect. Recent studies showed that NO plays a pivotal role in regulating ischemia-reperfusion injury and it has antibacterial and antiviral activity.Helium, due to its low density, is used in patients with upper airway obstruction and lower airway obstruction to facilitate gas flow and to reduce work of breathing.Carbon monoxide (CO) is a poisonous gas that acts as a signaling molecule involved in many biologic pathways. CO's anti-inflammatory and antiproliferative effects are under investigation in the setting of acute respiratory distress and idiopathic pulmonary fibrosis.Inhaled anesthetics are widely used in the operative room setting and, with the development of anesthetic reflectors, are now a valid option for sedation management in the intensive care unit.Many other gases such as xenon, argon, and hydrogen sulfide are under investigation for their neuroprotective and cardioprotective effects in post-cardiac arrest syndrome.With all these therapeutic options available, the clinician must have a clear understanding of the physiologic basis, therapeutic potential, and possible adverse events of these therapeutic gases. In this review, we will present the therapeutic gases other than oxygen used in clinical practice and we will describe other promising therapeutic gases that are in the early phases of investigation.
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Affiliation(s)
- Stefano Gianni
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Carlo Valsecchi
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Lorenzo Berra
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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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: 16] [Impact Index Per Article: 5.3] [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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Yang X, Lu W, Wang M, Tan C, Wang B. "CO in a pill": Towards oral delivery of carbon monoxide for therapeutic applications. J Control Release 2021; 338:593-609. [PMID: 34481027 PMCID: PMC8526413 DOI: 10.1016/j.jconrel.2021.08.059] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/28/2021] [Accepted: 08/30/2021] [Indexed: 02/08/2023]
Abstract
Along with the impressive achievements in understanding the endogenous signaling roles and mechanism(s) of action of carbon monoxide (CO), much research has demonstrated the potential of using CO as a therapeutic agent for treating various diseases. Because of CO's toxicity at high concentrations and the observed difference in toxicity profiles of CO depending on the route of administration, this review analyzes and presents the benefits of developing orally active CO donors. Such compounds have the potential for improved safety profiles, enhancing the chance for developing CO-based therapeutics. In this review, the difference between inhalation and oral administration in terms of toxicity, CO delivery efficiency, and the potential mechanism(s) of action is analyzed. The evolution from CO gas inhalation to oral administration is also extensively analyzed by summarizing published studies up to date. The concept of "CO in a pill" can be achieved by oral administration of novel formulations of CO gas or appropriate CO donors.
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Affiliation(s)
- Xiaoxiao Yang
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
| | - Wen Lu
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
| | - Minjia Wang
- Department of Pharmaceutical Sciences, University of Mississippi, MS 38677, USA
| | - Chalet Tan
- Department of Pharmaceutical Sciences, University of Mississippi, MS 38677, USA
| | - Binghe Wang
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
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CO-Releasing Molecule-2 Prevents Acute Kidney Injury through Suppression of ROS-Fyn-ER Stress Signaling in Mouse Model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9947772. [PMID: 34326922 PMCID: PMC8277502 DOI: 10.1155/2021/9947772] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/11/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022]
Abstract
Acute kidney injury (AKI) most commonly appears in critically ill patients in hospitals. AKI is characterized as a quick deterioration of kidney function and has recently been identified to be tightly interlinked with chronic kidney diseases. The emerging major mediators of AKI include oxidative stress and endoplasmic reticulum (ER) stress. Carbon monoxide (CO) attenuates oxidative stress and ER stress in various cells, while Fyn, a member of the Src kinase family, is activated by oxidative stress and contributes to ER stress in skeletal muscle. Considering these, the objective of the current research was to determine (i) the involvement of Fyn in ER stress-mediated AKI and (ii) the effect of CO-releasing molecule-2 (CORM2) on reactive oxygen species- (ROS-) Fyn-ER stress-mediated AKI. Pretreatment with CORM2 (30 mg/kg) efficiently inhibited LPS (30 mg/kg)-induced oxidative stress, inflammation, and cellular apoptosis during AKI in C57BL/6J mice. Also, CORM2 efficiently suppressed the activation of Fyn and ER stress in AKI mice. Consistently, pretreatment with CORM2 inhibited oxidative stress, Fyn activation, ER stress, inflammation, and apoptosis in LPS- or H2O2-stimulated proximal epithelial tubular cells. Fyn inhibition using siRNA or an inhibitor (PP2) significantly attenuated ER stress responses in the cells. These data suggest that CORM2 may become a potential treatment option against ROS-Fyn-ER stress-mediated AKI.
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Yang X, Lu W, Hopper CP, Ke B, Wang B. Nature's marvels endowed in gaseous molecules I: Carbon monoxide and its physiological and therapeutic roles. Acta Pharm Sin B 2021; 11:1434-1445. [PMID: 34221861 PMCID: PMC8245769 DOI: 10.1016/j.apsb.2020.10.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 08/03/2020] [Accepted: 09/07/2020] [Indexed: 02/08/2023] Open
Abstract
Nature has endowed gaseous molecules such as O2, CO2, CO, NO, H2S, and N2 with critical and diverse roles in sustaining life, from supplying energy needed to power life and building blocks for life's physical structure to mediating and coordinating cellular functions. In this article, we give a brief introduction of the complex functions of the various gaseous molecules in life and then focus on carbon monoxide as a specific example of an endogenously produced signaling molecule to highlight the importance of this class of molecules. The past twenty years have seen much progress in understanding CO's mechanism(s) of action and pharmacological effects as well as in developing delivery methods for easy administration. One remarkable trait of CO is its pleiotropic effects that have few parallels, except perhaps its sister gaseous signaling molecules such as nitric oxide and hydrogen sulfide. This review will delve into the sophistication of CO-mediated signaling as well as its validated pharmacological functions and possible therapeutic applications.
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Affiliation(s)
- Xiaoxiao Yang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
| | - Wen Lu
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
| | - Christopher P. Hopper
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
- Institut für Experimentelle Biomedizin, Universitätsklinikum Würzburg, Würzburg, Bavaria 97080, Germany
| | - Bowen Ke
- Department of Anesthesiology, West China Hospital, Chengdu 610041, China
| | - Binghe Wang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
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Chen RJ, Lee YH, Chen TH, Chen YY, Yeh YL, Chang CP, Huang CC, Guo HR, Wang YJ. Carbon monoxide-triggered health effects: the important role of the inflammasome and its possible crosstalk with autophagy and exosomes. Arch Toxicol 2021; 95:1141-1159. [PMID: 33554280 DOI: 10.1007/s00204-021-02976-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 01/04/2021] [Indexed: 12/18/2022]
Abstract
Carbon monoxide (CO) has long been known as a "silent killer" because of its ability to bind hemoglobin (Hb), leading to reduced oxygen carrying capacity of Hb, which is the main cause of CO poisoning (COP) in humans. Emerging studies suggest that mitochondria is a key target of CO action that can impact key biological processes, including apoptosis, cellular proliferation, inflammation, and autophagy. Despite its toxicity at high concentrations, CO also exhibits cyto- and tissue-protective effects at low concentrations in animal models of organ injury and disease. Specifically, CO modulates the production of pro- or anti-inflammatory cytokines and mediators by regulating the NLRP3 inflammasome. Given that human diseases are strongly associated with inflammation, a deep understanding of the exact mechanism is helpful for treatment. Autophagic factors and inflammasomes interact in various situations, including inflammatory disease, and exosomes might function as the bridge between the inflammasome and autophagy activation. Thus, the interplay among autophagy, mitochondrial dysfunction, exosomes, and the inflammasome may play pivotal roles in the health effects of CO. In this review, we summarize the latest research on the beneficial and toxic effects of CO and their underlying mechanisms, focusing on the important role of the inflammasome and its possible crosstalk with autophagy and exosomes. This knowledge may lead to the development of new therapies for inflammation-related diseases and is essential for the development of new therapeutic strategies and biomarkers of COP.
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Affiliation(s)
- Rong-Jane Chen
- Department of Food Safety/Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Hsuan Lee
- Department of Cosmeceutics, China Medical University, Taichung, Taiwan
| | - Tzu-Hao Chen
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Yu-Ying Chen
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan
| | - Ya-Ling Yeh
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan
| | - Ching-Ping Chang
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Chien-Cheng Huang
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan
- Department of Emergency Medicine, Chi Mei Medical Center, Tainan, Taiwan
- Department of Senior Services, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - How-Ran Guo
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan.
- Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
- Occupational Safety, Health and Medicine Research Center, National Cheng Kung University Hospital, Tainan, Taiwan.
| | - Ying-Jan Wang
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan.
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
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Yang XX, Ke BW, Lu W, Wang BH. CO as a therapeutic agent: discovery and delivery forms. Chin J Nat Med 2021; 18:284-295. [PMID: 32402406 DOI: 10.1016/s1875-5364(20)30036-4] [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: 02/20/2020] [Indexed: 02/08/2023]
Abstract
Carbon monoxide (CO) as one of the three important endogenously produced signaling molecules, termed as "gasotransmitter," has emerged as a promising therapeutic agent for treating various inflammation and cellular-stress related diseases. In this review, we discussed CO's evolution from a well-recognized toxic gas to a signaling molecule, and the effort to develop different approaches to deliver it for therapeutic application. We also summarize recently reported chemistry towards different CO delivery forms.
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Affiliation(s)
- Xiao-Xiao Yang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta GA 30303, USA
| | - Bo-Wen Ke
- Department of Anesthesiology, West China Hospital, Chengdu 610000, China
| | - Wen Lu
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta GA 30303, USA
| | - Bing-He Wang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta GA 30303, USA.
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12
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Taguchi K, Maruyama T, Otagiri M. Use of Hemoglobin for Delivering Exogenous Carbon Monoxide in Medicinal Applications. Curr Med Chem 2020; 27:2949-2963. [PMID: 30421669 DOI: 10.2174/0929867325666181113122340] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 09/25/2018] [Accepted: 11/09/2018] [Indexed: 01/02/2023]
Abstract
Carbon Monoxide (CO), at low concentrations, can have a variety of positive effects on the body including anti-apoptosis, anti-inflammatory, anti-oxidative and anti-proliferative effects. Although CO has great potential for use as a potent medical bioactive gas, for it to exist in the body in stable form, it must be associated with a carrier. Hemoglobin (Hb) represents a promising material for use as a CO carrier because most of the total CO in the body is stored associated with Hb in red blood cells (RBC). Attempts have been made to develop an Hb-based CO carrying system using RBC and Hb-based artificial oxygen carriers. Some of these have been reported to be safe and to have therapeutic value as a CO donor in preclinical and clinical studies. In the present review, we overview the potential of RBC and Hb-based artificial oxygen carriers as CO carriers based on the currently available literature evidence for their use in pharmaceutical therapy against intractable disorders.
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Affiliation(s)
- Kazuaki Taguchi
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.,DDS Research Institute, Sojo University, Kumamoto, Japan
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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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14
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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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15
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Effect of Polyethylene-glycolated Carboxyhemoglobin on Renal Microcirculation in a Rat Model of Hemorrhagic Shock. Anesthesiology 2020; 131:1110-1124. [PMID: 31490291 DOI: 10.1097/aln.0000000000002932] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Primary resuscitation fluid to treat hemorrhagic shock remains controversial. Use of hydroxyethyl starches raised concerns of acute kidney injury. Polyethylene-glycolated carboxyhemoglobin, which has carbon monoxide-releasing molecules and oxygen-carrying properties, was hypothesized to sustain cortical renal microcirculatory PO2 after hemorrhagic shock and reduce kidney injury. METHODS Anesthetized and ventilated rats (n = 42) were subjected to pressure-controlled hemorrhagic shock for 1 h. Renal cortical PO2 was measured in exposed kidneys using a phosphorescence quenching method. Rats were randomly assigned to six groups: polyethylene-glycolated carboxyhemoglobin 320 mg · kg, 6% hydroxyethyl starch (130/0.4) in Ringer's acetate, blood retransfusion, diluted blood retransfusion (~4 g · dl), nonresuscitated animals, and time control. Nitric oxide and heme oxygenase 1 levels were determined in plasma. Kidney immunohistochemistry (histologic scores of neutrophil gelatinase-associated lipocalin and tumor necrosis factor-α) and tubular histologic damages analyses were performed. RESULTS Blood and diluted blood restored renal PO2 to 51 ± 5 mmHg (mean difference, -18; 95% CI, -26 to -11; P < 0.0001) and 47 ± 5 mmHg (mean difference, -23; 95% CI, -31 to -15; P < 0.0001), respectively, compared with 29 ± 8 mmHg for hydroxyethyl starch. No differences between polyethylene-glycolated carboxyhemoglobin and hydroxyethyl starch were observed (33 ± 7 mmHg vs. 29 ± 8 mmHg; mean difference, -5; 95% CI, -12 to 3; P = 0.387), but significantly less volume was administered (4.5 [3.3-6.2] vs. 8.5[7.7-11.4] ml; mean rank difference, 11.98; P = 0.387). Blood and diluted blood increased the plasma bioavailability of nitric oxide compared with hydroxyethyl starch (mean rank difference, -20.97; P = 0.004; and -17.13; P = 0.029, respectively). No changes in heme oxygenase 1 levels were observed. Polyethylene-glycolated carboxyhemoglobin limited tubular histologic damages compared with hydroxyethyl starch (mean rank difference, 60.12; P = 0.0012) with reduced neutrophil gelatinase-associated lipocalin (mean rank difference, 84.43; P < 0.0001) and tumor necrosis factor-α (mean rank difference, 49.67; P = 0.026) histologic scores. CONCLUSIONS Polyethylene-glycolated carboxyhemoglobin resuscitation did not improve renal PO2 but limited tubular histologic damages and neutrophil gelatinase-associated lipocalin upregulation after hemorrhage compared with hydroxyethyl starch, whereas a lower volume was required to sustain macrocirculation.
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16
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Goebel U, Wollborn J. Carbon monoxide in intensive care medicine-time to start the therapeutic application?! Intensive Care Med Exp 2020; 8:2. [PMID: 31919605 PMCID: PMC6952485 DOI: 10.1186/s40635-020-0292-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/05/2020] [Indexed: 12/18/2022] Open
Abstract
Carbon monoxide (CO) is not only known as a toxic gas due to its characteristics as an odorless molecule and its rapid binding to haem-containing molecules, thus inhibiting the respiratory chain in cells resulting in hypoxia. For decades, scientists established evidence about its endogenously production in the breakdown of haem via haem-oxygenase (HO-1) and its physiological effects. Among these, the modulation of various systems inside the body are well described (e.g., anti-inflammatory, anti-oxidative, anti-apoptotic, and anti-proliferative). Carbon monoxide is able to modulate several extra- and intra-cellular signaling molecules leading to differentiated response according to the specific stimulus. With our growing understanding in the way CO exerts its effects, especially in the mitochondria and its intracellular pathways, it is tempting to speculate about a clinical application of this substance. Since HO-1 is not easy to induce, research focused on the application of the gaseous molecule CO by itself or the implementation of carbon monoxide releasing molecules (CO-RM) to deliver the molecule at a time- and dose dependently safe way to any target organ. After years of research in cellular systems and animal models, summing up data about safety issues as well as possible target to treat in various diseases, the first feasibility trials in humans were established. Up-to-date, safety issues have been cleared for low-dose carbon monoxide inhalation (up to 500 ppm), while there is no clinical data regarding the injection or intake of any kind of CO-RM so far. Current models of human research include sepsis, acute lung injury, and acute respiratory distress syndrome as well as acute kidney injury. Carbon monoxide is a most promising candidate in terms of a therapeutic agent to improve outbalanced organ conditions. In this paper, we summarized the current understanding of carbon monoxide’s biology and its possible organ targets to treating the critically ill patients in tomorrow’s ICU.
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Affiliation(s)
- Ulrich Goebel
- Department of Anaesthesiology and Critical Care, St. Franziskus-Hospital, Hohenzollernring 70, 48145, Münster, Germany.
| | - Jakob Wollborn
- Department of Anaesthesiology and Critical Care, Medical Centre - University of Freiburg, Faculty of Medicine, Freiburg im Breisgau, Germany
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17
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Yan H, Du J, Zhu S, Nie G, Zhang H, Gu Z, Zhao Y. Emerging Delivery Strategies of Carbon Monoxide for Therapeutic Applications: from CO Gas to CO Releasing Nanomaterials. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1904382. [PMID: 31663244 DOI: 10.1002/smll.201904382] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 10/08/2019] [Indexed: 06/10/2023]
Abstract
Carbon monoxide (CO) therapy has emerged as a hot topic under exploration in the field of gas therapy as it shows the promise of treating various diseases. Due to the gaseous property and the high affinity for human hemoglobin, the main challenges of administrating medicinal CO are the lack of target selectivity as well as the toxic profile at relatively high concentrations. Although abundant CO releasing molecules (CORMs) with the capacity to deliver CO in biological systems have been developed, several disadvantages related to CORMs, including random diffusion, poor solubility, potential toxicity, and lack of on-demand CO release in deep tissue, still confine their practical use. Recently, the advent of versatile nanomedicine has provided a promising chance for improving the properties of naked CORMs and simultaneously realizing the therapeutic applications of CO. This review presents a brief summarization of the emerging delivery strategies of CO based on nanomaterials for therapeutic application. First, an introduction covering the therapeutic roles of CO and several frequently used CORMs is provided. Then, recent advancements in the synthesis and application of versatile CO releasing nanomaterials are elaborated. Finally, the current challenges and future directions of these important delivery strategies are proposed.
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Affiliation(s)
- Haili Yan
- College of Medical Imaging, Shanxi Medical University, Taiyuan, 030001, P. R. China
| | - Jiangfeng Du
- College of Medical Imaging, Shanxi Medical University, Taiyuan, 030001, P. R. China
| | - Shuang Zhu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Guangjun Nie
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Chinese Academy of Sciences, Beijing, 100190, P. R. China
| | - Hui Zhang
- College of Medical Imaging, Shanxi Medical University, Taiyuan, 030001, P. R. China
| | - Zhanjun Gu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, P. R. China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Yuliang Zhao
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Chinese Academy of Sciences, Beijing, 100190, P. R. China
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18
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Heme oxygenase-1/carbon monoxide as modulators of autophagy and inflammation. Arch Biochem Biophys 2019; 678:108186. [PMID: 31704095 DOI: 10.1016/j.abb.2019.108186] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 10/10/2019] [Accepted: 11/04/2019] [Indexed: 12/29/2022]
Abstract
Heme oxygenase-1 (HO-1) catalyzes heme degradation to generate biliverdin-IXα, carbon monoxide (CO), and iron. The HO-1/CO system confers cytoprotection in animal models of organ injury and disease, via modulation of inflammation and apoptosis. Recent studies have uncovered novel anti-inflammatory targets of HO-1/CO including regulation of the autophagy and inflammasome pathways. Autophagy is a lysosome-dependent program for the turnover of cellular organelles such as mitochondria, proteins, and pathogens; which may downregulate inflammatory processes. Therapeutic modulation of autophagy by CO has been demonstrated in models of sepsis. The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome regulates the maturation of pro-inflammatory cytokines. CO can regulate NLRP3 inflammasome activation and associated pro-inflammatory cytokines production and promote the resolution of inflammation by upregulating the synthesis of specialized pro-resolving mediators (SPMs). Mitochondria may represent a proximal target of HO-1/CO action. HO-1 may localize to mitochondria in response to stress, while CO can moderate mitochondrial dysfunction and regulate mitochondrial autophagy (mitophagy) and biogenesis. The interplay between mitochondrial autophagy, mitochondrial dysfunction, and the regulation and resolution of inflammation may make important contributions to the protection afforded by HO-1/CO in cellular and organ injury models. Recent studies have continued to explore the potential of CO for clinical applications.
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19
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Chen Y, Joe Y, Park J, Song HC, Kim UH, Chung HT. Carbon monoxide induces the assembly of stress granule through the integrated stress response. Biochem Biophys Res Commun 2019; 512:289-294. [PMID: 30885431 DOI: 10.1016/j.bbrc.2019.03.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 03/03/2019] [Indexed: 12/18/2022]
Abstract
Stress granules (SGs) are membraneless and phase-dense organelles that form transiently in response to a variety of harmful stimuli, including oxidative, heat, osmotic, ultraviolet light and chemotoxic stresses, and thus providing protective effects, allowing survivals. Carbon monoxide (CO), a gaseous second messenger, is synthesized by heme-oxygenases, and exerts anti-inflammatory, anti-proliferative and anti-apoptotic effects in a variety of cellular- and tissue-injury models. Several reports indicate that low levels of mitochondrial reactive oxygen species (mtROS) generated by CO can selectively activate PERK-eIF2α integrated stress response (ISR) to preserve the cellular homeostasis. Hence, CO can confer protection against cellular stresses. However, the mechanisms underlying the cyto-protective effects of CO against various harmful stimuli remain to be elucidated. Here, we sought to examine whether CO induces the SG assembly, and uncover its molecular mechanisms. We treated WI-38 cells and primary mouse embryonic fibroblasts (MEFs) with CO-releasing molecule 2 (CORM2) or CO gas, and found the SG assemblies were gradually increased in time and dose dependent manners. Next, we used Mito-TEMPO, an mtROS scavenger, to explore if mtROS might be involved in the CO-induced SG assembly. Furthermore, we confirmed the involvement of ISR consisted of PERK-eIF2α signaling pathway induced by CO for the SGs assembly. Finally, the inhibition of SG assembly by ISR inhibitor further verified CO-induced ISR might be responsible for SG. Taken together, in this study, we first demonstrated that CO is a novel SG inducer by activating ISR. Moreover, mtROS might be an initiator for the CO-induced ISR responsible for SG assembly.
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Affiliation(s)
- Yingqing Chen
- Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea; Department of Pharmacology, Dalian University Medical College, Dalian, 116622, China
| | - Yeonsoo Joe
- Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea
| | - Jeongmin Park
- Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea
| | - Hyun-Chul Song
- Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea
| | - Uh-Hyun Kim
- National Creative Research Laboratory for Ca(2+) Signaling Network, Chonbuk National University Medical School, Jeonju, 54907, Republic of Korea.
| | - Hun Taeg Chung
- Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
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20
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Ji X, Pan Z, Li C, Kang T, De La Cruz LKC, Yang L, Yuan Z, Ke B, Wang B. Esterase-Sensitive and pH-Controlled Carbon Monoxide Prodrugs for Treating Systemic Inflammation. J Med Chem 2019; 62:3163-3168. [PMID: 30816714 DOI: 10.1021/acs.jmedchem.9b00073] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
A bottleneck for developing CO-based therapeutics is the lack of a safe and controllable delivery form. Herein, we describe efforts toward organic CO prodrugs with dual-responsive endogenous triggers. One representative CO prodrug showed significant anti-inflammatory effects both in vitro and in a LPS-simulated systemic inflammation model. These results firmly establish such CO prodrugs as either research tools or candidate compounds for the treatment of systemic inflammation or inflammation related organ injuries.
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Affiliation(s)
- Xingyue Ji
- Department of Chemistry and Center for Diagnostics and Therapeutics , Georgia State University , Atlanta , Georgia 30303 , United States.,Department of Medicinal Chemistry, College of Pharmaceutical Science , Soochow University , Suzhou , Jiangsu 215021 , China
| | - Zhixiang Pan
- Department of Chemistry and Center for Diagnostics and Therapeutics , Georgia State University , Atlanta , Georgia 30303 , United States
| | - Chunjie Li
- Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital , Sichuan University Chengdu , Sichuan 610041 , China
| | - Ting Kang
- Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital , Sichuan University Chengdu , Sichuan 610041 , China
| | - Ladie Kimberly C De La Cruz
- Department of Chemistry and Center for Diagnostics and Therapeutics , Georgia State University , Atlanta , Georgia 30303 , United States
| | - Lingyun Yang
- Department of Chemistry and Center for Diagnostics and Therapeutics , Georgia State University , Atlanta , Georgia 30303 , United States
| | - Zhengnan Yuan
- Department of Chemistry and Center for Diagnostics and Therapeutics , Georgia State University , Atlanta , Georgia 30303 , United States
| | - Bowen Ke
- Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital , Sichuan University Chengdu , Sichuan 610041 , China
| | - Binghe Wang
- Department of Chemistry and Center for Diagnostics and Therapeutics , Georgia State University , Atlanta , Georgia 30303 , United States
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21
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Aki T, Unuma K, Noritake K, Hirayama N, Funakoshi T, Uemura K. Formation of high molecular weight p62 by CORM-3. PLoS One 2019; 14:e0210474. [PMID: 30620762 PMCID: PMC6324786 DOI: 10.1371/journal.pone.0210474] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 12/25/2018] [Indexed: 11/25/2022] Open
Abstract
CORM-3 is a water-soluble carbon monoxide (CO)-releasing molecule developed for possible therapeutic use of CO. CORM-3 belongs to a group of metal carbonyl compounds that contain transition metals and carbonyls as the central scaffold and coordinated ligands, respectively. CORM-3 has been reported to be reactive with many proteins in eukaryotes including mammals. Among them, several extracellular proteins, such as lysozyme, as well as plasma albumin and fibronectin, have been shown to interact directly with CORM-3. p62 is an intracellular adaptor protein required for targeting ubiquitinated (Ub) proteins to lysosomal degradation through autophagy. p62 has been shown to undergo self-oligomerization via covalent crosslinking in response to treatment with verteporfin, a benzoporphyrin derivative used for photodynamic therapy. Here we show that CORM-3 also interacts directly with p62. When applied to mouse embryonic fibroblasts (MEFs) at a high concentration (1 mM), CORM-3 causes the formation of reduction- and detergent-resistant high molecular weight (HMW)-p62. HMW-p62 accumulates more in atg5-/- MEFs than in wild type (WT) MEFs, showing the elimination of HMW-p62 through autophagy. HMW-p62 is also generated in H9c2 rat cardiomyoblastoma as well as A549 human alveolar epithelial cells, suggesting that HMW-p62 formation is not specific to MEFs, but, rather, is a general event in mammalian cells. HMW-p62 formation by CORM-3 can be reproduced using purified p62 in vitro, demonstrating the direct interaction between CORM-3 and p62. These results show that p62 is a CORM-3-interactive intracellular protein.
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Affiliation(s)
- Toshihiko Aki
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
- * E-mail:
| | - Kana Unuma
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
| | - Kanako Noritake
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
| | - Naho Hirayama
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
| | - Takeshi Funakoshi
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
| | - Koichi Uemura
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
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22
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Fu X, Liu L. Pro-resolution of Inflammation: New Hints to Manage Sepsis? SEVERE TRAUMA AND SEPSIS 2019. [PMCID: PMC7121927 DOI: 10.1007/978-981-13-3353-8_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Sepsis is newly defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The pathophysiological mechanism of sepsis is highly complex, and the mortality of in-patients suffering from sepsis is more than 10%. Severe unmanaged inflammation and inappropriate immune response characterize sepsis. Anti-inflammation therapies alone are not successful for the reason that disbalance of anti-inflammatory and pro-resolving agents. In the recent researches, the host responses during the course of self-resolving infections are found to have the involvements of specialized pro-resolution mediators (SPMs), namely, lipoxins, resolvins, protectins and maresins. These endogenous lipid metabolites are core signal molecules in the resolution of inflammation, playing a key role in regulating the inflammation and promoting return to homeostasis. Besides, heme oxygenase-1 (HO-1, a sensitive marker for oxidative stress) is also known for upregulation in inflammation profiling. Carbon monoxide, synthesized by HO-1, performs multiple stances of anti-inflammation and pro-resolution along with the SPMs. If the potentially beneficial effects of these mediators would be well evaluated in clinical trials, they present encouraging new hints in managing infectious maladies especially sepsis.
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Affiliation(s)
- Xiaobing Fu
- Wound Healing and Cell Biology Lab, First Affiliated Hospital, Chinese PLA General Hospital, Beijing, China
| | - Liangming Liu
- State Key Laboratory of Trauma, Burns, and Combined Injury, Daping Hospital, Third Military Medical University, Chong Qing, China
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23
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Rezoagli E, McNicholas B, Moran P, Laffey JG. Sepsis Therapies: Insights from Population Health to Cellular Therapies and Genomic Medicine. Am J Respir Crit Care Med 2018; 198:1570-1572. [PMID: 30277812 DOI: 10.1164/rccm.201804-0782rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Emanuele Rezoagli
- Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Galway, Ireland
| | - Bairbre McNicholas
- Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Galway, Ireland
| | - Peter Moran
- Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Galway, Ireland
| | - John G Laffey
- Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Galway, Ireland
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24
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Fredenburgh LE, Perrella MA, Barragan-Bradford D, Hess DR, Peters E, Welty-Wolf KE, Kraft BD, Harris RS, Maurer R, Nakahira K, Oromendia C, Davies JD, Higuera A, Schiffer KT, Englert JA, Dieffenbach PB, Berlin DA, Lagambina S, Bouthot M, Sullivan AI, Nuccio PF, Kone MT, Malik MJ, Porras MAP, Finkelsztein E, Winkler T, Hurwitz S, Serhan CN, Piantadosi CA, Baron RM, Thompson BT, Choi AM. A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS. JCI Insight 2018; 3:124039. [PMID: 30518685 DOI: 10.1172/jci.insight.124039] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 10/29/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS. METHODS We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level ≥10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes. RESULTS No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% ± 0.7% [cohort 1]; 4.9% ± 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% ± 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects. CONCLUSION Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials. TRIAL REGISTRATION ClinicalTrials.gov NCT02425579. FUNDING NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695.
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Affiliation(s)
- Laura E Fredenburgh
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Mark A Perrella
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Diana Barragan-Bradford
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Dean R Hess
- Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Respiratory Care, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Elizabeth Peters
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Karen E Welty-Wolf
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Bryan D Kraft
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - R Scott Harris
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rie Maurer
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kiichi Nakahira
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Clara Oromendia
- Department of Healthcare Policy and Research, Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, New York, USA
| | - John D Davies
- Department of Respiratory Care, Duke University Medical Center, Durham, North Carolina, USA
| | - Angelica Higuera
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kristen T Schiffer
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Joshua A Englert
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Paul B Dieffenbach
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - David A Berlin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Susan Lagambina
- Department of Respiratory Care, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Mark Bouthot
- Department of Respiratory Care, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Andrew I Sullivan
- Department of Respiratory Care, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Paul F Nuccio
- Department of Respiratory Care, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Mamary T Kone
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mona J Malik
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Maria Angelica Pabon Porras
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Eli Finkelsztein
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Tilo Winkler
- Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shelley Hurwitz
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Claude A Piantadosi
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Rebecca M Baron
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - B Taylor Thompson
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Augustine Mk Choi
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
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25
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Tsai MH, Yang CM, Chang KT, Chuang CC, Lin WN, Jiang RS, Wu CH, Lee IT. Carbon monoxide ameliorates Staphylococcus aureus-elicited COX-2/IL-6/MMP-9-dependent human aortic endothelial cell migration and inflammatory responses. Immunol Lett 2018; 203:40-49. [PMID: 30236480 DOI: 10.1016/j.imlet.2018.09.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/28/2018] [Accepted: 09/14/2018] [Indexed: 12/14/2022]
Abstract
Staphylococcus aureus (S. aureus) can often lead to many life-threatening diseases. It has the ability to invade normal endovascular tissue. Acute inflammation and its resolution are important to ensure bacterial clearance and limit tissue injury. Carbon monoxide (CO) has been shown to exert anti-inflammatory effects in various tissues and organ systems. In our study, we investigated the effects and the mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on S. aureus-induced inflammatory responses in human aortic endothelial cells (HAECs). We proved that S. aureus induced cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2)/interleukin-6 (IL-6)/matrix metallopeptidase-9 (MMP-9) expression and cell migration, which were decreased by CORM-2. Moreover, CORM-2 had no effects on TLR2 mRNA levels in response to S. aureus. Interestingly, we proved that S. aureus decreased intracellular ROS generation, suggesting that the inhibition of ROS further promoted inflammatory responses. However, CORM-2 significantly inhibited S. aureus-induced inflammation by increasing intracellular ROS generation. S. aureus-induced NF-κB activation was also inhibited by CORM-2. Finally, we proved that S. aureus induced levels of the biomarkers of inflammation in cardiovascular diseases, which were inhibited by CORM-2. Taken together, these results suggest that CORM-2 inhibits S. aureus-induced COX-2/PGE2/IL-6/MMP-9 expression and aorta inflammatory responses by increasing the ROS generation and reducing the inflammatory molecules levels.
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Affiliation(s)
- Ming-Horng Tsai
- Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan
| | - Chuen-Mao Yang
- Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan; Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo and Chang Gung University, Kwei-San, Tao-Yuan, Taiwan; Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
| | - Kuo-Ting Chang
- Translational Medicine Center, Taoyuan General Hospital, Ministry of Healthy and Welfare, Taoyuan, Taiwan
| | - Chu-Chun Chuang
- Department of Physical Therapy, China Medical University, Taichung, Taiwan
| | - Wei-Ning Lin
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Rong-San Jiang
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Cheng-Hsun Wu
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
| | - I-Ta Lee
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Nursing, College of Nursing, Hungkuang University, Taichung, Taiwan.
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26
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Uddin MJ, Pak ES, Ha H. Carbon monoxide releasing molecule-2 protects mice against acute kidney injury through inhibition of ER stress. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2018; 22:567-575. [PMID: 30181703 PMCID: PMC6115348 DOI: 10.4196/kjpp.2018.22.5.567] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/28/2018] [Accepted: 07/12/2018] [Indexed: 12/21/2022]
Abstract
Acute kidney injury (AKI), which is defined as a rapid decline of renal function, becomes common and recently recognized to be closely intertwined with chronic kidney diseases. Current treatment for AKI is largely supportive, and endoplasmic reticulum (ER) stress has emerged as a novel mediator of AKI. Since carbon monoxide attenuates ER stress, the objective of the present study aimed to determine the protective effect of carbon monoxide releasing molecule-2 (CORM2) on AKI associated with ER stress. Kidney injury was induced after LPS (15 mg/kg) treatment at 12 to 24 h in C57BL/6J mice. Pretreatment of CORM2 (30 mg/kg) effectively prevented LPS-induced oxidative stress and inflammation during AKI in mice. CORM2 treatment also effectively inhibited LPS-induced ER stress in AKI mice. In order to confirm effect of CO on the pathophysiological role of tubular epithelial cells in AKI, we used mProx24 cells. Pretreatment of CORM2 attenuated LPS-induced ER stress, oxidative stress, and inflammation in mProx24 cells. These data suggest that CO therapy may prevent ER stress-mediated AKI.
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Affiliation(s)
- Md Jamal Uddin
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea
| | - Eun Seon Pak
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea
| | - Hunjoo Ha
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea
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27
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Shao L, Liu C, Wang S, Liu J, Wang L, Lv L, Zou Y. The impact of exogenous CO releasing molecule CORM-2 on inflammation and signaling of orthotopic lung cancer. Oncol Lett 2018; 16:3223-3230. [PMID: 30127918 DOI: 10.3892/ol.2018.9022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 06/06/2018] [Indexed: 11/05/2022] Open
Abstract
The present study aimed to evaluate the therapeutic effect of CO-releasing molecule-2 (CORM-2) in an established mouse orthotopic lung cancer model and investigate the underlying mechanism associated with inflammation pathway. A total of 80 mice were randomly divided into two groups with 20 serving as a normal control and 60 used for the orthotopic lung cancer model. The tumor group was either untreated, or administrated with DMSO or CORM-2. The mice were sacrificed at day 7 and 14 post-treatment, and the body weight, and thymus and spleen indices were determined. Pathological analysis was performed with hematoxylin and eosin (HE) staining. Serous inflammatory factors were measured using an ELISA. The expression levels of eukaryotic translation initiation factor 4E, p70S6K and toll-like receptor-4 (TLR4) were quantified by reverse transcription-polymerase chain reaction. The effects of CORM-2 on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), TLR4/nuclear factor (NF)-κB signaling pathways were determined by western blotting. The body weight increased over time in the control group, while it significantly declined in tumor-bearing mice (P<0.05). CORM-2 treatment significantly increased body weight in comparison with the model and DSMO treatment groups (P<0.05). The thymus and spleen indices both reduced in the model and DMSO treatment groups, which was significantly rescued with CORM-2 administration (P<0.05). The HE staining results demonstrated few nodule formations, fibrous hyperplasia and extensive necrosis, which suggested overt inhibitory effects against cancer of CORM-2. The serous contents of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the CORM-2 group was significantly lower compared with that in the model and DMSO groups (P<0.05). The ratio of phosphorylated (p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, p-NF-κB-p65/NF-κB-p65 and expression of TLR4 significantly decreased in the CORM-2 group compared with the model and DMSO groups (P<0.05). To the best of our knowledge, the data in the present study demonstrated in vivo for the first time, the therapeutic potential of the CORM complex, which is associated with suppression of inflammation and general protein synthesis.
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Affiliation(s)
- Li Shao
- Department of Integrated Traditional Chinese and Western Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Congyang Liu
- Department of Integrated Traditional Chinese and Western Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Shuhua Wang
- Department of Information, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Jiannan Liu
- Department of Medical Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Li Wang
- Department of Integrated Traditional Chinese and Western Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Liping Lv
- Department of Integrated Traditional Chinese and Western Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Yong Zou
- Department of Integrated Traditional Chinese and Western Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
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28
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Mora AL, Rojas M. Seeing CO in a New Light: Enhancing Autophagy in Mesenchymal Stromal Cells and Implications for Cell Therapy. Am J Respir Cell Mol Biol 2018; 56:275-276. [PMID: 28248130 DOI: 10.1165/rcmb.2016-0400ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Ana L Mora
- 1 Division of Pulmonary, Allergy and Critical Care Medicine.,2 McGowan Institute of Regenerative Medicine of the University of Pittsburgh University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania and
| | - Mauricio Rojas
- 2 McGowan Institute of Regenerative Medicine of the University of Pittsburgh University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania and.,3 Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania
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29
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Ryter SW, Ma KC, Choi AMK. Carbon monoxide in lung cell physiology and disease. Am J Physiol Cell Physiol 2017; 314:C211-C227. [PMID: 29118026 DOI: 10.1152/ajpcell.00022.2017] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Carbon monoxide (CO) is an endogenously produced gas that has gained recognition as a biological signal transduction effector with properties similar, but not identical, to that of nitric oxide (NO). CO, which binds primarily to heme iron, may activate the hemoprotein guanylate cyclase, although with lower potency than NO. Furthermore, CO can modulate the activities of several cellular signaling molecules such as p38 MAPK, ERK1/2, JNK, Akt, NF-κB, and others. Emerging studies suggest that mitochondria, the energy-generating organelle of cells, represent a key target of CO action in eukaryotes. Dose-dependent modulation of mitochondrial function by CO can result in alteration of mitochondrial membrane potential, mitochondrial reactive oxygen species production, release of proapoptotic and proinflammatory mediators, as well as the inhibition of respiration at high concentration. CO, through modulation of signaling pathways, can impact key biological processes including autophagy, mitochondrial biogenesis, programmed cell death (apoptosis), cellular proliferation, inflammation, and innate immune responses. Inhaled CO is widely known as an inhalation hazard due to its rapid complexation with hemoglobin, resulting in impaired oxygen delivery to tissues and hypoxemia. Despite systemic and cellular toxicity at high concentrations, CO has demonstrated cyto- and tissue-protective effects at low concentration in animal models of organ injury and disease. These include models of acute lung injury (e.g., hyperoxia, hypoxia, ischemia-reperfusion, mechanical ventilation, bleomycin) and sepsis. The success of CO as a candidate therapeutic in preclinical models suggests potential clinical application in inflammatory and proliferative disorders, which is currently under evaluation in clinical trials.
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Affiliation(s)
- Stefan W Ryter
- Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College , New York, New York
| | - Kevin C Ma
- Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College , New York, New York.,New York Presbyterian Hospital , New York, New York
| | - Augustine M K Choi
- Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College , New York, New York.,New York Presbyterian Hospital , New York, New York
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30
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Surate Solaligue DE, Rodríguez-Castillo JA, Ahlbrecht K, Morty RE. Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2017; 313:L1101-L1153. [PMID: 28971976 DOI: 10.1152/ajplung.00343.2017] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 09/21/2017] [Accepted: 09/23/2017] [Indexed: 02/08/2023] Open
Abstract
The objective of lung development is to generate an organ of gas exchange that provides both a thin gas diffusion barrier and a large gas diffusion surface area, which concomitantly generates a steep gas diffusion concentration gradient. As such, the lung is perfectly structured to undertake the function of gas exchange: a large number of small alveoli provide extensive surface area within the limited volume of the lung, and a delicate alveolo-capillary barrier brings circulating blood into close proximity to the inspired air. Efficient movement of inspired air and circulating blood through the conducting airways and conducting vessels, respectively, generates steep oxygen and carbon dioxide concentration gradients across the alveolo-capillary barrier, providing ideal conditions for effective diffusion of both gases during breathing. The development of the gas exchange apparatus of the lung occurs during the second phase of lung development-namely, late lung development-which includes the canalicular, saccular, and alveolar stages of lung development. It is during these stages of lung development that preterm-born infants are delivered, when the lung is not yet competent for effective gas exchange. These infants may develop bronchopulmonary dysplasia (BPD), a syndrome complicated by disturbances to the development of the alveoli and the pulmonary vasculature. It is the objective of this review to update the reader about recent developments that further our understanding of the mechanisms of lung alveolarization and vascularization and the pathogenesis of BPD and other neonatal lung diseases that feature lung hypoplasia.
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Affiliation(s)
- David E Surate Solaligue
- Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; and.,Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany
| | - José Alberto Rodríguez-Castillo
- Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; and.,Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany
| | - Katrin Ahlbrecht
- Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; and.,Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany
| | - Rory E Morty
- Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; and .,Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany
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31
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Kim HJ, Joe Y, Kim SK, Park SU, Park J, Chen Y, Kim J, Ryu J, Cho GJ, Surh YJ, Ryter SW, Kim UH, Chung HT. Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin-2 via the PERK-eIF2α-ATF4 pathway. Free Radic Biol Med 2017; 110:81-91. [PMID: 28578014 DOI: 10.1016/j.freeradbiomed.2017.05.026] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Revised: 05/08/2017] [Accepted: 05/30/2017] [Indexed: 12/18/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has emerged as one of the most common causes of chronic liver disease in developed countries over the last decade. NAFLD comprises a spectrum of pathological hepatic changes, including steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Autophagy, a homeostatic process for protein and organelle turnover, is decreased in the liver during the development of NAFLD. Previously, we have shown that carbon monoxide (CO), a reaction product of heme oxygenase (HO) activity, can confer protection in NAFLD, though the molecular mechanisms remain unclear. We therefore investigated the mechanisms underlying the protective effect of CO on methionine/choline-deficient (MCD) diet-induced hepatic steatosis. We found that CO induced sestrin-2 (SESN2) expression through enhanced mitochondrial ROS production and protected against MCD-induced NAFLD progression through activation of autophagy. SESN2 expression was increased by CO or CO-releasing molecule (CORM2), in a manner dependent on signaling through the protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor-2 alpha (eIF2α)/ activating transcription factor-4 (ATF4)-dependent pathway. CO-induced SESN2 upregulation in hepatocytes contributed to autophagy induction through activation of 5'-AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) complex I (mTORC1). Furthermore, we demonstrate that CO significantly induced the expression of SESN2 and enhanced autophagy in the livers of MCD-fed mice or in MCD-media treated hepatocytes. Conversely, knockdown of SESN2 abrogated autophagy activation and mTOR inhibition in response to CO. We conclude that CO ameliorates hepatic steatosis through the autophagy pathway induced by SESN2 upregulation.
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Affiliation(s)
- Hyo Jeong Kim
- Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea
| | - Yeonsoo Joe
- Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea
| | - Seul-Ki Kim
- Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea
| | - Se-Ung Park
- Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea
| | - Jeongmin Park
- Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea
| | - Yingqing Chen
- Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea
| | - Jin Kim
- Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea
| | - Jinhyun Ryu
- Department of Anatomy, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea
| | - Gyeong Jae Cho
- Department of Anatomy, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Stefan W Ryter
- Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center, New York, NY, USA
| | - Uh-Hyun Kim
- National Creative Research Laboratory for Ca(2+) Signaling Network, Chonbuk National University, Medical School, Jeonju, Republic of Korea.
| | - Hun-Taeg Chung
- Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
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32
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Li ZY, Wu YF, Xu XC, Zhou JS, Wang Y, Shen HH, Chen ZH. Autophagy as a double-edged sword in pulmonary epithelial injury: a review and perspective. Am J Physiol Lung Cell Mol Physiol 2017; 313:L207-L217. [DOI: 10.1152/ajplung.00562.2016] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 04/11/2017] [Accepted: 04/30/2017] [Indexed: 01/11/2023] Open
Abstract
Pulmonary epithelial cells form the first line of defense of human airways against foreign irritants and also represent as the primary injury target of these pathogenic assaults. Autophagy is a revolutionary conserved ubiquitous process by which cytoplasmic materials are delivered to lysosomes for degradation when facing environmental and/or developmental changes, and emerging evidence suggests that autophagy plays pivotal but controversial roles in pulmonary epithelial injury. Here we review recent studies focusing on the roles of autophagy in regulating airway epithelial injury induced by various stimuli. Articles eligible for this purpose are divided into two groups according to the eventual roles of autophagy, either protective or deleterious. From the evidence summarized in this review, we draw several conclusions as follows: 1) in all cases when autophagy is decreased from its basal level, autophagy is protective; 2) when autophagy is deleterious, it is generally upregulated by stimulation; and 3) a plausible conclusion is that the endosomal/exosomal pathways may be associated with the deleterious function of autophagy in airway epithelial injury, although this needs to be clarified in future investigations.
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Affiliation(s)
- Zhou-Yang Li
- Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang; and
| | - Yin-Fang Wu
- Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang; and
| | - Xu-Chen Xu
- Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang; and
| | - Jie-Sen Zhou
- Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang; and
| | - Yong Wang
- Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang; and
| | - Hua-Hao Shen
- Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang; and
- State Key Lab of Respiratory Disease, Guangzhou, China
| | - Zhi-Hua Chen
- Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang; and
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Lazarus LS, Esquer HJ, Benninghoff AD, Berreau LM. Sense and Release: A Thiol-Responsive Flavonol-Based Photonically Driven Carbon Monoxide-Releasing Molecule That Operates via a Multiple-Input AND Logic Gate. J Am Chem Soc 2017; 139:9435-9438. [DOI: 10.1021/jacs.7b04077] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Livia S. Lazarus
- Department of Chemistry and Biochemistry, Utah State University, Logan, Utah 84322-0300, United States
| | - Hector J. Esquer
- Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah 84322-4815, United States
| | - Abby D. Benninghoff
- Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah 84322-4815, United States
| | - Lisa M. Berreau
- Department of Chemistry and Biochemistry, Utah State University, Logan, Utah 84322-0300, United States
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Peng QY, Zou Y, Zhang LN, Ai ML, Liu W, Ai YH. Blocking Cyclic Adenosine Diphosphate Ribose-mediated Calcium Overload Attenuates Sepsis-induced Acute Lung Injury in Rats. Chin Med J (Engl) 2017; 129:1725-30. [PMID: 27411462 PMCID: PMC4960964 DOI: 10.4103/0366-6999.185854] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Background: Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality. Intracellular Ca2+ overload plays an important role in the pathophysiology of sepsis-induced ALI, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALI is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALI and whether blocking cADPR-mediated calcium overload attenuates ALI. Methods: Septic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-α, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured. Results: NAD+, cADPR, CD38, and intracellular Ca2+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-α and MDA levels (P < 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats. Conclusions: The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALI.
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Affiliation(s)
- Qian-Yi Peng
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yu Zou
- Department of Anesthesia, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Li-Na Zhang
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Mei-Lin Ai
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Wei Liu
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yu-Hang Ai
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Tsai MH, Lee CW, Hsu LF, Li SY, Chiang YC, Lee MH, Chen CH, Liang HF, How JM, Chang PJ, Wu CM, Lee IT. CO-releasing molecules CORM2 attenuates angiotensin II-induced human aortic smooth muscle cell migration through inhibition of ROS/IL-6 generation and matrix metalloproteinases-9 expression. Redox Biol 2017; 12:377-388. [PMID: 28292711 PMCID: PMC5349464 DOI: 10.1016/j.redox.2017.02.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 02/22/2017] [Accepted: 02/23/2017] [Indexed: 12/29/2022] Open
Abstract
Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9) induced migration of human aortic smooth muscle cells (HASMCs) is the most common and basic pathological feature. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47phox, Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R) and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47phox translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed.
Angiotensin II can induce HASMCs migration via activating ROS/NF-κB/IL-6/ MMP-9. CORM-2 can inhibit Ang II-induced ROS/NF-κB/IL-6/MMP-9-dependent HASMCs migration. The blockade of ROS by CORM-2 can be a preventive strategy of cardiovascular diseases.
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Affiliation(s)
- Ming-Horng Tsai
- Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taiwan
| | - Chiang-Wen Lee
- Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan; Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
| | - Lee-Fen Hsu
- Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan
| | - Shu-Yu Li
- Department of Pharmacy, College of Pharmacy & Health Care, Tajen University, Taiwan
| | - Yao-Chang Chiang
- Center for Drug Abuse and Addiction, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Ming-Hsueh Lee
- Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, Chia-Yi 61363, Taiwan
| | - Chun-Han Chen
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan
| | - Hwey-Fang Liang
- Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan
| | - Jia-Mei How
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Pey-Jium Chang
- Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taiwan
| | - Ching-Mei Wu
- Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
| | - I-Ta Lee
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan.
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Meng YX, Liu QH, Chen DH, Meng Y. Pathway cross-talk network analysis identifies critical pathways in neonatal sepsis. Comput Biol Chem 2017; 68:101-106. [PMID: 28292731 DOI: 10.1016/j.compbiolchem.2017.02.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/07/2017] [Accepted: 02/21/2017] [Indexed: 11/17/2022]
Abstract
BACKGROUND Despite advances in neonatal care, sepsis remains a major cause of morbidity and mortality in neonates worldwide. Pathway cross-talk analysis might contribute to the inference of the driving forces in bacterial sepsis and facilitate a better understanding of underlying pathogenesis of neonatal sepsis. OBJECTIVE This study aimed to explore the critical pathways associated with the progression of neonatal sepsis by the pathway cross-talk analysis. METHODS By integrating neonatal transcriptome data with known pathway data and protein-protein interaction data, we systematically uncovered the disease pathway cross-talks and constructed a disease pathway cross-talk network for neonatal sepsis. Then, attract method was employed to explore the dysregulated pathways associated with neonatal sepsis. To determine the critical pathways in neonatal sepsis, rank product (RP) algorithm, centrality analysis and impact factor (IF) were introduced sequentially, which synthetically considered the differential expression of genes and pathways, pathways cross-talks and pathway parameters in the network. The dysregulated pathways with the highest IF values as well as RP<0.01 were defined as critical pathways in neonatal sepsis. RESULTS By integrating three kinds of data, only 6919 common genes were included to perform the pathway cross-talk analysis. By statistic analysis, a total of 1249 significant pathway cross-talks were selected to construct the pathway cross-talk network. Moreover, 47 dys-regulated pathways were identified via attract method, 20 pathways were identified under RP<0.01, and the top 10 pathways with the highest IF were also screened from the pathway cross-talk network. Among them, we selected 8 common pathways, i.e. critical pathways. CONCLUSIONS In this study, we systematically tracked 8 critical pathways involved in neonatal sepsis by integrating attract method and pathway cross-talk network. These pathways might be responsible for the host response in infection, and of great value for advancing diagnosis and therapy of neonatal sepsis.
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Affiliation(s)
- Yu-Xiu Meng
- Department of Neonatology, First People's Hospital of Jining, Jining, Shandong 272011, PR China
| | - Quan-Hong Liu
- Department of Neonatology, Maternal and Child Health Hospital of Sishui, Jining, Shandong 273200, PR China
| | - Deng-Hong Chen
- Department of Obstetrics, First People's Hospital of Jining, Jining, Shandong 272011, PR China.
| | - Ying Meng
- Department of Internal Medicine, Traditional Chinese Medicine Hospital of Yanzhou, Jining, Shandong 272000, PR China
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Buechler C, Pohl R, Aslanidis C. Pro-Resolving Molecules-New Approaches to Treat Sepsis? Int J Mol Sci 2017; 18:ijms18030476. [PMID: 28241480 PMCID: PMC5372492 DOI: 10.3390/ijms18030476] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 02/15/2017] [Accepted: 02/15/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammation is a complex response of the body to exogenous and endogenous insults. Chronic and systemic diseases are attributed to uncontrolled inflammation. Molecules involved in the initiation of inflammation are very well studied while pathways regulating its resolution are insufficiently investigated. Approaches to down-modulate mediators relevant for the onset and duration of inflammation are successful in some chronic diseases, while all of them have failed in sepsis patients. Inflammation and immune suppression characterize sepsis, indicating that anti-inflammatory strategies alone are inappropriate for its therapy. Heme oxygenase 1 is a sensitive marker for oxidative stress and is upregulated in inflammation. Carbon monoxide, which is produced by this enzyme, initiates multiple anti-inflammatory and pro-resolving activities with higher production of omega-3 fatty acid-derived lipid metabolites being one of its protective actions. Pro-resolving lipids named maresins, resolvins and protectins originate from the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid while lipoxins are derived from arachidonic acid. These endogenously produced lipids do not simply limit inflammation but actively contribute to its resolution, and thus provide an opportunity to combat chronic inflammatory diseases and eventually sepsis.
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Affiliation(s)
- Christa Buechler
- Department of Internal Medicine I, Regensburg University Hospital, 93042 Regensburg, Germany.
| | - Rebekka Pohl
- Department of Internal Medicine I, Regensburg University Hospital, 93042 Regensburg, Germany.
| | - Charalampos Aslanidis
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, 93042 Regensburg, Germany.
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Gahlot S, Nasreen N, Johnson JA, Sahn SA, Mohammed KA. Heme Oxygenase-1 Deficiency Diminishes Methicillin-Resistant Staphylococcus aureus Clearance Due to Reduced TLR9 Expression in Pleural Mesothelial Cells. PLoS One 2017; 12:e0169245. [PMID: 28052108 PMCID: PMC5215390 DOI: 10.1371/journal.pone.0169245] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 12/14/2016] [Indexed: 11/18/2022] Open
Abstract
Methicillin Resistant Staphylococcus aureus (MRSA) cause pneumonia and empyema thoraces. TLR9 activation provides protection against bacterial infections and Heme oxygenase-1 (HO-1) is known to enhance host innate immunity against bacterial infections. However, it is still unclear whether HO-1 regulates TLR-9 expression in the pleura and modulates the host innate defenses during MRSA empyema. In order to determine if HO-1 regulates host innate immune functions via modulating TLR expression, in MRSA empyema, HO-1+/+ and HO-1-/- mouse pleural mesothelial cells (PMCs) were infected with MRSA (1:10, MOI) in the presence or absence of Cobalt Protoporphyrin (CoPP) and Zinc Protoporphyrin (ZnPP) or CORM-2 (a Carbon monoxide donor) and the expression of mTLR9 and mBD14 was assessed by RT-PCR. In vivo, HO-1+/+ and HO-1-/- mice were inoculated with MRSA (5x106 CFU) intra-pleurally and host bacterial load was measured by CFU, and TLR9 expression in the pleura was determined by histochemical-immunostaining. We noticed MRSA inducing differential expression of TLR9 in HO-1+/+ and HO-1 -/- PMCs. In MRSA infected HO-1+/+ PMCs, TLR1, TLR4, and TLR9 expression was several fold higher than MRSA infected HO-1-/- PMCs. Particularly TLR9 expression was very low in MRSA infected HO-1-/- PMCs both in vivo and in vitro. Bacterial clearance was significantly higher in HO-1+/+ PMCs than compared to HO-1-/- PMCs in vitro, and blocking TLR9 activation diminished MRSA clearance significantly. In addition, HO-1-/- mice were unable to clear the MRSA bacterial load in vivo. MRSA induced TLR9 and mBD14 expression was significantly high in HO-1+/+ PMCs and it was dependent on HO-1 activity. Our findings suggest that HO-1 by modulating TLR9 expression in PMCs promotes pleural innate immunity in MRSA empyema.
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Affiliation(s)
- Satindra Gahlot
- North Florida/South Georgia Veterans Health System, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida, United States of America
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Najmunnisa Nasreen
- North Florida/South Georgia Veterans Health System, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida, United States of America
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Judith A. Johnson
- Emerging Pathogens Institute, University of Florida, Gainesville, Florida, United States of America
| | - Steven A. Sahn
- Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Kamal A. Mohammed
- North Florida/South Georgia Veterans Health System, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida, United States of America
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Florida, Gainesville, Florida, United States of America
- * E-mail:
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Shi J, Yu JB, Liu W, Wang D, Zhang Y, Gong LR, Dong SA, Liu DQ. Carbon monoxide alleviates lipopolysaccharide-induced oxidative stress injury through suppressing the expression of Fis1 in NR8383 cells. Exp Cell Res 2016; 349:162-167. [DOI: 10.1016/j.yexcr.2016.10.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 10/07/2016] [Accepted: 10/13/2016] [Indexed: 02/07/2023]
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Fujisaki N, Kohama K, Nishimura T, Yamashita H, Ishikawa M, Kanematsu A, Yamada T, Lee S, Yumoto T, Tsukahara K, Kotani J, Nakao A. Donor pretreatment with carbon monoxide prevents ischemia/reperfusion injury following heart transplantation in rats. Med Gas Res 2016; 6:122-129. [PMID: 27867479 PMCID: PMC5110145 DOI: 10.4103/2045-9912.191357] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Because inhaled carbon monoxide (CO) provides potent anti-inflammatory and antioxidant effects against ischemia reperfusion injury, we hypothesized that treatment of organ donors with inhaled CO would decrease graft injury after heart transplantation. Hearts were heterotopically transplanted into syngeneic Lewis rats after 8 hours of cold preservation in University of Wisconsin solution. Donor rats were exposed to CO at a concentration of 250 parts per million for 24 hours via a gas-exposure chamber. Severity of myocardial injury was determined by total serum creatine phosphokinase and troponin I levels at three hours after reperfusion. In addition, Affymetrix gene array analysis of mRNA transcripts was performed on the heart graft tissue prior to implantation. Recipients of grafts from CO-exposed donors had lower levels of serum troponin I and creatine phosphokinase; less upregulation of mRNA for interleukin-6, intercellular adhesion molecule-1, and tumor necrosis factor-α; and fewer infiltrating cells. Although donor pretreatment with CO altered the expression of 49 genes expressly represented on the array, we could not obtain meaningful data to explain the mechanisms by which CO potentiated the protective effects. Pretreatment with CO gas before organ procurement effectively protected cardiac grafts from ischemia reperfusion-induced injury in a rat heterotopic cardiac transplant model. A clinical report review indicated that CO-poisoned organ donors may be comparable to non-poisoned donors.
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Affiliation(s)
- Noritomo Fujisaki
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Keisuke Kohama
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan; Senri Critical Care Medical Center, Saiseikai Senri Hospital, Suita, Osaka, Japan
| | - Takeshi Nishimura
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Hayato Yamashita
- Kobe University Graduate School of Health Sciences, Kobe, Hyogo, Japan
| | - Michiko Ishikawa
- Kobe University Graduate School of Health Sciences, Kobe, Hyogo, Japan
| | - Akihiro Kanematsu
- Department of Urology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Taihei Yamada
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Sungsoo Lee
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Tetsuya Yumoto
- Department of Emergency and Critical Care Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kohei Tsukahara
- Department of Emergency and Critical Care Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Joji Kotani
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Atsunori Nakao
- Department of Emergency and Critical Care Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Carbon monoxide treatment reduces microglial activation in the ischemic rat retina. Graefes Arch Clin Exp Ophthalmol 2016; 254:1967-1976. [PMID: 27443355 DOI: 10.1007/s00417-016-3435-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 06/06/2016] [Accepted: 07/04/2016] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Ischemia and reperfusion (I/R) injury damages retinal neurons. Retinal injury is accompanied by activation of microglia, which scavenge the dead or dying neurons, but increasing evidence now indicates that amoeboid-shaped microglia cells activated in the brain after ischemia have neurotoxic and damaging properties in their own right. A previous study showed that postconditioning with carbon monoxide (CO) protects retinal ganglion cells (RGCs) after I/R through anti-apoptotic and anti-inflammatory mechanisms. The present study was designed to investigate and quantify the activation of retinal microglia after I/R with and without CO postconditioning. METHODS Adult Sprague-Dawley rats underwent retinal ischemia by increasing the ocular pressure to 120 mmHg for 1 h through a needle inserted into the anterior chamber. Reperfusion was induced by removing the needle. After I/R, one group of animals was kept in a CO (250 ppm) atmosphere for 1 h; the other group was kept in room air (Air). At 1, 2, 3, and 7 days after I/R, the eyes were enucleated and fixed. Intracardiac blood was analyzed for systemic effects of CO or I/R. Retinal cross sections were taken from the middle third of the eye and were stained with anti-Iba-1. Microglia cells were graded as amoeboid or ramified phenotypes according to morphologic criteria. Retinal thicknesses were determined. RESULTS Evaluation of retinal tissue revealed a significant reduction of amoeboid microglia cells after I/R + CO when compared to the I/R + Air group. The peak number of amoeboid microglia was observed at day 2 post-I/R + Air. This rise was attenuated by CO postconditioning (815 versus 572 cells/mm2 for I/R + Air versus I/R + CO, respectively; p = 0.005). CO reduced and further postponed the peak in the numbers of amoeboid and ramified microglia cells in ischemic eyes and prevented microglial activation in the contralateral eyes. I/R-induced leucocytosis was inhibited by CO inhalation. The reduction of retinal thickness after I/R was more serious after Air inhalation when compared to the CO group. CONCLUSIONS Numerous activated microglia cells appear in the inner retina after I/R, and CO-treatment significantly attenuates this glial response. Antagonism of microglial activation may be a further neuroprotective effect of CO, apart from its direct anti-apoptotic capacity.
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Strasser B, Sperner-Unterweger B, Fuchs D, Gostner JM. Mechanisms of Inflammation-Associated Depression: Immune Influences on Tryptophan and Phenylalanine Metabolisms. Curr Top Behav Neurosci 2016; 31:95-115. [PMID: 27278641 DOI: 10.1007/7854_2016_23] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metabolic parameters have a direct role in the regulation of immune cell function. Thereby the inflammation-induced metabolism of aromatic amino acids, most importantly of tryptophan and phenylalanine, plays a central role. In addition, neuropsychiatric conditions that go along with disorders that are characterized by acute or chronic inflammation, such as the development of depression, decreased quality of life or cognitive impairments, are connected to disturbed amino acid and subsequent neurotransmitter metabolism.The bioanalytical procedures for the determination of concentrations of tryptophan and phenylalanine and their respective first stable intermediates kynurenine and tyrosine as well as some analytical finesses and potential sources of errors are discussed in this chapter. Monitoring of these immunometabolic parameters throughout therapies in addition to biomarkers of immune response and inflammation such as neopterin can be useful to determine disease progression but also to plan psychiatric interventions timely, thus to establish personalized treatments.
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Affiliation(s)
- Barbara Strasser
- Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
| | | | - Dietmar Fuchs
- Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innrain 80, Innsbruck, Austria.
| | - Johanna M Gostner
- Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
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Strasser B, Gostner JM, Fuchs D. Carbon monoxide exposure may underlie the increased leukaemia risk in children living next to motor highways. Eur J Epidemiol 2015; 30:1329-30. [PMID: 26666543 DOI: 10.1007/s10654-015-0108-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 12/07/2015] [Indexed: 10/25/2022]
Affiliation(s)
- Barbara Strasser
- Division of Medical Biochemistry, Biocenter, Medical University, Innsbruck, Austria
| | - Johann M Gostner
- Division of Medical Biochemistry, Biocenter, Medical University, Innsbruck, Austria
| | - Dietmar Fuchs
- Division of Biological Chemistry, Biocenter, Medical University, Innsbruck, Austria.
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