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Danielak A, Magierowski M. Obesity and mitochondrial uncoupling - an opportunity for the carbon monoxide-based pharmacology of metabolic diseases. Pharmacol Res 2025; 215:107741. [PMID: 40252782 DOI: 10.1016/j.phrs.2025.107741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 04/16/2025] [Accepted: 04/16/2025] [Indexed: 04/21/2025]
Abstract
Obesity, a chronic and progressive disease with a complex etiology, remains a significant global health challenge. Despite advancements in lifestyle interventions, pharmacological therapies, and bariatric surgery, substantial barriers to effective and sustained obesity management persist. Resistance to weight loss and gradual weight regain are commonly reported, limiting the long-term success of both non-pharmacological and pharmacological strategies. A possible contributor is metabolic adaptation, a phenomenon characterized by reduced metabolic rate and energy expenditure following weight loss, which hinders therapeutic efficacy. To address these challenges, increasing attention has been directed toward strategies that counteract maladaptive mechanisms by modulating metabolic rate and enhancing energy expenditure. One promising approach involves mitochondrial uncoupling, where electron transport and oxygen consumption are disconnected from ATP synthesis, promoting energy dissipation. Preclinical studies have demonstrated the potential of various chemical compounds with uncoupling activity as anti-obesity agents. Additionally, carbon monoxide (CO) has emerged as a significant gaseous signaling molecule in human physiology, with anti-inflammatory, antioxidative, and cytoprotective properties. Advances in CO-based pharmacology have led to the development of controlled-release CO donors, enabling precise therapeutic application. Experimental studies suggest that CO modulates mitochondrial bioenergetics, induces mild mitochondrial uncoupling, and regulates mitochondrial biogenesis. By integrating these findings, this review uniquely connects scientific threads, offering a comprehensive synthesis of current knowledge while proposing innovative directions in mitochondrial, metabolic and CO-based pharmacological research. It highlights the potential of CO-based pharmacology to regulate metabolic rate, support weight loss, and address obesity-related dysfunctions, thus suggesting novel pathways for advancing obesity treatment.
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Affiliation(s)
- Aleksandra Danielak
- Center for Biomedicine and Interdisciplinary Sciences, Jagiellonian University - Medical College, Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University - Medical College, Krakow, Poland
| | - Marcin Magierowski
- Center for Biomedicine and Interdisciplinary Sciences, Jagiellonian University - Medical College, Krakow, Poland.
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2
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Zrilić SS, Ninković DB, Etinski M, Zarić SD. Perturbational and Variational Energy Decomposition Analysis on Hydrogen Bonds of Coordinated Glycine and Water Molecule. Chemphyschem 2025; 26:e202400948. [PMID: 39565332 DOI: 10.1002/cphc.202400948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/21/2024]
Abstract
Three types of hydrogen bonds of coordinated glycine and water had been investigated: NH/O of α-amino group, O1/HO involving oxygen coordinated to the metal ion (O1), and O2/HO involving α-carbonyl oxygen (O2). Various glycine complexes were investigated: octahedral cobalt(III) and nickel(II), square pyramidal copper(II), and square planar copper(II), palladium(II), and platinum(II) complexes. Nature of these three hydrogen bond types was analyzed using symmetry-adapted perturbation theory (SAPT) and variational energy decomposition analysis (EDA) method (TPSS-D3/def2-TZVPP). The results of the EDA decomposition are in good agreement with the reliable SAPT2+3/def2-TZVPP and its total interaction values with CCSD(T)/CBS energies. Electrostatic interaction is generally the dominant attractive energy term in most of the interactions, followed by orbital relaxation, and lastly dispersion as the weakest. We compared EDA results of various complexes to determine the effects of complex charge, metal oxidation, coordination, and atomic number on the energy decomposition terms. The complex charge influences the values of decomposition terms the most, followed by metal oxidation and coordination number, while atomic number effects them the least. All complex and metal changes have a more significant effect on the results of NH/O and O1/HO than O2/HO interactions, due to its location further away from the metal ion.
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Affiliation(s)
- Sonja S Zrilić
- Innovation Center of the Faculty of Chemistry, Studentski trg 12-16, Belgrade, Serbia
| | - Dragan B Ninković
- Innovation Center of the Faculty of Chemistry, Studentski trg 12-16, Belgrade, Serbia
| | - Mihajlo Etinski
- Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, Belgrade, Serbia
| | - Snežana D Zarić
- Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, Belgrade, Serbia
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Khaled RM, Hegazy YS, Arafa MM, Sadek MS, Radacki K, A E Mostafa G, Ali EA, Shehab OR, Mansour AM. Insights into the photoactivatable CO releasing properties of dicarbonyl Ru(II) complex with 8-amino quinoline ligand: Experimental and theoretical studies. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2024; 320:124644. [PMID: 38901235 DOI: 10.1016/j.saa.2024.124644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 05/19/2024] [Accepted: 06/10/2024] [Indexed: 06/22/2024]
Abstract
Reaction between the polymeric [RuCl2(CO)2]n and the N,N-bidentate ligand, 8-amino-quinoline (Quin), in methanol, afforded the photoactivated CO releasing molecule with the formula of trans-(Cl,Cl)-[RuCl2(CO)2Quin]. In the presence of biomolecules or in solvents with varying polarity and coordinating abilities, the solvatochromic characteristics and dark stability were investigated. A new board band emerged in the visible spectrum during the illumination, and its position varies according to the type of solvent used, indicating the role of the solvent in controlling the nature of the CO-depleted species. Spectral methods were used in combination with density functional theory simulations to get insight into the local minimum structure and the electronic properties of the Ru(II) complex. The results of the myoglobin assay showed that within the first two hours of illumination, one of the two CO molecules was released. The cytotoxic properties of the Ru(II)-based complex were investigated against normal mice bone marrow stromal cells and malignant human acute monocytic leukaemia cells.
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Affiliation(s)
- Rabaa M Khaled
- Department of Chemistry, Faculty of Science, Cairo University, Gamma Street, Giza, Cairo 12613, Egypt
| | - Yara S Hegazy
- Department of Chemistry, Faculty of Science, Cairo University, Gamma Street, Giza, Cairo 12613, Egypt
| | - Mohamed M Arafa
- Department of Chemistry, Faculty of Science, Cairo University, Gamma Street, Giza, Cairo 12613, Egypt
| | - Muhammed S Sadek
- Department of Chemistry, Faculty of Science, Cairo University, Gamma Street, Giza, Cairo 12613, Egypt
| | - Krzysztof Radacki
- institut für Anorganische Chemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany
| | - Gamal A E Mostafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Essam A Ali
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ola R Shehab
- Department of Chemistry, Faculty of Science, Cairo University, Gamma Street, Giza, Cairo 12613, Egypt
| | - Ahmed M Mansour
- Department of Chemistry, United Arab Emirates University, Al-Ain, United Arab Emirates.
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Zhao Y, Yao Z, Lu L, Xu S, Sun J, Zhu Y, Wu Y, Yu Z. Carbon monoxide-releasing molecule-3 exerts neuroprotection effects after cardiac arrest in mice: A randomized controlled study. Resusc Plus 2024; 19:100703. [PMID: 39040821 PMCID: PMC11260602 DOI: 10.1016/j.resplu.2024.100703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 07/24/2024] Open
Abstract
Background Post-cardiac arrest brain injury (PCABI) is the leading cause of death in survivors of cardiac arrest (CA). Carbon monoxide-releasing molecule (CORM-3) is a water-soluble exogenous carbon monoxide that has been shown to have neuroprotection benefits in several neurological disease models. However, the effects of CORM-3 on PCABI is still unclear. Methods A mice model combined asystole with hemorrhage was used. Mice were anesthetized and randomized into 4 groups (n = 12/group) and underwent either 9.5 min CA followed by cardiopulmonary resuscitation (CPR) or sham surgery. CORM-3 (30 mg/kg) or vehicle (normal saline) were administered at 1 h after return of spontaneous circulation or sham surgery. Survival, neurologic deficits, alterations in the permeability of the brain-blood barrier and cerebral blood flow, changes of oxidative stress level, level of neuroinflammation and neuronal degeneration, and the activation of Nrf2/HO-1 signaling pathway were measured. Results In CORM-3 treated mice that underwent CA/CPR, significantly improved survival (75.00% vs. 58.33%, P = 0.0146 (24 h) and 66.67% vs. 16.67%, P < 0.0001 (72 h)) and neurological function were observed at 24 h and 72 h after ROSC (P < 0.05 for each). Additionally, increased cerebral blood flow, expression of tight junctions, and reduced reactive oxygen species generation at 24 h after ROSC were observed (P < 0.05 for each). CORM-3 treated mice had less neuron death and alleviated neuroinflammation at 72 h after ROSC (P < 0.05 for each). Notably, the Nrf2/HO-1 signaling pathway was significantly activated in mice subjected to CA/CPR with CORM-3 treatment. Conclusions CORM-3 could improve survival and exert neuroprotection after CA/CPR in mice. CORM-3 may be a novel and promising pharmacological therapy for PCABI.
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Affiliation(s)
- Yuanrui Zhao
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhun Yao
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Liping Lu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Song Xu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jianfei Sun
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ying Zhu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yanping Wu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhui Yu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
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Lee SJ, Lee S, Kim YH, Cha YS. Risk of lung diseases in patients with previous carbon monoxide poisoning: a nationwide population-based cohort study in the Republic of Korea. Clin Toxicol (Phila) 2024; 62:425-431. [PMID: 38946481 DOI: 10.1080/15563650.2024.2371020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 06/17/2024] [Indexed: 07/02/2024]
Abstract
INTRODUCTION Carbon monoxide poisoning is associated with severe damage to various organs. In this study, we aimed to determine if previous carbon monoxide poisoning was associated with an increased risk of lung diseases. METHODS The study population was derived from the National Health Insurance Service database of Korea between 1 January 2002 and 31 December 2021. Adults with carbon monoxide poisoning, with at least one visit to medical facilities between 2002 and 2021, were included. For comparison, an equal number of matched controls with the same index date were selected from the database. RESULTS A total of 28,618 patients with carbon monoxide poisoning and 28,618 matched controls were included in this study. Approximately 42.8 per cent of the patient and control groups were female, with a mean age of 51.3 years. In patients with carbon monoxide poisoning, there was a significant increase in the risk of lung cancer (adjusted hazard ratio, 1.84; 95 per cent confidence interval, 1.42-2.39; P < 0.001), chronic obstructive pulmonary disease (adjusted hazard ratio, 1.60; 95 per cent confidence interval, 1.36-1.89; P < 0.001), pulmonary tuberculosis (adjusted hazard ratio, 1.46; 95 per cent confidence interval, 1.13-1.88; P = 0.003), and non-tuberculous mycobacterial infection (adjusted hazard ratio, 1.54; 95 per cent confidence interval, 1.01-2.36; P = 0.047). DISCUSSION In this retrospective cohort study, previous carbon monoxide poisoning was associated with an increased risk of lung cancer, chronic obstructive pulmonary disease, pulmonary tuberculosis, and non-tuberculous mycobacterial infection. Further studies are needed to confirm such an association in other populations and the risk of lung diseases due to the toxic effect of carbon monoxide from different sources. CONCLUSIONS Previous carbon monoxide poisoning was associated with an increased risk of lung diseases, but the relative importance of the causes and sources of exposure was not known. The long-term management of survivors of acute carbon monoxide poisoning should include monitoring for lung cancer, chronic obstructive pulmonary disease, pulmonary tuberculosis, and non-tuberculous mycobacterial infection.
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Affiliation(s)
- Seok Jeong Lee
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Solam Lee
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - You Hyun Kim
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Yong Sung Cha
- Department of Emergency Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
- Research Institute of Hyperbaric Medicine and Science, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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Mansour AM, Khaled RM, Ferraro G, Shehab OR, Merlino A. Metal-based carbon monoxide releasing molecules with promising cytotoxic properties. Dalton Trans 2024; 53:9612-9656. [PMID: 38808485 DOI: 10.1039/d4dt00087k] [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: 05/30/2024]
Abstract
Carbon monoxide, the "silent killer" gas, is increasingly recognised as an important signalling molecule in human physiology, which has beneficial biological properties. A particular way of achieving controlled CO administration is based on the use of biocompatible molecules that only release CO when triggered by internal or external factors. These approaches include the development of pharmacologically effective prodrugs known as CO releasing molecules (CORMs), which can supply biological systems with CO in well-regulated doses. An overview of transition metal-based CORMs with cytotoxic properties is here reported. The mechanisms at the basis of the biological activities of these molecules and their potential therapeutical applications with respect to their stability and CO releasing properties have been discussed. The activation of metal-based CORMs is determined by the type of metal and by the nature and features of the auxiliary ligands, which affect the metal core electronic density and therefore the prodrug resistance towards oxidation and CO release ability. A major role in regulating the cytotoxic properties of these CORMs is played by CO and/or CO-depleted species. However, several mysteries concerning the cytotoxicity of CORMs remain as intriguing questions for scientists.
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Affiliation(s)
- Ahmed M Mansour
- Department of Chemistry, United Arab Emirates University, Al-Ain, United Arab Emirates.
| | - Rabaa M Khaled
- Department of Chemistry, Faculty of Science, Cairo University, Gamma Street, 12613, Egypt.
| | - Giarita Ferraro
- Department of Chemical Sciences, University of Naples Federico II, Napoli, Italy.
| | - Ola R Shehab
- Department of Chemistry, Faculty of Science, Cairo University, Gamma Street, 12613, Egypt.
| | - Antonello Merlino
- Department of Chemical Sciences, University of Naples Federico II, Napoli, Italy.
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Zrilić SS, Živković JM, Zarić SD. Computational and crystallographic study of hydrogen bonds in the second coordination sphere of chelated amino acids with a free water molecule: Influence of complex charge and metal ion. J Inorg Biochem 2024; 251:112442. [PMID: 38100904 DOI: 10.1016/j.jinorgbio.2023.112442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 12/17/2023]
Abstract
Hydrogen bonds of glycine complexes were calculated using quantum chemistry calculations at M06L-GD3/def2-TZVPP level and by analyzing the crystal structures from the Cambridge Structural Database (CSD). One hydrogen bond where amino acid plays the role of the H-donor (NH/O), and two where it plays the role of the H-acceptor (O1/HO, O1 is a coordinated oxygen atom, and, O2/HO, O2 is a non-coordinated oxygen atom) were investigated. The calculations were done on octahedral nickel(II), square pyramidal copper(II), square planar copper(II), palladium(II), and platinum(II) glycine complexes with different charges adjusted using water(s) and/or chlorine ion(s) as the remaining ligands. For NH/O hydrogen bond, interaction energies of neutral complexes are the weakest, from -5.2 to -7.2 kcal/mol for neutral, stronger for singly positive, from -8.3 to -12.1 kcal/mol, and the strongest for doubly positive complex, -16.9 kcal/mol. For O1/HO and O2/HO interactions, neutral complexes have weaker interaction energies (from -2.2 to -5.1 kcal/mol for O1/HO, and from -3.7 to -5.0 kcal/mol for O2/HO), than for singly negative complexes (from -6.9 to -8.2 kcal/mol for O1/HO, and from -8.0 to -9.0 kcal/mol for O2/HO). Additionally to the complex charge, metal oxidation number, coordination number, and metal atomic number also influence the hydrogen bond strength, however, the influence is smaller.
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Affiliation(s)
- Sonja S Zrilić
- Innovation Center of the Faculty of Chemistry, Studentski trg 12-16, Belgrade, Serbia
| | - Jelena M Živković
- Innovation Center of the Faculty of Chemistry, Studentski trg 12-16, Belgrade, Serbia
| | - Snežana D Zarić
- Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, Belgrade, Serbia.
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Oza PP, Kashfi K. The Triple Crown: NO, CO, and H 2S in cancer cell biology. Pharmacol Ther 2023; 249:108502. [PMID: 37517510 PMCID: PMC10529678 DOI: 10.1016/j.pharmthera.2023.108502] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/16/2023] [Accepted: 07/19/2023] [Indexed: 08/01/2023]
Abstract
Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are three endogenously produced gases with important functions in the vasculature, immune defense, and inflammation. It is increasingly apparent that, far from working in isolation, these three exert many effects by modulating each other's activity. Each gas is produced by three enzymes, which have some tissue specificities and can also be non-enzymatically produced by redox reactions of various substrates. Both NO and CO share similar properties, such as activating soluble guanylate cyclase (sGC) to increase cyclic guanosine monophosphate (cGMP) levels. At the same time, H2S both inhibits phosphodiesterase 5A (PDE5A), an enzyme that metabolizes sGC and exerts redox regulation on sGC. The role of NO, CO, and H2S in the setting of cancer has been quite perplexing, as there is evidence for both tumor-promoting and pro-inflammatory effects and anti-tumor and anti-inflammatory activities. Each gasotransmitter has been found to have dual effects on different aspects of cancer biology, including cancer cell proliferation and apoptosis, invasion and metastasis, angiogenesis, and immunomodulation. These seemingly contradictory actions may relate to each gas having a dual effect dependent on its local flux. In this review, we discuss the major roles of NO, CO, and H2S in the context of cancer, with an effort to highlight the dual nature of each gas in different events occurring during cancer progression.
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Affiliation(s)
- Palak P Oza
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA; Graduate Program in Biology, City University of New York Graduate Center, New York 10091, USA.
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Bauer N, Yang X, Yuan Z, Wang B. Reassessing CORM-A1: redox chemistry and idiosyncratic CO-releasing characteristics of the widely used carbon monoxide donor. Chem Sci 2023; 14:3215-3228. [PMID: 36970102 PMCID: PMC10033827 DOI: 10.1039/d3sc00411b] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 02/19/2023] [Indexed: 03/06/2023] Open
Abstract
Redox activity and unreliable carbon monoxide production of CO donor, CORM-A1, presents new complications in its use for studying CO biology.
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Affiliation(s)
- Nicola Bauer
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303, USA
| | - Xiaoxiao Yang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303, USA
| | - Zhengnan Yuan
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303, USA
| | - Binghe Wang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303, USA
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Water-Soluble Carbon Monoxide-Releasing Molecules (CORMs). Top Curr Chem (Cham) 2022; 381:3. [PMID: 36515756 DOI: 10.1007/s41061-022-00413-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 11/12/2022] [Indexed: 12/15/2022]
Abstract
Carbon monoxide-releasing molecules (CORMs) are promising candidates for producing carbon monoxide in the mammalian body for therapeutic purposes. At higher concentrations, CO has a harmful effect on the mammalian organism. However, lower doses at a controlled rate can provide cellular signaling for mandatory pharmacokinetic and pathological activities. To date, exploring the therapeutic implications of CO dose as a prodrug has attracted much attention due to its therapeutic significance. There are two different methods of CO insertion, i.e., indirect and direct exogenous insertion. Indirect exogenous insertion of CO suggests an advantage of reduced toxicity over direct exogenous insertion. For indirect exogenous insertion, researchers are facing the issue of tissue selectivity. To solve this issue, developers have considered the newly produced CORMs. Herein, metal carbonyl complexes (MCCs) are covalently linked with CO molecules to produce different CORMs such as CORM-1, CORM-2, and CORM-3, etc. All these CORMs required exogenous CO insertion to achieve the therapeutic targets at the optimized rate under peculiar conditions or/and triggering. Meanwhile, the metal residue was generated from i-CORMs, which can propagate toxicity. Herein, we explain CO administration, water-soluble CORMs, tissue accumulation, and cytotoxicity of depleted CORMs and the kinetic profile of CO release.
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Dai Q, Wang L, Ren E, Chen H, Gao X, Cheng H, An Y, Chu C, Liu G. Ruthenium-Based Metal-Organic Nanoradiosensitizers Enhance Radiotherapy by Combining ROS Generation and CO Gas Release. Angew Chem Int Ed Engl 2022; 61:e202211674. [PMID: 36184566 DOI: 10.1002/anie.202211674] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Indexed: 11/05/2022]
Abstract
A lack of targeting accuracy and radiosensitivity severely limits clinical radiotherapy. In this study, we developed a radiosensitizer comprised of Ru-based metal-organic nanostructures (ZrRuMn-MONs@mem) to optimize irradiation by maximizing reactive oxygen species (ROS) generation and CO release in X-ray-induced dynamic therapy (XDT). The well-designed nanostructures increase the direct absorption of radiation doses (primary radiation) and promote the deposition of photons and electrons (secondary radiation). The secondary electrons were trapped and transferred in the constrained MONs where they induce a cascade of reactions to increase the therapeutic efficiency. Meanwhile, the full-length antiglypican 3 (GPC3) antibody (hGC33) expressed a cell membrane coating enabling active targeting of tumor sites with optimized biocompatibility. The ZrRuMn-MONs@mem represents a starting point for advancing an all-around radiosensitizer that operates efficiently in clinical XDT.
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Affiliation(s)
- Qixuan Dai
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Lin Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - En Ren
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Hu Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Xing Gao
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Hongwei Cheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Yibo An
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Chengchao Chu
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen University, Xiamen, 361102, China
- Shenzhen Research Institute of Xiamen University, Shenzhen, 518057, China
| | - Gang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
- Shenzhen Research Institute of Xiamen University, Shenzhen, 518057, China
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12
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Majewski M, Klett-Mingo M, Verdasco-Martín CM, Otero C, Ferrer M. Spirulina extract improves age-induced vascular dysfunction. PHARMACEUTICAL BIOLOGY 2022; 60:627-637. [PMID: 35294322 PMCID: PMC8933018 DOI: 10.1080/13880209.2022.2047209] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
CONTEXT Vascular dysfunction is considered a hallmark of ageing that has been associated with altered vasomotor responses, in which nitric oxide (NO) and reactive oxygen species participate. The consumption of Spirulina extracts, with antioxidant properties, increased recently. OBJECTIVE This study investigates the effect of Spirulina aqueous extract (SAE) on the vascular function of the aorta from aged rats. MATERIALS AND METHODS Aortic segments from aged male Sprague-Dawley rats (20-22 months old) were exposed to SAE (0.1% w/v, for 3 h) to analyse: (i) the vasodilator response induced by acetylcholine (ACh), by the NO donor sodium nitroprusside (SNP), by the carbon monoxide releasing molecule (CORM) and by the KATP channel opener, cromakalim (CK); (ii) the vasoconstrictor response induced by KCl and noradrenaline (NA); (iii) the production of NO and superoxide anion, and (iv) the expression of the p-eNOS and HO-1 proteins. RESULTS Incubation with SAE increased the expression of p-eNOS (1.6-fold) and HO-1 (2.0-fold), enhanced NO release (1.4-fold in basal and 1.9-fold in ACh-stimulated conditions) while decreased the production of superoxide (0.7-fold). SAE also increased the sensitivity (measured as pEC50) to ACh (control: -7.06 ± 0.11; SAE: -8.16 ± 0.21), SNP (control: -7.96 ± 0.16; SAE: -9.11 ± 0.14) and CK (control: -7.05 ± 0.39; SAE: -8.29 ± 0.53), and potentiated the response to KCl (1.3-fold) and to NA (1.7-fold). CONCLUSION The antioxidant properties of SAE improved the vasomotor responses of aorta from aged rats. These results may support the use of Spirulina as a protection against vascular dysfunction.
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Affiliation(s)
- Michal Majewski
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Warmia and Mazury, Olsztyn, Poland
| | - Mercedes Klett-Mingo
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Carlos M. Verdasco-Martín
- Departamento de Biocatálisis, Instituto de Catálisis y Petroleoquímica, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Cristina Otero
- Departamento de Biocatálisis, Instituto de Catálisis y Petroleoquímica, Consejo Superior de Investigaciones Científicas, Madrid, Spain
- Cristina Otero Departamento de Biocatálisis, Instituto de Catálisis y Petroleoquímica, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Mercedes Ferrer
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) Madrid, Madrid, Spain
- CONTACT Mercedes Ferrer Departamento de Fisiología, Facultad de Medicina, UAM. C/Arzobispo Morcillo, 4, 28029Madrid, Spain
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13
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Choi HI, Zeb A, Kim MS, Rana I, Khan N, Qureshi OS, Lim CW, Park JS, Gao Z, Maeng HJ, Kim JK. Controlled therapeutic delivery of CO from carbon monoxide-releasing molecules (CORMs). J Control Release 2022; 350:652-667. [PMID: 36063960 DOI: 10.1016/j.jconrel.2022.08.055] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/26/2022] [Accepted: 08/27/2022] [Indexed: 01/06/2023]
Abstract
Carbon monoxide (CO) has been regarded as a "silent killer" for its toxicity toward biological systems. However, a low concentration of endogenously produced CO has shown a number of therapeutic benefits such as anti-inflammatory, anti-proliferative, anti-apoptosis, and cytoprotective activities. Carbon monoxide-releasing molecules (CORMs) have been developed as alternatives to direct CO inhalation, which requires a specialized setting for strict dose control. CORMs are efficient CO donors, with central transition metals (such as ruthenium, iron, cobalt, and manganese) surrounded by CO as a ligand. CORMs can stably store and subsequently release their CO payload in the presence of certain triggers including solvent, light, temperature, and ligand substitution. However, CORMs require appropriate delivery strategies to improve short CO release half-life and target specificity. Herein, we highlighted the therapeutic potential of inhalation and CORMs-delivered CO. The applications of conjugate and nanocarrier systems for controlling CO release and improving therapeutic efficacy of CORMs are also described in detail. The review concludes with some of the hurdles that limit clinical translation of CORMs. Keeping in mind the tremendous potential and growing interest in CORMs, this review would be helpful for designing controlled CO release systems for clinical applications.
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Affiliation(s)
- Ho-Ik Choi
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi, Republic of Korea
| | - Alam Zeb
- College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon, Republic of Korea; Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Min-Su Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi, Republic of Korea
| | - Isra Rana
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Namrah Khan
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Omer Salman Qureshi
- Department of Pharmacy, Faculty of Natural Sciences, Forman Christian College University, Lahore, Pakistan
| | - Chang-Wan Lim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi, Republic of Korea
| | - Jeong-Sook Park
- College of Pharmacy, Institute of Drug Research and Development, Chungnam National University, Daejeon, Republic of Korea
| | - Zhonggao Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Han-Joo Maeng
- College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon, Republic of Korea.
| | - Jin-Ki Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi, Republic of Korea.
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Hemmersbach L, Schreiner Y, Zhang X, Dicke F, Hünemeyer L, Neudörfl J, Fleming T, Yard B, Schmalz H. Synthesis and Biological Evaluation of Water‐Soluble Esterase‐Activated CO‐Releasing Molecules Targeting Mitochondria. Chemistry 2022; 28:e202201670. [PMID: 35771078 PMCID: PMC9543658 DOI: 10.1002/chem.202201670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Indexed: 12/25/2022]
Affiliation(s)
- Lars Hemmersbach
- Department of Chemistry Universität zu Köln Greinstrasse 4 50939 Köln Germany
| | - Yannick Schreiner
- Vth Medical Department Medical Faculty Mannheim University of Heidelberg Theodor-Kutzer-Ufer 1–3 68167 Mannheim Germany
| | - Xinmiao Zhang
- Vth Medical Department Medical Faculty Mannheim University of Heidelberg Theodor-Kutzer-Ufer 1–3 68167 Mannheim Germany
| | - Finn Dicke
- Department of Chemistry Universität zu Köln Greinstrasse 4 50939 Köln Germany
| | - Leon Hünemeyer
- Department of Chemistry Universität zu Köln Greinstrasse 4 50939 Köln Germany
| | | | - Thomas Fleming
- Department of Internal Medicine I and Clinical Chemistry University Hospital of Heidelberg 69120 Heidelberg Germany
- German Center for Diabetes Research (DZD) 85764 Neuherberg Germany
| | - Benito Yard
- Vth Medical Department Medical Faculty Mannheim University of Heidelberg Theodor-Kutzer-Ufer 1–3 68167 Mannheim Germany
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15
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Obara T, Yamamoto H, Aokage T, Igawa T, Nojima T, Hirayama T, Seya M, Ishikawa-Aoyama M, Nakao A, Motterlini R, Naito H. Luminal Administration of a Water-soluble Carbon Monoxide-releasing Molecule (CORM-3) Mitigates Ischemia/Reperfusion Injury in Rats Following Intestinal Transplantation. Transplantation 2022; 106:1365-1375. [PMID: 34966108 PMCID: PMC9213078 DOI: 10.1097/tp.0000000000004007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/05/2021] [Accepted: 10/22/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND The protective effects of carbon monoxide (CO) against ischemia/reperfusion (IR) injury during organ transplantation have been extensively investigated. Likewise, CO-releasing molecules (CORMs) are known to exert a variety of pharmacological activities via liberation of controlled amounts of CO in organs. Therefore, we hypothesized that intraluminal administration of water-soluble CORM-3 during cold storage of intestinal grafts would provide protective effects against IR injury. METHODS Orthotopic syngeneic intestinal transplantation was performed in Lewis rats following 6 h of cold preservation in Ringer solution or University of Wisconsin solution. Saline containing CORM-3 (100 µmol/L) or its inactive counterpart (iCORM-3) was intraluminally introduced in the intestinal graft before cold preservation. RESULTS Histopathological analysis of untreated and iCORM-3-treated grafts revealed a similar erosion and blunting of the intestinal villi. These changes in the mucosa structure were significantly attenuated by intraluminal administration of CORM-3. Intestinal mucosa damage caused by IR injury led to considerable deterioration of gut barrier function 3 h postreperfusion. CORM-3 significantly inhibited upregulation of proinflammatory mRNA levels, ameliorated intestinal morphological changes, and improved graft blood flow and mucosal barrier function. Additionally, CORM-3-treated grafts increased recipient survival rates. Pharmacological blockade of soluble guanylyl cyclase activity significantly reversed the protective effects conferred by CORM-3, indicating that CO partially mediates its therapeutic actions via soluble guanylyl cyclase activation. CONCLUSIONS Our study demonstrates that luminally delivered CORM-3 provides beneficial effects in cold-stored rat small intestinal grafts and could be an attractive therapeutic application of CO in the clinical setting of organ preservation and transplantation.
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Affiliation(s)
- Takafumi Obara
- Department of Emergency, Critical Care, and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hirotsugu Yamamoto
- Department of Emergency, Critical Care, and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Toshiyuki Aokage
- Department of Emergency, Critical Care, and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Takuro Igawa
- Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Tsuyoshi Nojima
- Department of Emergency, Critical Care, and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Takahiro Hirayama
- Department of Emergency, Critical Care, and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Mizuki Seya
- Department of Emergency, Critical Care, and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Michiko Ishikawa-Aoyama
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Atsunori Nakao
- Department of Emergency, Critical Care, and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | | | - Hiromichi Naito
- Department of Emergency, Critical Care, and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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16
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Lee SX, Tan CH, Mah WL, Wong RCS, Manan NSA, Cheow YL, Sim KS, Tan KW. Group 6 photo-activable carbon monoxide-releasing molecules (PhotoCORMs) with 1’10-phenanthroline based ligand as potential anti-proliferative and anti-microbial agents. Inorganica Chim Acta 2022. [DOI: 10.1016/j.ica.2022.120931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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17
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Li J, Han Q, Chen H, Liu T, Song J, Hou M, Wei L, Song H. Carbon Monoxide-Releasing Molecule-3 Enhances Osteogenic Differentiation of Rat Bone Marrow Mesenchymal Stem Cells via miR-195-5p/Wnt3a Pathway. Drug Des Devel Ther 2022; 16:2101-2117. [PMID: 35812136 PMCID: PMC9259429 DOI: 10.2147/dddt.s367277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/25/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Bone marrow-derived mesenchymal stem cells (BMSCs) are hopeful in promoting bone regeneration as their pluripotency in differentiation. Our previous study showed that carbon monoxide-releasing molecule-3 (CORM-3) increased the osteogenic differentiation of rat BMSCs in vitro. However, the mechanism remained unclear. MicroRNAs (miRNAs) play a very important role in modulating the osteogenic differentiation of BMSCs. Therefore, we researched the miRNAs involved in CORM-3-stimulated osteogenic differentiation. Methods The CORM-3-stimulated osteogenic differentiation of rat BMSCs was further studied in vivo. Based on the gene sequencing experiment, the rat BMSCs were transfected with miR-195-5p mimics and inhibitor, pcDNA3.1-Wnt3a and Wnt3a siRNA. The osteogenic differentiation of rat BMSCs was measured by quantitative real-time polymerase chain reaction, Western blot and alizarin red staining. Additionally, the targeting relationship between miR-195-5p and Wnt3a was confirmed by the dual-luciferase assay. Results MiR-195-5p was down-expressed during the CORM-3-stimulated osteogenic differentiation of rat BMSCs. CORM-3-stimulated osteogenic differentiation of rat BMSCs was inhibited with miR-195-5p overexpression, evidenced by significantly reduced mRNA and protein expressions of runt-related transcription factor 2 and osteopontin, and matrix mineralization demonstrated. On the contrary, the osteogenic differentiation was enhanced with inhibition of miR-195-5p. CORM-3-stimulated osteogenic differentiation of rat BMSCs was increased by overexpression of Wnt3a, while the opposite was observed in the Wnt3a-deficient cells. Moreover, the decreased osteogenic differentiation capacity by increased expression of miR-195-5p was rescued by Wnt3a overexpression, showing miR-195-5p directly targeted Wnt3a. Conclusion These results demonstrate that CORM-3 promoted osteogenic differentiation of rat BMSCs via miR-195-5p/Wnt3a, which bodes well for the application of CORM-3 in the treatment of periodontal disease and other bone-defect diseases.
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Affiliation(s)
- Jingyuan Li
- School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, People’s Republic of China
| | - Qingbin Han
- Department of Oral and Maxillofacial Surgery, Shandong Linyi People’s Hospital, Linyi, People’s Republic of China
| | - Hui Chen
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, People’s Republic of China
| | - Tingting Liu
- School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, People’s Republic of China
| | - Jiahui Song
- School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, People’s Republic of China
| | - Meng Hou
- School of Stomatology, Jining Medical College, Jining, People’s Republic of China
| | - Lingling Wei
- School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, People’s Republic of China
| | - Hui Song
- School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, People’s Republic of China
- Correspondence: Hui Song, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, 250012, People’s Republic of China, Tel +86-531-88382912, Fax +86-531-88382923, Email
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18
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Lehr M, Neumann T, Näther C, McConnell AJ. M-CPOnes: transition metal complexes with cyclopropenone-based ligands for light-triggered carbon monoxide release. Dalton Trans 2022; 51:6936-6943. [PMID: 35448899 DOI: 10.1039/d2dt00835a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A new class of CO-releasing molecules, M-CPOnes, was prepared combining cyclopropenone-based ligands for CO release with the modular scaffold of transition metal complexes. In proof-of-concept studies, M-CPOnes based on ZnII, FeII and CoII are stable in the dark but undergo light-triggered CO release with the cyclopropenone substituents and metal ions enabling tuning of the photophysical properties. Furthermore, the choice of metal allows the use of different spectroscopic methods to monitor photodecarbonylation from fluorescence spectroscopy to UV/vis spectroscopy and paramagnetic NMR spectroscopy. The modularity of M-CPOnes from the metal ion to the cyclopropenone substitution and potential for further functionalisation of the ligand make M-CPOnes appealing for tailored functionality in applications.
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Affiliation(s)
- Marc Lehr
- Otto Diels Institute of Organic Chemistry, Christian-Albrechts-Universität zu Kiel, Otto-Hahn-Platz 4, Kiel 24098, Germany.
| | - Tjorge Neumann
- Otto Diels Institute of Organic Chemistry, Christian-Albrechts-Universität zu Kiel, Otto-Hahn-Platz 4, Kiel 24098, Germany.
| | - Christian Näther
- Institute of Inorganic Chemistry, Christian-Albrechts-Universität zu Kiel, Max-Eyth-Straße 2, Kiel 24118, Germany
| | - Anna J McConnell
- Otto Diels Institute of Organic Chemistry, Christian-Albrechts-Universität zu Kiel, Otto-Hahn-Platz 4, Kiel 24098, Germany.
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Li S, Yang K, Zeng J, Ding Y, Cheng D, He L. Golgi-Targeting Fluorescent Probe for Monitoring CO-Releasing Molecule-3 In Vitro and In Vivo. ACS OMEGA 2022; 7:9929-9935. [PMID: 35350336 PMCID: PMC8945126 DOI: 10.1021/acsomega.2c00422] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/03/2022] [Indexed: 06/14/2023]
Abstract
CO-releasing molecule-3 (CORM-3), mainly metal carbonyl compounds, is widely used as experimental tools to deliver CO, a biological "gasotransmitter", in mammalian systems. CORM-3 is also proposed as a potential new antimicrobial agent, which kills bacteria effectively and rapidly in vitro and in animal models. Organelle-targeting therapy, as a highly effective therapeutic strategy with little toxic and side effects, has important research significance and development prospects. Therefore, the development of effective methods for detecting and tracking CORM-3 at the subcellular level has important implications. In this paper, an easily available Golgi-targetable fluorescent probe (Golgi-Nap-CORM-3) was proposed for CORM-3 detection. In the probe Golgi-Nap-CORM-3, the phenyl sulfonamide group was selected as the Golgi-targetable unit, naphthalimide dye was chosen as a fluorophore, and the nitro group was selected as a CORM-3-responsive unit. Golgi-Nap-CORM-3 shows a CORM-3-reponsive increase of fluorescence emission at 520 nm. Using the excellent probe, the change of CORM-3 in HeLa cells, HepG2 cells, and zebrafish is successfully monitored. This study demonstrates very important information for the study of CORM-3 in vivo systems.
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Affiliation(s)
- Songjiao Li
- Cancer
Research Institute, Hunan Province Cooperative Innovation Center for
Molecular Target New Drug Study, Department of Pharmacy and Pharmacology,
Hengyang Medical School, University of South
China, Hengyang 421001, China
| | - Ke Yang
- Cancer
Research Institute, Hunan Province Cooperative Innovation Center for
Molecular Target New Drug Study, Department of Pharmacy and Pharmacology,
Hengyang Medical School, University of South
China, Hengyang 421001, China
| | - Jiayu Zeng
- Cancer
Research Institute, Hunan Province Cooperative Innovation Center for
Molecular Target New Drug Study, Department of Pharmacy and Pharmacology,
Hengyang Medical School, University of South
China, Hengyang 421001, China
| | - Yiteng Ding
- Clinical
Research Institute, The Affiliated Nanhua Hospital, Hengyang Medical
School, University of South China, Hengyang 421001, China
| | - Dan Cheng
- Clinical
Research Institute, The Affiliated Nanhua Hospital, Hengyang Medical
School, University of South China, Hengyang 421001, China
- State
Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan University, Changsha 410000, China
| | - Longwei He
- Cancer
Research Institute, Hunan Province Cooperative Innovation Center for
Molecular Target New Drug Study, Department of Pharmacy and Pharmacology,
Hengyang Medical School, University of South
China, Hengyang 421001, China
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20
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Liu B, Zhang X, Li J, Yao S, Lu Y, Cao B, Liu Z. X-ray-Triggered CO Release Based on GdW 10/MnBr(CO) 5 Nanomicelles for Synergistic Radiotherapy and Gas Therapy. ACS APPLIED MATERIALS & INTERFACES 2022; 14:7636-7645. [PMID: 35109649 DOI: 10.1021/acsami.1c22575] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Carbon monoxide (CO) therapy has become a hot topic in the field of gas therapy because of its application prospect in the treatment of various diseases. Due to the high affinity for human hemoglobin, the main challenge of CO-loaded nanomedicine is the lack of selectivity and toxicity in the delivery process. Although many commercial CO-releasing molecules (CORMs) have been widely developed because of their ability to deliver CO, CORMs still have some disadvantages, including difficult on-demand controlled CO release, poor solubility, and potential toxicity, which are limiting their further application. Herein, an X-ray-triggered CO-releasing nanomicelle system (GW/MnCO@PLGA) based on GdW10 nanoparticles (NPs) (GW) and MnBr(CO)5 (MnCO) encapsulating in the poly(lactic-co-glycolic acid) (PLGA) polymer was constructed for synergistic CO radiotherapy (RT). The production of strongly oxidative superoxide anion (O2-•) active species can lead to cell apoptosis under the X-ray sensitization of GW. Moreover, strongly oxidative O2-• radicals further oxidize and compete with the Mn center, resulting in the on-demand release of CO. The radio/gas therapy synergy to enhance the efficient tumor inhibition of the nanomicelles was investigated in vivo and in vitro. Therefore, the establishment of an X-ray-triggered controlled CO release system has great application potential for further synergistic RT CO therapy in deep tumor sites.
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Affiliation(s)
- Bin Liu
- School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, China
| | - Xiaolei Zhang
- School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, China
| | - Jinkai Li
- School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, China
| | - Shu Yao
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
- Division of Gynecologic Oncology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Yizhong Lu
- School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, China
| | - Bingqiang Cao
- School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, China
| | - Zongming Liu
- School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, China
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Lazarus L, Dederich CT, Anderson SN, Benninghoff AD, Berreau LM. Flavonol-Based Carbon Monoxide Delivery Molecule with Endoplasmic Reticulum, Mitochondria, And Lysosome Localization. ACS Med Chem Lett 2022; 13:236-242. [PMID: 35178180 PMCID: PMC8842101 DOI: 10.1021/acsmedchemlett.1c00595] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/26/2022] [Indexed: 12/14/2022] Open
Abstract
Light-triggered carbon monoxide (CO) delivery molecules are of significant current interest for evaluating the role of CO in biology and as potential therapeutics. Herein we report the first example of a metal free CO delivery molecule that can be tracked via confocal microscopy at low micromolar concentrations in cells prior to CO release. The NEt2-appended extended flavonol (4) localizes to the endoplasmic reticulum, mitochondria, and lysosomes. Subcellular localization of 4 results in CO-induced toxicity effects that are distinct as compared to a nonlocalized analog. Anti-inflammatory effects of 4, as measured by TNF-α suppression, occur at the nanomolar level in the absence of CO release, and are enhanced with visible-light-induced CO release. Overall, the highly trackable nature of 4 enables studies of the biological effects of both a localized flavonol and CO release at low micromolar to nanomolar concentrations.
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Affiliation(s)
- Livia
S. Lazarus
- Department
of Chemistry and Biochemistry, Utah State
University, Logan, Utah 84322-0300, United States
| | - C. Taylor Dederich
- Department
of Chemistry and Biochemistry, Utah State
University, Logan, Utah 84322-0300, United States
| | - Stephen N. Anderson
- Department
of Chemistry and Biochemistry, Utah State
University, Logan, Utah 84322-0300, 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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22
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Gong S, Zhou E, Liu Y, Gui Z, Feng G. A Pd2+-Free Near-Infrared Fluorescent Probe Based on Allyl Ether Isomerization for Tracking CORM-3 with High Contrast Imaging in Living Systems. Anal Chem 2022; 94:2042-2047. [DOI: 10.1021/acs.analchem.1c04082] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Shengyi Gong
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, China
| | - Enbo Zhou
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, China
| | - Yijia Liu
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, China
| | - Zhisheng Gui
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, China
| | - Guoqiang Feng
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, China
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Li S, Yang K, Zeng J, Xia Y, Cheng D, He L. A NIR-emissive probe with a remarkable Stokes shift for CO-releasing molecule-3 detection in cells and in vivo. Analyst 2022; 147:1169-1174. [DOI: 10.1039/d2an00038e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A NIR-emitting probe with a remarkable Stokes shift for detecting CO-releasing molecule-3 in living cells and in vivo.
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Affiliation(s)
- Songjiao Li
- Cancer Research Institute, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Department of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, China
| | - Ke Yang
- Cancer Research Institute, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Department of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, China
| | - Jiayu Zeng
- Cancer Research Institute, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Department of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, China
| | - Yuqing Xia
- Clinical Research Institute, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Dan Cheng
- Clinical Research Institute, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Longwei He
- Cancer Research Institute, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Department of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, China
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Yang Y, Liu Y, Jiang K, Liu Y. Fluorescent detection mechanism of CO-releasing molecule-3: Competition of inter-/intra-molecular hydrogen bonds. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 263:120227. [PMID: 34332242 DOI: 10.1016/j.saa.2021.120227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 07/14/2021] [Accepted: 07/23/2021] [Indexed: 06/13/2023]
Abstract
The fluorescent detection mechanism of 2-(4-nitro-1,3-dioxoisoindolin-2-yl) acetic acid (CORM3-green) on CO-Releasing Molecule-3 (CORM-3) is theoretically studied. Upon reaction with CORM-3, the non-fluorescent CORM3-green is transferred to the keto form of 2-(4-amino-1,3-dioxoisoindolin-2-yl)acetic acid (PTI) to produce strong fluorescence peak located at 423 nm. This peak red-shifts to 489 nm, which is induced by the strengthening of intermolecular hydrogen bond (HB) between PTI and water molecules and attributed to the experimentally observed fluorescence emission at 503 nm. This result is dramatically different from previous reports that the experimental fluorescence corresponds to the proton transferred enol form of PTI. To illustrate this confusion, the calculated fluorescence peak of PTI-Enol is located at 689 nm, which is much larger than that of experimental result. This result excludes the occurrence of excited state intramolecular proton transfer (ESIPT). It is concluded that intermolecular HBs hinders the formation of intramolecular HB and the ESIPT of the keto form of PTI. This conclusion confirms that experimental Stokes shift of 113 nm is mainly caused by the intermolecular hydrogen bonding rather than by ESIPT process. This work proposes a reasonable explanation for the detection mechanism of CORM3-green and experimental fluorescence phenomenon.
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Affiliation(s)
- Yonggang Yang
- Henan Key Laboratory of Infrared Materials & Spectrum Measures and Applications, School of Physics, Henan Normal University, Xinxiang 453007, China.
| | - Yang Liu
- Henan Key Laboratory of Infrared Materials & Spectrum Measures and Applications, School of Physics, Henan Normal University, Xinxiang 453007, China
| | - Kai Jiang
- School of Environment, Henan Normal University, Xinxiang 453007, China
| | - Yufang Liu
- Henan Key Laboratory of Infrared Materials & Spectrum Measures and Applications, School of Physics, Henan Normal University, Xinxiang 453007, China.
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25
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A simple theoretical approach to converging of Myoglobin-Assay with different pH values. ACTA CHIMICA SLOVACA 2021. [DOI: 10.2478/acs-2021-0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Many metal carbonyl complexes have been synthesized and analyzed as CO-releasing agents. As in many bioactivity assays, differences between in-vitro and in-vivo studies in Myoglobin Assay have been observed. Adjustment of in-vitro conditions to in-vivo conditions is one way to overcoming this problem. Changing the conditions of each in-vivo assay is not possible considering the available grant, material, and labor facilities. In-silico methods are suitable as they provide better in-vitro conditions before experimental procedures. A method which is easy to employ on a basic computer could be more suitable to observe the assay convergence. In this study, global reactivity descriptors were used as an approach to investigate pH differences in myoglobin assay. Global reactivity descriptors of the molecules were compared with myoglobin assay results at different pH values and molecular docking results performed with optimized molecules in different solvents. The following complexes were studied: [Mn(CO)3(bpy)(L)]PF6 (bpy: 2,2-bipyridyl, L: benzylbenzimidazole, 4-chlorobenzylbenzimidazole).
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Li Y, Hemmersbach L, Krause B, Sitnikov N, Schlundt Née Göderz A, Pastene Maldonado DO, Schmalz HG, Yard B. Head-to-Head Comparison of Selected Extra- and Intracellular CO-Releasing Molecules on Their CO-Releasing and Anti-Inflammatory Properties. Chembiochem 2021; 23:e202100452. [PMID: 34643986 PMCID: PMC9298253 DOI: 10.1002/cbic.202100452] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/12/2021] [Indexed: 01/31/2023]
Abstract
Over the past decade, a variety of carbon monoxide releasing molecules (CORMs) have been developed and tested. Some CORMs spontaneously release CO once in solution, while others require a trigger mechanism to release the bound CO from its molecular complex. The modulation of biological systems by CORMs depends largely on the spatiotemporal release of CO, which likely differs among the different types of CORMs. In spontaneously releasing CORMs, CO is released extracellularly and crosses the cell membrane to interact with intracellular targets. Other CORMs can directly release CO intracellularly, which may be a more efficient method to modulate biological systems. In the present study, we compared the efficacy of extracellular and intracellular CO-releasing CORMs that either release CO spontaneously or require an enzymatic trigger. The efficacy of such CORMs to modulate HO-1 and VCAM-1 expression in TNF-α-stimulated human umbilical vein endothelial cells (HUVEC) was evaluated.
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Affiliation(s)
- Yingchun Li
- Vth medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | | | | | | | | | - Diego O Pastene Maldonado
- Vth medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | | | - Benito Yard
- Vth medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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Cheng J, Hu J. Recent Advances on Carbon Monoxide Releasing Molecules for Antibacterial Applications. ChemMedChem 2021; 16:3628-3634. [PMID: 34613654 DOI: 10.1002/cmdc.202100555] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/21/2021] [Indexed: 12/26/2022]
Abstract
Carbon monoxide (CO) has been known as an endogenous signaling molecule in addition to an air pollutant. It plays a critical role in many physiological and pathological processes. Therefore, CO has been recognized as a potent therapeutic agent for the treatment of numerous diseases such as cancers, rheumatoid arthritis, and so on. Instead of direct CO inhalation, two main categories of CO-releasing molecules (CORMs) (i. e., metal carbonyls and nonmetallic CO donors) have been developed to safely and locally deliver CO to target tissues. In this minireview, we summarize the recent achievements of CORMs on antibacterial applications. It appears that the antibacterial activity of CORMs is different from CO gas, which is tightly correlated to not only the types of CORMs applied but also the tested bacterial strains. In some circumstances, the antibacterial mechanisms are debated and need to be clarified. We hope more attention can be paid to this emerging field and new antibacterial agents with a low risk of drug resistance can be developed.
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Affiliation(s)
- Jian Cheng
- Department of Polymer Science and Engineering, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, 96 Jinzhai Road, Anhui 230026, Hefei, China
| | - Jinming Hu
- Department of Polymer Science and Engineering, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, 96 Jinzhai Road, Anhui 230026, Hefei, China
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Dugbartey GJ, Alornyo KK, Luke PPW, Sener A. Application of carbon monoxide in kidney and heart transplantation: A novel pharmacological strategy for a broader use of suboptimal renal and cardiac grafts. Pharmacol Res 2021; 173:105883. [PMID: 34525329 DOI: 10.1016/j.phrs.2021.105883] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 12/28/2022]
Abstract
Carbon monoxide (CO) was historically regarded solely as a poisonous gas that binds to hemoglobin and reduces oxygen-carrying capacity of blood at high concentrations. However, recent findings show that it is endogenously produced in mammalian cells as a by-product of heme degradation by heme oxygenase, and has received a significant attention as a medical gas that influences a myriad of physiological and pathological processes. At low physiological concentrations, CO exhibits several therapeutic properties including antioxidant, anti-inflammatory, anti-apoptotic, anti-fibrotic, anti-thrombotic, anti-proliferative and vasodilatory properties, making it a candidate molecule that could protect organs in various pathological conditions including cold ischemia-reperfusion injury (IRI) in kidney and heart transplantation. Cold IRI is a well-recognized and complicated cascade of interconnected pathological pathways that poses a significant barrier to successful outcomes after kidney and heart transplantation. A substantial body of preclinical evidence demonstrates that CO gas and CO-releasing molecules (CO-RMs) prevent cold IRI in renal and cardiac grafts through several molecular and cellular mechanisms. In this review, we discuss recent advances in research involving the use of CO as a novel pharmacological strategy to attenuate cold IRI in preclinical models of kidney and heart transplantation through its administration to the organ donor prior to organ procurement or delivery into organ preservation solution during cold storage and to the organ recipient during reperfusion and after transplantation. We also discuss the underlying molecular mechanisms of cyto- and organ protection by CO during transplantation, and suggest its clinical use in the near future to improve long-term transplantation outcomes.
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Affiliation(s)
- George J Dugbartey
- Department of Surgery, Division of Urology, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; Multi-Organ Transplant Program, Western University, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Karl K Alornyo
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Patrick P W Luke
- Department of Surgery, Division of Urology, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; Multi-Organ Transplant Program, Western University, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada
| | - Alp Sener
- Department of Surgery, Division of Urology, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; Multi-Organ Transplant Program, Western University, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada.
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Dugbartey GJ. Carbon monoxide as an emerging pharmacological tool to improve lung and liver transplantation protocols. Biochem Pharmacol 2021; 193:114752. [PMID: 34487717 DOI: 10.1016/j.bcp.2021.114752] [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: 07/21/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 12/16/2022]
Abstract
Carbon monoxide (CO) has long been considered purely as a toxic gas. It binds to hemoglobin at high concentrations and displaces oxygen from its binding site, resulting in carboxyhemoglobin formation, which reduces oxygen-carrying capacity of blood and culminates in tissue hypoxia and its associated complications. Recently, however, CO is quickly moving past its historic notorious tag as a poisonous gas to a physiological signaling molecule with therapeutic potentials in several clinical situations including transplant-induced injury. This review discusses current knowledge of CO gas and CO-releasing molecules (CO-RMs) in preclinical models of lung and liver transplantation, and underlying molecular mechanisms of cyto- and organ protection during organ procurement, preservation, implantation and post-transplant periods. In addition, a discussion of the future of CO in clinical organ transplantation is provided.
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Affiliation(s)
- George J Dugbartey
- Department of Surgery, Division of Urology, London Health Sciences Center, Western University, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, Ontario, Canada; Multi-Organ Transplant Program, Western University, London Health Sciences Center, Western University, London, Ontario, Canada; Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana.
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Park J, Zeng JS, Sahasrabudhe A, Jin K, Fink Y, Manthiram K, Anikeeva P. Electrochemical Modulation of Carbon Monoxide‐Mediated Cell Signaling. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202103228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Jimin Park
- Department of Materials Science and Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
- Research Laboratory of Electronics and McGovern Institute for Brain Research Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Joy S. Zeng
- Department of Chemical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Atharva Sahasrabudhe
- Research Laboratory of Electronics and McGovern Institute for Brain Research Massachusetts Institute of Technology Cambridge MA 02139 USA
- Department of Chemistry Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Kyoungsuk Jin
- Department of Chemical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Yoel Fink
- Department of Materials Science and Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Karthish Manthiram
- Department of Chemical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Polina Anikeeva
- Department of Materials Science and Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
- Research Laboratory of Electronics and McGovern Institute for Brain Research Massachusetts Institute of Technology Cambridge MA 02139 USA
- Department of Brain and Cognitive Sciences Massachusetts Institute of Technology Cambridge MA 02139 USA
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31
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Park J, Zeng JS, Sahasrabudhe A, Jin K, Fink Y, Manthiram K, Anikeeva P. Electrochemical Modulation of Carbon Monoxide-Mediated Cell Signaling. Angew Chem Int Ed Engl 2021; 60:20325-20330. [PMID: 34265141 PMCID: PMC8405587 DOI: 10.1002/anie.202103228] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Indexed: 11/08/2022]
Abstract
Despite the critical role played by carbon monoxide (CO) in physiological and pathological signaling events, current approaches to deliver this messenger molecule are often accompanied by off-target effects and offer limited control over release kinetics. To address these challenges, we develop an electrochemical approach that affords on-demand release of CO through reduction of carbon dioxide (CO2 ) dissolved in the extracellular space. Electrocatalytic generation of CO by cobalt phthalocyanine molecular catalysts modulates signaling pathways mediated by a CO receptor soluble guanylyl cyclase. Furthermore, by tuning the applied voltage during electrocatalysis, we explore the effect of the CO release kinetics on CO-dependent neuronal signaling. Finally, we integrate components of our electrochemical platform into microscale fibers to produce CO in a spatially-restricted manner and to activate signaling cascades in the targeted cells. By offering on-demand local synthesis of CO, our approach may facilitate the studies of physiological processes affected by this gaseous molecular messenger.
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Affiliation(s)
- Jimin Park
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Research Laboratory of Electronics and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Joy S Zeng
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Atharva Sahasrabudhe
- Research Laboratory of Electronics and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Kyoungsuk Jin
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Yoel Fink
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Karthish Manthiram
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Polina Anikeeva
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Research Laboratory of Electronics and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
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Danielak A, Wallace JL, Brzozowski T, Magierowski M. Gaseous Mediators as a Key Molecular Targets for the Development of Gastrointestinal-Safe Anti-Inflammatory Pharmacology. Front Pharmacol 2021; 12:657457. [PMID: 33995080 PMCID: PMC8116801 DOI: 10.3389/fphar.2021.657457] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/23/2021] [Indexed: 12/14/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most widely used classes of drugs and play a pivotal role in the therapy of numerous inflammatory diseases. However, the adverse effects of these drugs, especially when applied chronically, frequently affect gastrointestinal (GI) tract, resulting in ulceration and bleeding, which constitutes a significant limitation in clinical practice. On the other hand, it has been recently discovered that gaseous mediators nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) contribute to many physiological processes in the GI tract, including the maintenance of GI mucosal barrier integrity. Therefore, based on the possible therapeutic properties of NO, H2S and CO, a novel NSAIDs with ability to release one or more of those gaseous messengers have been synthesized. Until now, both preclinical and clinical studies have shown promising effects with respect to the anti-inflammatory potency as well as GI-safety of these novel NSAIDs. This review provides an overview of the gaseous mediators-based NSAIDs along with their mechanisms of action, with special emphasis on possible implications for GI mucosal defense mechanisms.
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Affiliation(s)
- Aleksandra Danielak
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - John L Wallace
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
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Chen H, Dai Y, Cui J, Yin X, Feng W, Lv M, Song H. Carbon Monoxide Releasing Molecule-3 Enhances Osteogenic Differentiation of Human Periodontal Ligament Stem Cells by Carbon Monoxide Release. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:1691-1704. [PMID: 33911854 PMCID: PMC8075314 DOI: 10.2147/dddt.s300356] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/19/2021] [Indexed: 12/25/2022]
Abstract
Purpose Limited intrinsic regeneration capacity following bone destruction remains a significant medical problem. Multiple regulatory effects of carbon monoxide releasing molecule-3 (CORM-3) have been reported. The aim of this study was to investigate the effect of CORM-3 on the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) during osteogenesis. Patients and Methods hPDLSCs obtained from healthy periodontal ligament tissues were cultured and identified with specific surface antigens by flow cytometry. Effect of CORM-3 on the proliferation of hPDLSCs was determined by CCK-8 assay. Alizarin red staining and alkaline phosphatase (ALP) activity were used to assess the osteogenic differentiation of hPDLSCs. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were used to detect the expression of the indicated genes. Critical-sized skull defect was made in Balb/c-nude mice, microcomputed tomography (Micro-CT) and Masson trichrome staining were used to assess the new bone regeneration in mice. Results CORM-3 (400 μmol/l) significantly promoted the proliferation of hPDLSCs. CORM-3 pretreatment not only notably enhanced the mRNA and protein expression of osteo-specific marker OPN, Runx2 and ALP, but also increased mineral deposition and ALP activity by the release of CO on day 3, 7 and 14 (P<0.05). Degassed CORM-3 did not show the same effect as CORM-3. In animal model, application of CORM-3 with hPDLSCs transplantation highly increased new bone formation in skull defect region. Conclusion CORM-3 promoted osteogenic differentiation of hPDLSCs, and increased hPDLSCs-induced new bone formation in mice with critical-sized skull defect, which suggests an efficient and promising strategy in the treatment of disease with bone defect.
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Affiliation(s)
- Hui Chen
- Department of VIP Center, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, 250012, Shandong, People's Republic of China.,Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong Province, People's Republic of China
| | - Yan Dai
- Department of VIP Center, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, 250012, Shandong, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Zibo Central Hospital, Zibo, Shandong Province, People's Republic of China
| | - Jing Cui
- Department of Oral and Maxillofacial Surgery, Jinan Stomatological Hospital, Jinan, Shandong Province, People's Republic of China
| | - Xiaochun Yin
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong Province, People's Republic of China
| | - Wei Feng
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong Province, People's Republic of China
| | - Meiyi Lv
- Department of VIP Center, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, 250012, Shandong, People's Republic of China.,Pediatric Dentistry, Jinan Stomatological Hospital, Jinan, Shandong Province, People's Republic of China
| | - Hui Song
- Department of VIP Center, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, 250012, Shandong, People's Republic of China
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Choi YK, Kim YM. Regulation of Endothelial and Vascular Functions by Carbon Monoxide via Crosstalk With Nitric Oxide. Front Cardiovasc Med 2021; 8:649630. [PMID: 33912601 PMCID: PMC8071856 DOI: 10.3389/fcvm.2021.649630] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/16/2021] [Indexed: 12/21/2022] Open
Abstract
Carbon monoxide (CO), generated by heme oxygenase (HO), has been considered a signaling molecule in both the cardiovascular and central nervous systems. The biological function of the HO/CO axis is mostly related to other gaseous molecules, including nitric oxide (NO), which is synthesized by nitric oxide synthase (NOS). Healthy blood vessels are essential for the maintenance of tissue homeostasis and whole-body metabolism; however, decreased or impaired vascular function is a high-risk factor of cardiovascular and neuronal diseases. Accumulating evidence supports that the interplay between CO and NO plays a crucial role in vascular homeostasis and regeneration by improving endothelial function. Moreover, endothelial cells communicate with neighboring cells, such as, smooth muscle cells, immune cells, pericytes, and astrocytes in the periphery and neuronal vascular systems. Endogenous CO could mediate the cell-cell communication and improve the physiological functions of the cardiovascular and neurovascular systems via crosstalk with NO. Thus, a forward, positive feedback circuit between HO/CO and NOS/NO pathways can maintain cardiovascular and neurovascular homeostasis and prevent various human diseases. We discussed the crucial role of CO-NO crosstalk in the cardiovascular and neurovascular systems.
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Affiliation(s)
- Yoon Kyung Choi
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, South Korea
| | - Young-Myeong Kim
- Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea
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Zhou E, Gong S, Xia Q, Feng G. In Vivo Imaging and Tracking Carbon Monoxide-Releasing Molecule-3 with an NIR Fluorescent Probe. ACS Sens 2021; 6:1312-1320. [PMID: 33576235 DOI: 10.1021/acssensors.0c02624] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
As a water-soluble carbon monoxide-releasing molecule, CORM-3 is widely used as a CO donor to study CO in the life system. CORM-3 can also replace gaseous CO as a therapeutic drug molecule to reveal the physiological and pathological effects of CO in life. Therefore, it is of great importance to visualize and track CORM-3 in the life system. We develop herein a near-infrared (NIR) fluorescent probe CORM3-NIR that can detect CORM-3 both in living cells and in vivo effectively. The probe is based on the unique fluorescent QCy7 and uses a 4-nitrobenzyl group to trap CORM-3, and importantly, it shows good water solubility and responds rapidly, selectively, and sensitively to CORM-3, releasing QCy-7 and producing distinct colorimetric and significant NIR fluorescence change signals at 743 nm. The Stokes shift is up to 81 nm. The probe is also able to detect CORM-3 ratiometrically with fluorescence at 743 and 600 nm. Besides, with low cytotoxicity, the probe also shows good NIR fluorescence bioimaging ability for CORM-3 in live cells and mice, which indicates that CORM3-NIR is an effective probe for tracking and studying CORM-3 in the life system.
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Affiliation(s)
- Enbo Zhou
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University (CCNU), 152 Luoyu Road, Wuhan 430079, P. R. China
| | - Shengyi Gong
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University (CCNU), 152 Luoyu Road, Wuhan 430079, P. R. China
| | - Qingfeng Xia
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University (CCNU), 152 Luoyu Road, Wuhan 430079, P. R. China
| | - Guoqiang Feng
- Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University (CCNU), 152 Luoyu Road, Wuhan 430079, P. R. China
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Liu T, Han Q, Pan Y, Li J, Song H. Carbon Monoxide-Releasing Molecule-3 Regulates the Polarization of Lipopolysaccharide-Induced Macrophages. Inflammation 2021; 44:1737-1749. [PMID: 33751324 DOI: 10.1007/s10753-021-01450-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/26/2021] [Accepted: 03/07/2021] [Indexed: 10/21/2022]
Abstract
Macrophages show two main phenotypes, the M1-type (pro-inflammatory) and the M2-type (anti-inflammatory). The purpose of this research was to investigate the regulatory effect of carbon monoxide releasing molecule-3 (CORM-3) on LPS-induced macrophage polarization. LPS-induced RAW264.7 cells were exposed to CORM-3 for 24 h. Polarization of cells was checked by flow cytometry; expression of M1 or M2 macrophage-related factors and NF-κB signaling factors was examined by RT-PCR, ELISA, and Western blot. Male C57 mice were divided into three groups: normal group; periodontitis group, where experimental periodontitis was established in mice; LPS+CORM-3 group, where mice with experimental periodontitis were treated with CORM-3. Polarization of macrophages and the expression of M1 or M2 macrophage-related factors were detected by immunofluorescence, ELISA, and RT-PCR. CORM-3 significantly reduced M1 macrophage proportion, but increased M2 proportion in LPS-stimulated cells. Accordingly, CORM-3 significantly suppressed the expression of M1 macrophage-related TNF-α, iNOS, IL-1β, and IL-6, but promoted M2-related IL-10 and Arg-1. The expression of p-p65, p-p50, and p-IκB induced with LPS was inhibited by CORM-3. In vivo experiments indicated that CORM-3 induced more M2 macrophages in periodontal tissues in mice with experimental periodontitis. The expression of M1 macrophage-related factor in periodontitis was inhibited, but the expression of M2-related factors was increased by CORM-3. CORM-3 inhibits macrophage polarization to pro-inflammatory M1-type and promotes to anti-inflammatory M2-type, which provides scientific basis for the application of CORM-3 in the treatment of periodontitis.
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Affiliation(s)
- Tingting Liu
- Department of Vip Center, School and Hospital of Stomatology & Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Cheeloo College of Medicine, Shandong University, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China
| | - Qingbin Han
- Department of Vip Center, School and Hospital of Stomatology & Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Cheeloo College of Medicine, Shandong University, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China.,Department of Stomatology, Linyi People's Hospital, Linyi, Shandong, China
| | - Yan Pan
- Yantai Stomatological Hospital, Yantai, Shandong, China
| | - Jingyuan Li
- Department of Vip Center, School and Hospital of Stomatology & Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Cheeloo College of Medicine, Shandong University, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China
| | - Hui Song
- Department of Vip Center, School and Hospital of Stomatology & Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Cheeloo College of Medicine, Shandong University, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China.
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Mukherjee S, Dutta A, Chakraborty A. External modulators and redox homeostasis: Scenario in radiation-induced bystander cells. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2021; 787:108368. [PMID: 34083032 DOI: 10.1016/j.mrrev.2021.108368] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 12/10/2020] [Accepted: 01/16/2021] [Indexed: 01/07/2023]
Abstract
Redox homeostasis is imperative to maintain normal physiologic and metabolic functions. Radiotherapy disturbs this balance and induces genomic instability in diseased cells. However, radiation-induced effects propagate beyond the targeted cells, affecting the adjacent non-targeted cells (bystander effects). The cellular impact of radiation, thus, encompasses both targeted and non-targeted effects. Use of external modulators along with radiation can increase radio-therapeutic efficiency. The modulators' classification as protectors or sensitizers depends on interactions with damaged DNA molecules. Thus, it is necessary to realize the functions of various radio-sensitizers or radio-protectors in both irradiated and bystander cells. This review focuses on some modulators of radiation-induced bystander effects (RIBE) and their action mechanisms. Knowledge about the underlying signaling cross-talk may promote selective sensitization of radiation-targeted cells and protection of bystander cells.
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Affiliation(s)
- Sharmi Mukherjee
- Stress Biology Lab, UGC-DAE Consortium for Scientific Research, Kolkata Centre, India
| | - Anindita Dutta
- Stress Biology Lab, UGC-DAE Consortium for Scientific Research, Kolkata Centre, India
| | - Anindita Chakraborty
- Stress Biology Lab, UGC-DAE Consortium for Scientific Research, Kolkata Centre, India.
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Liu HP, Liao Y, Ren MZ, Quan ZJ, Wang XC. Synthesis, structural characterization, molecular docking study, biological activity of carbon monoxide release molecules as potent antitumor agents. Bioorg Chem 2021; 107:104621. [PMID: 33465671 DOI: 10.1016/j.bioorg.2020.104621] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/15/2020] [Accepted: 12/29/2020] [Indexed: 11/12/2022]
Abstract
In this study, two series of novel carbon monoxide-releasing molecules (CO-RMs) containing Co were designed and synthesized. The synthesized complexes were characterized by IR, ESI-MS, 1H NMR and 13C NMR spectroscopies. The antitumor activity of all complexes on HepG2 cells, Hela cells and MDA-MB-231 cells were assayed by MTT. IC50 values of complexes 1-13 were 4.7-548.6 µM. Among these complexes, complex 1 was presented with a high selectivity to HepG2 cells (IC50 = 4.7 ± 0.76 μM). Compared with iCORM (inactive CORM), CORM (complex 1) showed a remarkable activity against tumor cells owing to co-effect of CO and the ligand of COX-2 inhibitor. In addition, complex 1 increased ROS in mitochondria and caused a decrease of dose-dependent mitochondrial membrane potential against HepG2 cells. Complex 1 down-regulated the expression of COX-2 protein in western blot analysis. The molecular docking study suggested that the complex 1 formed a hydrogen bond with amino acid R120 in the active site of the Human cyclooxygenase-2 (COX-2). Therefore, the complex 1 could induce apoptosis of HepG2 cells through targeting COX-2 and mitochondria pathways, and it maybe a potential therapeutic agent for cancer.
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Affiliation(s)
- Hua-Peng Liu
- College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, PR China; Department of Pharmacy, Gansu Medical College, Pingliang, Gansu 744000, PR China
| | - Yuan Liao
- College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, PR China
| | - Ming-Zhe Ren
- College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, PR China
| | - Zheng-Jun Quan
- College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, PR China; Gansu International Scientific and Technological Cooperation Base of Water-Retention Chemical Functional Materials, Lanzhou, Gansu 730070, PR China.
| | - Xi-Cun Wang
- College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, PR China; Gansu International Scientific and Technological Cooperation Base of Water-Retention Chemical Functional Materials, Lanzhou, Gansu 730070, PR China.
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Opoku-Damoah Y, Zhang R, Ta HT, Amilan Jose D, Sakla R, Xu ZP. Lipid-encapsulated upconversion nanoparticle for near-infrared light-mediated carbon monoxide release for cancer gas therapy. Eur J Pharm Biopharm 2021; 158:211-221. [DOI: 10.1016/j.ejpb.2020.11.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/15/2020] [Accepted: 11/22/2020] [Indexed: 12/16/2022]
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Lee SY, Kim CY, Nam TG. Ruthenium Complexes as Anticancer Agents: A Brief History and Perspectives. Drug Des Devel Ther 2020; 14:5375-5392. [PMID: 33299303 PMCID: PMC7721113 DOI: 10.2147/dddt.s275007] [Citation(s) in RCA: 196] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 11/03/2020] [Indexed: 12/28/2022] Open
Abstract
Platinum (Pt)-based anticancer drugs such as cisplatin have been used to treat various cancers. However, they have some limitations including poor selectivity and toxicity towards normal cells and increasing chemoresistance. Therefore, there is a need for novel metallo-anticancers, which has not been met for decades. Since the initial introduction of ruthenium (Ru) polypyridyl complex, a number of attempts at structural evolution have been conducted to improve efficacy. Among them, half-sandwich Ru-arene complexes have been the most prominent as an anticancer platform. Such complexes have clearly shown superior anticancer profiles such as increased selectivity toward cancer cells and ameliorating toxicity against normal cells compared to existing Pt-based anticancers. Currently, several Ru complexes are under human clinical trials. For improvement in selectivity and toxicity associated with chemotherapy, Ru complexes as photodynamic therapy (PDT), and photoactivated chemotherapy (PACT), which can selectively activate prodrug moieties in a specific region, have also been investigated. With all these studies on these interesting entities, new metallo-anticancer drugs to at least partially replace existing Pt-based anticancers are anticipated. This review covers a brief description of Ru-based anticancer complexes and perspectives.
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Affiliation(s)
- Sang Yeul Lee
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do15588, Republic of Korea
| | - Chul Young Kim
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do15588, Republic of Korea
| | - Tae-Gyu Nam
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do15588, Republic of Korea
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Lazarus LS, Benninghoff AD, Berreau LM. Development of Triggerable, Trackable, and Targetable Carbon Monoxide Releasing Molecules. Acc Chem Res 2020; 53:2273-2285. [PMID: 32929957 PMCID: PMC7654722 DOI: 10.1021/acs.accounts.0c00402] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Carbon monoxide (CO) is a gaseous signaling molecule produced in humans via the breakdown of heme in an O2-dependent reaction catalyzed by heme oxygenase enzymes. A long-lived species relative to other signaling molecules (e.g., NO, H2S), CO exerts its physiological effects via binding to low-valent transition metal centers in proteins and enzymes. Studies involving the administration of low doses of CO have shown its potential as a therapeutic agent to produce vasodilation, anti-inflammatory, antiapoptotic, and anticancer effects. In pursuit of developing tools to define better the role and therapeutic potential of CO, carbon monoxide releasing molecules (CORMs) were developed. To date, the vast majority of reported CORMs have been metal carbonyl complexes, with the most well-known being Ru2Cl4(CO)6 (CORM-2), Ru(CO)3Cl(glycinate) (CORM-3), and Mn(CO)4(S2CNMe(CH2CO2H)) (CORM-401). These complexes have been used to probe the effects of CO in hundreds of cell- and animal-based experiments. However, through recent investigations, it has become evident that these reagents exhibit complicated reactivity in biological environments. The interpretation of the effects produced by some of these complexes is obscured by protein binding, such that their formulation is not clear, and by CO leakage and potential redox activity. An additional weakness with regard to CORM-2 and CORM-3 is that these compounds cannot be tracked via fluorescence. Therefore, it is unclear where or when CO release occurs, which confounds the interpretation of experiments using these molecules. To address these weaknesses, our research team has pioneered the development of metal-free CORMs based on structurally tunable extended flavonol or quinolone scaffolds. In addition to being highly controlled, with CO release only occurring upon triggering with visible light (photoCORMs), these CO donors are trackable via fluorescence prior to CO release in cellular environments and can be targeted to specific cellular locations.In the Account, we highlight the development and application of a series of structurally related flavonol photoCORMs that (1) sense characteristics of cellular environments prior to CO release; (2) enable evaluation of the influence of cytosolic versus mitochondrial-localized CO release on cellular bioenergetics; (3) probe the cytotoxicity and anti-inflammatory effects of intracellular versus extracellular CO delivery; and (4) demonstrate that albumin delivery of a photoCORM enables potent anticancer and anti-inflammatory effects. A key advantage of using triggered CO release compounds in these investigations is the ability to examine the effects of the molecular delivery vehicle in the absence and presence of localized CO release, thus providing insight into the independent contributions of CO. Overall, flavonol-based CO delivery molecules offer opportunities for triggerable, trackable, and targetable CO delivery that are unprecedented in terms of previously reported CORMs and, thus, offer significant potential for applications in biological systems.
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Affiliation(s)
- Livia S Lazarus
- Department of Chemistry & Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, United States
| | - Abby D Benninghoff
- Department of Animal, Dairy and Veterinary Sciences, Utah State University, 4815 Old Main Hill, Logan, Utah 84322-4815, United States
| | - Lisa M Berreau
- Department of Chemistry & Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, United States
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Peng L, Gao DD, Xu JW, Xu JB, Ke LJ, Qiu ZE, Zhu YX, Zhang YL, Zhou WL. Cellular mechanisms underlying carbon monoxide stimulated anion secretion in rat epididymal epithelium. Nitric Oxide 2020; 100-101:30-37. [DOI: 10.1016/j.niox.2020.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 03/13/2020] [Accepted: 04/06/2020] [Indexed: 12/17/2022]
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Liu Y, Zhang T, Li G, Li S, Li J, Zhao Q, Wu Q, Xu D, Hu X, Zhang L, Li Q, Zhang H, Liu B. Radiosensitivity enhancement by Co-NMS-mediated mitochondrial impairment in glioblastoma. J Cell Physiol 2020; 235:9623-9634. [PMID: 32394470 DOI: 10.1002/jcp.29774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/27/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023]
Abstract
We investigated the radiosensitizing effects of Co-NMS, a derivative of nimesulide based on a cobalt carbonyl complex, on malignant glioma cells. In the zebrafish exposed to Co-NMS ranging from 5 to 20 μM, cell death and heat shock protein 70 expression in the brain and neurobehavioral performance were evaluated. Our data showed that Co-NMS at 5 μM did not cause the appreciable neurotoxicity, and thereby was given as a novel radiation sensitizer in further study. In the U251 cells, Co-NMS combined with irradiation treatment resulted in significant inhibition of cell growth and clonogenic capability as well as remarkable increases of G2/M arrest and apoptotic cell population compared to the irradiation alone treatment. This demonstrated that the Co-NMS administration exerted a strong potential of sensitizing effect on the irradiated cells. With regard to the tumor radiosensitization of Co-NMS, it could be primarily attributed to the Co-NMS-derived mitochondrial impairment, reflected by the loss of mitochondrial membrane potential, the disruption of mitochondrial fusion and fission balance as well as redox homeostasis. Furthermore, the energy metabolism of the U251 cells was obviously suppressed by cotreatment with Co-NMS and irradiation through repressing mitochondrial function. Taken together, our findings suggested that Co-NMS could be a desirable drug to enhance the radiotherapeutic effects in glioblastoma patients.
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Affiliation(s)
- Yang Liu
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Taofeng Zhang
- Institute of Radiochemistry, School of Nuclear Science and Technology, Lanzhou University, Lanzhou, China
| | - Guo Li
- School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Sirui Li
- School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Jili Li
- Institute of Medicinal Chemistry, School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Quanyi Zhao
- Institute of Medicinal Chemistry, School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Qingfen Wu
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Dan Xu
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoli Hu
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Luwei Zhang
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Qiang Li
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Hong Zhang
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Bin Liu
- School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
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Figueiredo-Pereira C, Dias-Pedroso D, Soares NL, Vieira HLA. CO-mediated cytoprotection is dependent on cell metabolism modulation. Redox Biol 2020; 32:101470. [PMID: 32120335 PMCID: PMC7049654 DOI: 10.1016/j.redox.2020.101470] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/11/2020] [Accepted: 02/17/2020] [Indexed: 12/19/2022] Open
Abstract
Carbon monoxide (CO) is a gasotransmitter endogenously produced by the activity of heme oxygenase, which is a stress-response enzyme. Endogenous CO or low concentrations of exogenous CO have been described to present several cytoprotective functions: anti-apoptosis, anti-inflammatory, vasomodulation, maintenance of homeostasis, stimulation of preconditioning and modulation of cell differentiation. The present review revises and discuss how CO regulates cell metabolism and how it is involved in the distinct cytoprotective roles of CO. The first found metabolic effect of CO was its increase on cellular ATP production, and since then much data have been generated. Mitochondria are the most described and studied cellular targets of CO. Mitochondria exposure to this gasotransmitter leads several consequences: ROS generation, stimulation of mitochondrial biogenesis, increased oxidative phosphorylation or mild uncoupling effect. Likewise, CO negatively regulates glycolysis and improves pentose phosphate pathway. More recently, CO has also been disclosed as a regulating molecule for metabolic diseases, such as obesity and diabetes with promising results.
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Affiliation(s)
- Cláudia Figueiredo-Pereira
- CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal
| | - Daniela Dias-Pedroso
- CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal; UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal
| | - Nuno L Soares
- CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal; UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal
| | - Helena L A Vieira
- CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal; UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal; Instituto de Biologia Experimental e Tecnológica (iBET), Apartado 12, 2781-901, Oeiras, Portugal.
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Cheng J, Zheng B, Cheng S, Zhang G, Hu J. Metal-free carbon monoxide-releasing micelles undergo tandem photochemical reactions for cutaneous wound healing. Chem Sci 2020; 11:4499-4507. [PMID: 34122908 PMCID: PMC8159483 DOI: 10.1039/d0sc00135j] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Carbon monoxide (CO) has shown broad biomedical applications. The site-specific delivery and controlled release of CO is of crucial importance to achieve maximum therapeutic benefits. The development of carbon monoxide (CO)-releasing polymers (CORPs) can increase the stability, optimize pharmacokinetic behavior, and reduce the side effects of small molecule precursors. However, almost all established CORPs were synthesized through a post functional approach, although the direct polymerization strategy is more powerful in controlling the chain compositions and architectures. Herein, a direct polymerization strategy is proposed toward metal-free CO-releasing polymers (CORPs) based on photoresponsive 3-hydroxyflavone (3-HF) derivatives. Such CO-releasing amphiphiles self-assemble into micelles, having excellent water-dispersity. Intriguingly, photo-triggered tandem photochemical reactions confer successive fluorescence transitions from blue-to-red-to-colorless, enabling self-reporting CO release in vitro and in vivo as a result of the incorporation of 3-HF derivatives. More importantly, the localized CO delivery of CORPs by taking advantage of the spatiotemporal control of light stimulus outperformed conventional metal carbonyls such as CORMs in terms of anti-inflammation and cutaneous wound healing. This work opens a novel avenue toward metal-free CORPs for potential biomedical applications.
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Affiliation(s)
- Jian Cheng
- CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Science at the Microscale, Department of Polymer Science and Engineering, University of Science and Technology of China Hefei 230026 Anhui China
| | - Bin Zheng
- School of Chemistry and Chemical Engineering, Hefei Normal University Hefei Anhui 230061 P. R. China
| | - Sheng Cheng
- Instrumental Analysis Center, Hefei University of Technology Hefei Anhui 230009 China
| | - Guoying Zhang
- CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Science at the Microscale, Department of Polymer Science and Engineering, University of Science and Technology of China Hefei 230026 Anhui China
| | - Jinming Hu
- CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Science at the Microscale, Department of Polymer Science and Engineering, University of Science and Technology of China Hefei 230026 Anhui China
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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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Wright MA, Wooldridge T, O’Connell MA, Wright JA. Ferracyclic carbonyl complexes as anti-inflammatory agents. Chem Commun (Camb) 2020; 56:4300-4303. [DOI: 10.1039/d0cc01449d] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Reaction of Fe(CO)4Br2 with 2-aminopyridine and 2-aminonapthalene yields ferracyclic iron(ii) complexes bearing two CO ligands. These release CO in the light, but suppress inflammation only in the dark.
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Affiliation(s)
- Mark A. Wright
- Energy Materials Laboratory
- School of Chemistry
- University of East Anglia
- Norwich Research Park
- Norwich
| | - Tyler Wooldridge
- School of Pharmacy
- University of East Anglia
- Norwich Research Park
- Norwich
- UK
| | - Maria A. O’Connell
- School of Pharmacy
- University of East Anglia
- Norwich Research Park
- Norwich
- UK
| | - Joseph A. Wright
- Energy Materials Laboratory
- School of Chemistry
- University of East Anglia
- Norwich Research Park
- Norwich
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49
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Lazarus LS, Simons CR, Arcidiacono A, Benninghoff AD, Berreau LM. Extracellular vs Intracellular Delivery of CO: Does It Matter for a Stable, Diffusible Gasotransmitter? J Med Chem 2019; 62:9990-9995. [PMID: 31577143 DOI: 10.1021/acs.jmedchem.9b01254] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Carbon monoxide (CO) is a gasotransmitter produced in humans. An essential unanswered question in the design of carbon monoxide releasing molecules (CORMs) is whether the delivery molecule should be localized extra- or intracellularly to produce desired biological effects. Herein we show that extracellular CO release is less toxic and is sufficient to produce an anti-inflammatory effect similar to that of intracellular CO release at nanomolar concentrations. This information is valuable for the design of CORMs.
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Affiliation(s)
- Livia S Lazarus
- Department of Chemistry & Biochemistry , Utah State University , Logan , Utah 84322-0300 , United States
| | - Casey R Simons
- Department of Chemistry & Biochemistry , Utah State University , Logan , Utah 84322-0300 , United States
| | - Ashley Arcidiacono
- Department of Chemistry & Biochemistry , Florida State University , Tallahassee , Florida 32306-4390 , 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 & Biochemistry , Utah State University , Logan , Utah 84322-0300 , United States
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Systemic Administration of Carbon Monoxide-Releasing Molecule-3 Protects the Skeletal Muscle in Porcine Model of Compartment Syndrome. Crit Care Med 2019; 46:e469-e472. [PMID: 29384781 DOI: 10.1097/ccm.0000000000002998] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVES Acute limb compartment syndrome, a complication of musculoskeletal trauma, results in muscle necrosis and cell death. Carbon monoxide, liberated from the carbon monoxide-releasing molecule-3, has been shown protective in a rat model of compartment syndrome. The purpose of this study was to test the effect of carbon monoxide-releasing molecule-3 in a preclinical large animal model of compartment syndrome, with the ultimate goal of developing a pharmacologic adjunct treatment for compartment syndrome. DESIGN Animal research study. SETTING Basic research laboratory in a hospital setting. SUBJECTS Male Yorkshire-Landrace pigs (50-60 kg). INTERVENTIONS Pigs underwent 6 hours of intracompartmental pressure elevation by infusing fluid into the anterior compartment of the right hind limb. Carbon monoxide-releasing molecule-3 was administered systemically (2 mg/kg, IV) at fasciotomy, followed by 3-hour reperfusion. MEASUREMENTS AND MAIN RESULTS Muscle perfusion, inflammation, injury, and apoptosis were assessed in the skeletal muscle. Systemic leukocyte activation was assessed during compartment syndrome and reperfusion. Elevation of hind limb intracompartmental pressure resulted in significant microvascular perfusion deficits (44% ± 1% continuously perfused capillaries in compartment syndrome vs 76% ± 4% in sham; p < 0.001), increased tissue injury (ethidium bromide/bisbenzimide of 0.31 ± 0.07 in compartment syndrome vs 0.17 ± 0.03 in sham; p < 0.05), apoptosis (fluorescence in vivo/bisbenzimide of 0.26 ± 0.06 in compartment syndrome vs 0.13 ± 0.03 in sham; p < 0.05), and systemic leukocyte activation (14.7 relative luminescence units/10 polymorphonuclear leukocytes in compartment syndrome vs 1.0 ± 0.1 in baseline; p < 0.001). Systemic application of carbon monoxide-releasing molecule-3 at fasciotomy increased the number of continuously perfused capillaries (68% ± 3%; p < 0.001), diminished tissue injury (ethidium bromide/bisbenzimide of 0.13 ± 0.04; p < 0.05), apoptosis (fluorescence in vivo/bisbenzimide of 0.12 ± 0.03; p < 0.05), and blocked systemic leukocyte activation (3.9 ± 0.3 relative luminescence unit/10 polymorphonuclear leukocytes; p < 0.001). CONCLUSIONS Administration of carbon monoxide-releasing molecule-3 at fasciotomy offered protection against compartment syndrome-induced microvascular perfusion deficit, tissue injury, and systemic leukocyte activation. The data suggest the potential therapeutic application of carbon monoxide-releasing molecule-3 to patients at risk of developing compartment syndrome.
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