17 results on '"CO-RMS"'
Search Results
2. Distinct Pharmacological Properties of Gaseous CO and CO-Releasing Molecule in Human Platelets
- Author
-
Patrycja Kaczara, Kamil Przyborowski, Tasnim Mohaissen, and Stefan Chlopicki
- Subjects
platelet aggregation ,carbon monoxide ,soluble guanylate cyclase ,energy metabolism ,CO-RMs ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Carbon monoxide (CO)—gaseous or released by CO-RMs—both possess antiplatelet properties; however, it remains uncertain whether the mechanisms involved are the same. Here, we characterise the involvement of soluble guanylate cyclase (sGC) in the effects of CO—delivered by gaseous CO–saturated buffer (COG) and generated by CORM-A1—on platelet aggregation and energy metabolism, as well as on vasodilatation in aorta, using light transmission aggregometry, Seahorse XFe technique, and wire myography, respectively. ODQ completely prevented the inhibitory effect of COG on platelet aggregation, but did not modify antiplatelet effect of CORM-A1. In turn, COG did not affect, whereas CORM-A1 substantially inhibited energy metabolism in platelets. Even though activation of sGC by BAY 41-2272 or BAY 58-2667 inhibited significantly platelet aggregation, their effects on energy metabolism in platelets were absent or weak and could not contribute to antiplatelet effects of sGC activation. In contrast, vasodilatation of murine aortic rings, induced either by COG or CORM-A1, was dependent on sGC. We conclude that the source (COG vs. CORM-A1) and kinetics (rapid vs. slow) of CO delivery represent key determinants of the mechanism of antiplatelet action of CO, involving either impairment of energy metabolism or activation of sGG.
- Published
- 2021
- Full Text
- View/download PDF
3. Dual Carbonic Anhydrase IX/XII Inhibitors and Carbon Monoxide Releasing Molecules Modulate LPS-Mediated Inflammation in Mouse Macrophages
- Author
-
Emanuela Berrino, Simone Carradori, Andrea Angeli, Fabrizio Carta, Claudiu T. Supuran, Paolo Guglielmi, Cecilia Coletti, Roberto Paciotti, Helmut Schweikl, Francesca Maestrelli, Elisabetta Cerbai, and Marialucia Gallorini
- Subjects
CO-RMs ,carbonic anhydrase inhibitor ,cobalt ,macrophages ,inflammation ,carbon monoxide ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Low concentrations of carbon monoxide (CO) were reported to exhibit anti-inflammatory effects when administered in cells by suitable chemotypes such as CO releasing molecules (CO-RMs). In addition, the pH-modulating abilities of specific carbonic anhydrase isoforms played a crucial role in different models of inflammation and neuropathic pain. Herein, we report a series of chemical hybrids consisting of a Carbonic Anhydrase (CA) inhibitor linked to a CO-RM tail (CAI/CO-RMs). All compounds and their precursors were first tested in vitro for their inhibition activity against the human CA I, II, IX, and XII isoforms as well their CO releasing properties, aiming at corroborating the data by means of molecular modelling techniques. Then, their impact on metabolic activity modulation of RAW 264.7 mouse macrophages for 24 and 48 h was assessed with or without lipopolysaccharide (LPS) stimulation. The compounds were shown to counteract the inflammatory stimulus as also indicated by the reduced tumor necrosis factor alpha (TNF-α) release after treatment. All the biological results were compared to those of N-acetylcysteine (NAC) as a reference antioxidant compound. Within the series, two CAI/CO-RM hybrids (1 and 2), bearing both the well-known scaffold able to inhibit CAs (acesulfame) and the cobalt-based CO releasing portion, induced a higher anti-inflammatory effect up to 48 h at concentrations lower than NAC.
- Published
- 2021
- Full Text
- View/download PDF
4. Toward Carbon Monoxidee-Based Therapeutics: Critical Drug Delivery and Developability Issues.
- Author
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Xingyue Ji, Damera, Krishna, Yueqin Zheng, Bingchen Yu, Otterbein, Leo E., and Binghe Wang
- Subjects
- *
THERAPEUTIC use of carbon monoxide , *NITRIC oxide , *DRUG administration , *INFUSION therapy , *DRUG therapy - Abstract
Carbon monoxide (CO) is an intrinsic signaling molecule with importance on par with that of nitric oxide. During the past decade, pharmacologic studies have amply demonstrated the therapeutic potential of carbon monoxide. However, such studies were mostly based on CO inhalation and metal-based CO-releasing molecules. The field is now at the stage that a major effort is needed to develop pharmaceutically acceptable forms of CO for delivery via various routes such as oral, injection, infusion, or topical applications. This review examines the state of the art, discusses the existing hurdles to overcome, and proposes developmental strategies necessary to address remaining drug delivery issues. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
5. Distinct Pharmacological Properties of Gaseous CO and CO-Releasing Molecule in Human Platelets
- Author
-
Stefan Chlopicki, Kamil Przyborowski, Tasnim Mohaissen, and Patrycja Kaczara
- Subjects
0301 basic medicine ,Male ,Platelet Aggregation ,Physics::Instrumentation and Detectors ,Vasodilation ,030204 cardiovascular system & hematology ,lcsh:Chemistry ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Soluble Guanylyl Cyclase ,energy metabolism ,Platelet ,Physics::Chemical Physics ,lcsh:QH301-705.5 ,Spectroscopy ,Aorta ,Carbon Monoxide ,Electrical impedance myography ,Chemistry ,General Medicine ,Healthy Volunteers ,Computer Science Applications ,Astrophysics::Earth and Planetary Astrophysics ,Gases ,Adult ,Blood Platelets ,soluble guanylate cyclase ,Kinetics ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Cog ,medicine.artery ,medicine ,Molecule ,Animals ,Humans ,CO-RMs ,Physical and Theoretical Chemistry ,Molecular Biology ,Astrophysics::Galaxy Astrophysics ,Organic Chemistry ,Mice, Inbred C57BL ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Guanylate Cyclase ,Biophysics ,Physics::Accelerator Physics ,Carbon monoxide - Abstract
Carbon monoxide (CO)—gaseous or released by CO-RMs—both possess antiplatelet properties, however, it remains uncertain whether the mechanisms involved are the same. Here, we characterise the involvement of soluble guanylate cyclase (sGC) in the effects of CO—delivered by gaseous CO–saturated buffer (COG) and generated by CORM-A1—on platelet aggregation and energy metabolism, as well as on vasodilatation in aorta, using light transmission aggregometry, Seahorse XFe technique, and wire myography, respectively. ODQ completely prevented the inhibitory effect of COG on platelet aggregation, but did not modify antiplatelet effect of CORM-A1. In turn, COG did not affect, whereas CORM-A1 substantially inhibited energy metabolism in platelets. Even though activation of sGC by BAY 41-2272 or BAY 58-2667 inhibited significantly platelet aggregation, their effects on energy metabolism in platelets were absent or weak and could not contribute to antiplatelet effects of sGC activation. In contrast, vasodilatation of murine aortic rings, induced either by COG or CORM-A1, was dependent on sGC. We conclude that the source (COG vs. CORM-A1) and kinetics (rapid vs. slow) of CO delivery represent key determinants of the mechanism of antiplatelet action of CO, involving either impairment of energy metabolism or activation of sGG.
- Published
- 2021
6. Carbon monoxide: Mechanisms of action and potential clinical implications
- Author
-
Rochette, Luc, Cottin, Yves, Zeller, Marianne, and Vergely, Catherine
- Subjects
- *
THERAPEUTIC use of carbon monoxide , *BIOCHEMICAL mechanism of action , *HEME oxygenase , *TETRAHYDROBIOPTERIN , *CAVEOLINS , *NF-kappa B , *MITOGEN-activated protein kinases - Abstract
Small amounts of carbon monoxide (CO) are continuously produced in mammals. The intracellular levels of CO can increase under stressful conditions following the induction of HO-1 (heme oxygnase-1), a ubiquitous enzyme responsible for the catabolism of heme. Unlike nitric oxide, which is a free radical, CO does not contain free electrons but may be involved in oxidative stress. The carbonate radical has been proposed to be a key mediator of oxidative damage resulting from peroxynitrite production, likewise, the precursor of the carbonate radical anion being bicarbonate and carbon dioxide. We report herein some of the transcription factors and protein kinases involved in the regulation of vascular HO-1 expression. Beyond its widely feared toxicity, CO has revealed a very important biological activity as a signaling molecule with marked protective actions namely against apoptosis and endothelial oxidative damage. Abnormal metabolism and function of CO contribute to the pathogenesis and development of cardiovascular diseases. Important results have been reported in which CO and CO-releasing molecules (CO-RMs) prevent intimal hyperplasia by arresting hyperproliferative vascular smooth muscle cells and increased mobilization and recruitment of bone-marrow-derived progenitor cells. Clinical studies have demonstrated beneficial properties of CO-RMs in transplantation. The anti-inflammatory properties of CO and CO-RMs have been demonstrated in a multitude of animal models of inflammation, suggesting a possible therapeutic application for inflammatory diseases. The development of a technology concerning CO-RMs that controls the delivery and action of CO under different pathological conditions represents a major step forward in the development of CO-based pharmaceuticals with therapeutic applications. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
7. Could carbon monoxide and bilirubin be friends as well as foes of the body?
- Author
-
Breimer, Lars H. and Mikhailidis, Dimitri P.
- Subjects
- *
CARBON monoxide , *BILIRUBIN , *BIOCHEMISTRY , *BIOMARKERS , *REACTIVE oxygen species - Abstract
Endogenous carbon monoxide (CO) production was first described 60 years ago. CO is a by-product of the metabolism of haeme to biliverdin. This, in turn, becomes bilirubin. During the past 15 years epidemiological studies and animal experiments have identified bilirubin as a molecule at the crossroads of the protection of the body against reactive oxygen species (ROS). The studies have focused on bilirubin as a biomarker of arterial disease. Recently the potential of CO as a therapeutic agent has been explored. This review assesses the current state of evidence and sets the data in the context of whether CO is an endogenous signalling molecule, a marker of vascular disease and, whether, together with bilirubin, CO could be a potential therapeutic agent. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
8. Dual Carbonic Anhydrase IX/XII Inhibitors and Carbon Monoxide Releasing Molecules Modulate LPS-Mediated Inflammation in Mouse Macrophages
- Author
-
Simone Carradori, Marialucia Gallorini, Andrea Angeli, Cecilia Coletti, Emanuela Berrino, Paolo Guglielmi, Claudiu T. Supuran, Helmut Schweikl, Francesca Maestrelli, Fabrizio Carta, Elisabetta Cerbai, and Roberto Paciotti
- Subjects
0301 basic medicine ,Lipopolysaccharide ,Physiology ,medicine.drug_class ,Clinical Biochemistry ,Inflammation ,Stimulation ,01 natural sciences ,Biochemistry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Carbonic anhydrase ,medicine ,Carbonic anhydrase inhibitor ,CO-RMs ,Carbon monoxide ,Cobalt ,Macrophages ,Molecular Biology ,biology ,010405 organic chemistry ,lcsh:RM1-950 ,Cell Biology ,Carbon monoxide-releasing molecules ,In vitro ,0104 chemical sciences ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,chemistry ,biology.protein ,Tumor necrosis factor alpha ,medicine.symptom - Abstract
Low concentrations of carbon monoxide (CO) were reported to exhibit anti-inflammatory effects when administered in cells by suitable chemotypes such as CO releasing molecules (CO-RMs). In addition, the pH-modulating abilities of specific carbonic anhydrase isoforms played a crucial role in different models of inflammation and neuropathic pain. Herein, we report a series of chemical hybrids consisting of a Carbonic Anhydrase (CA) inhibitor linked to a CO-RM tail (CAI/CO-RMs). All compounds and their precursors were first tested in vitro for their inhibition activity against the human CA I, II, IX, and XII isoforms as well their CO releasing properties, aiming at corroborating the data by means of molecular modelling techniques. Then, their impact on metabolic activity modulation of RAW 264.7 mouse macrophages for 24 and 48 h was assessed with or without lipopolysaccharide (LPS) stimulation. The compounds were shown to counteract the inflammatory stimulus as also indicated by the reduced tumor necrosis factor alpha (TNF-&alpha, ) release after treatment. All the biological results were compared to those of N-acetylcysteine (NAC) as a reference antioxidant compound. Within the series, two CAI/CO-RM hybrids (1 and 2), bearing both the well-known scaffold able to inhibit CAs (acesulfame) and the cobalt-based CO releasing portion, induced a higher anti-inflammatory effect up to 48 h at concentrations lower than NAC.
- Published
- 2021
9. Distinct Pharmacological Properties of Gaseous CO and CO-Releasing Molecule in Human Platelets.
- Author
-
Kaczara, Patrycja, Przyborowski, Kamil, Mohaissen, Tasnim, Chlopicki, Stefan, and Magierowski, Marcin
- Subjects
- *
BLOOD platelet aggregation , *BLOOD platelets , *GUANYLATE cyclase , *ENERGY metabolism , *VASODILATION , *CARBOXYHEMOGLOBIN , *AORTA - Abstract
Carbon monoxide (CO)—gaseous or released by CO-RMs—both possess antiplatelet properties; however, it remains uncertain whether the mechanisms involved are the same. Here, we characterise the involvement of soluble guanylate cyclase (sGC) in the effects of CO—delivered by gaseous CO–saturated buffer (COG) and generated by CORM-A1—on platelet aggregation and energy metabolism, as well as on vasodilatation in aorta, using light transmission aggregometry, Seahorse XFe technique, and wire myography, respectively. ODQ completely prevented the inhibitory effect of COG on platelet aggregation, but did not modify antiplatelet effect of CORM-A1. In turn, COG did not affect, whereas CORM-A1 substantially inhibited energy metabolism in platelets. Even though activation of sGC by BAY 41-2272 or BAY 58-2667 inhibited significantly platelet aggregation, their effects on energy metabolism in platelets were absent or weak and could not contribute to antiplatelet effects of sGC activation. In contrast, vasodilatation of murine aortic rings, induced either by COG or CORM-A1, was dependent on sGC. We conclude that the source (COG vs. CORM-A1) and kinetics (rapid vs. slow) of CO delivery represent key determinants of the mechanism of antiplatelet action of CO, involving either impairment of energy metabolism or activation of sGG. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
10. Dual Carbonic Anhydrase IX/XII Inhibitors and Carbon Monoxide Releasing Molecules Modulate LPS-Mediated Inflammation in Mouse Macrophages.
- Author
-
Berrino, Emanuela, Carradori, Simone, Angeli, Andrea, Carta, Fabrizio, Supuran, Claudiu T., Guglielmi, Paolo, Coletti, Cecilia, Paciotti, Roberto, Schweikl, Helmut, Maestrelli, Francesca, Cerbai, Elisabetta, and Gallorini, Marialucia
- Subjects
CARBONIC anhydrase ,CARBON monoxide ,TUMOR necrosis factors ,MACROPHAGES ,MOLECULES - Abstract
Low concentrations of carbon monoxide (CO) were reported to exhibit anti-inflammatory effects when administered in cells by suitable chemotypes such as CO releasing molecules (CO-RMs). In addition, the pH-modulating abilities of specific carbonic anhydrase isoforms played a crucial role in different models of inflammation and neuropathic pain. Herein, we report a series of chemical hybrids consisting of a Carbonic Anhydrase (CA) inhibitor linked to a CO-RM tail (CAI/CO-RMs). All compounds and their precursors were first tested in vitro for their inhibition activity against the human CA I, II, IX, and XII isoforms as well their CO releasing properties, aiming at corroborating the data by means of molecular modelling techniques. Then, their impact on metabolic activity modulation of RAW 264.7 mouse macrophages for 24 and 48 h was assessed with or without lipopolysaccharide (LPS) stimulation. The compounds were shown to counteract the inflammatory stimulus as also indicated by the reduced tumor necrosis factor alpha (TNF-α) release after treatment. All the biological results were compared to those of N-acetylcysteine (NAC) as a reference antioxidant compound. Within the series, two CAI/CO-RM hybrids (1 and 2), bearing both the well-known scaffold able to inhibit CAs (acesulfame) and the cobalt-based CO releasing portion, induced a higher anti-inflammatory effect up to 48 h at concentrations lower than NAC. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
11. Differential Effects of CORM-2 and CORM-401 in Murine Intestinal Epithelial MODE-K Cells under Oxidative Stress
- Author
-
Georges Leclercq, Romain Lefebvre, Dinesh Babu, and Roberto Motterlini
- Subjects
0301 basic medicine ,Mitochondrial ROS ,Programmed cell death ,SUPEROXIDE ANION ,SPECIES FORMATION ,hydrogen peroxide ,Oxidative phosphorylation ,Mitochondrion ,medicine.disease_cause ,MONOXIDE-RELEASING MOLECULES ,03 medical and health sciences ,0302 clinical medicine ,HYDROGEN-PEROXIDE PRODUCTION ,medicine ,TNF-α/CHX ,oxidative stress ,Pharmacology (medical) ,CARBON-MONOXIDE ,HEME OXYGENASE ,IN-VIVO ,Original Research ,chemistry.chemical_classification ,Pharmacology ,reactive oxygen species ,Reactive oxygen species ,NADPH oxidase ,biology ,TNF-alpha/CHX ,carbon monoxide-releasing molecules ,solubility ,Biology and Life Sciences ,Carbon monoxide-releasing molecules ,Cell biology ,mitochondria ,030104 developmental biology ,chemistry ,Biochemistry ,ULCERATIVE-COLITIS ,030220 oncology & carcinogenesis ,THERAPEUTIC APPLICATIONS ,biology.protein ,intestinal epithelial cells ,CO-RMS ,Oxidative stress - Abstract
Carbon monoxide (CO)-releasing molecules (CO-RMs) are intensively studied to provide cytoprotective and anti-inflammatory effects of CO in inflammatory conditions including intestinal inflammation. The water-soluble CORM-A1 reduced apoptosis and NADPH oxidase (NOX)-derived reactive oxygen species (ROS) induced by tumor necrosis factor (TNF)-alpha/cycloheximide (CHX) in mouse MODE-K intestinal epithelial cells (IECs), without influencing TNF-alpha/CHX-induced mitochondrial superoxide anion (O-2(center dot-)). The aim of the present study in the same model was to comparatively investigate the influence of lipid-soluble CORM-2 and water-soluble CORM-401, shown in vitro to release more CO under oxidative conditions. CORM-2 abolished TNF-alpha/CHX-induced total cellular ROS whereas CORM-401 partially reduced it, both partially reducing TNF-alpha/CHXinduced cell death. Only CORM-2 increased mitochondrial O-2(center dot-) production after 2 h of incubation. CORM-2 reduced TNF-alpha/CHX-, rotenone-and antimycin-A-induced mitochondrial O-2(center dot-) production; CORM-401 only reduced the effect of antimycin-A. Co-treatment with CORM-401 during 1 h exposure to H2O2 reduced H2O2 (7.5 mM)induced ROS production and cell death, whereas CORM-2 did not. The study illustrates the importance of the chemical characteristics of different CO-RMs. The lipid solubility of CORM-2 might contribute to its interference with TNF-alpha/CHX-induced mitochondrial ROS signaling, at least in mouse IECs. CORM-401 is more effective than other CO-RMs under H2O2-induced oxidative stress conditions.
- Published
- 2017
12. Carbon Monoxide as a Therapeutic for Airway Diseases: Contrast and Comparison of Various CO Delivery Modalities.
- Author
-
Tripathi R, Yang X, Ryter SW, and Wang B
- Subjects
- Animals, Carbon Monoxide pharmacokinetics, Carbon Monoxide pharmacology, Cytoprotection drug effects, Humans, Signal Transduction drug effects, Carbon Monoxide administration & dosage, Carbon Monoxide therapeutic use, Drug Delivery Systems, Respiration Disorders drug therapy
- Abstract
The quest to find novel strategies to tackle respiratory illnesses has led to the exploration of the potential therapeutic effects of carbon monoxide (CO) as an endogenous signaling molecule and a cytoprotective agent. Further, several studies have demonstrated the pharmacological efficacy of CO in animal models of respiratory disorders, such as acute lung injury and pulmonary hypertension. Because of the gaseous nature of CO and its affinity for multiple targets, its controlled delivery has been a challenge. Past studies have employed different delivery modalities, including CO gas, HO-1 inducers, and CO donors, sometimes leading to substantive variations in the resulting pharmacological effects for various reasons. Herein, this review summarizes and analyzes the differences among the profiles of various CO-delivery modalities in terms of their efficacy, dosing regimen, and pharmacokinetics in airways models. We believe that analysis of these issues will help in understanding the fundamental roles of CO in airways, and eventually, contribute to its development as a medicine for respiratory diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2021
- Full Text
- View/download PDF
13. Carbon monoxide: mechanisms of action and potential clinical implications
- Author
-
Luc Rochette, Catherine Vergely, Yves Cottin, Marianne Zeller, Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (U866, Lipides et nutrition, équipe 5) (LPPCM), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, This work was supported by grants from the French Ministry of Research, from the Regional Council of Burgundy and from the Association de Cardiologie de Bourgogne, Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Vergely, Catherine, Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (U866, Lipides et nutrition, équipe 5) ( LPPCM ), Lipides - Nutrition - Cancer (U866) ( LNC ), and Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA )
- Subjects
Carbonate radical ,Inflammation ,Heme ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Nitric Oxide ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Sepsis ,medicine ,Transcription factors ,Animals ,Humans ,Pharmacology (medical) ,NRF1 ,CO-RMs ,Carbon monoxide ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Catabolism ,CO-releasing molecules ,[ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,3. Good health ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Transplantation ,Vasodilation ,chemistry ,Biochemistry ,Cardiovascular Diseases ,Endothelium, Vascular ,medicine.symptom ,Oxidative stress ,Peroxynitrite ,Heme Oxygenase-1 - Abstract
International audience; Small amounts of carbon monoxide (CO) are continuously produced in mammals. The intracellular levels of CO can increase under stressful conditions following the induction of HO-1 (heme oxygnase-1), a ubiquitous enzyme responsible for the catabolism of heme. Unlike nitric oxide, which is a free radical, CO does not contain free electrons but may be involved in oxidative stress. The carbonate radical has been proposed to be a key mediator of oxidative damage resulting from peroxynitrite production, likewise, the precursor of the carbonate radical anion being bicarbonate and carbon dioxide. We report herein some of the transcription factors and protein kinases involved in the regulation of vascular HO-1 expression. Beyond its widely feared toxicity, CO has revealed a very important biological activity as a signaling molecule with marked protective actions namely against apoptosis and endothelial oxidative damage. Abnormal metabolism and function of CO contribute to the pathogenesis and development of cardiovascular diseases. Important results have been reported in which CO and CO-releasing molecules (CO-RMs) prevent intimal hyperplasia by arresting hyperproliferative vascular smooth muscle cells and increased mobilization and recruitment of bone-marrow-derived progenitor cells. Clinical studies have demonstrated beneficial properties of CO-RMs in transplantation. The anti-inflammatory properties of CO and CO-RMs have been demonstrated in a multitude of animal models of inflammation, suggesting a possible therapeutic application for inflammatory diseases. The development of a technology concerning CO-RMs that controls the delivery and action of CO under different pathological conditions represents a major step forward in the development of CO-based pharmaceuticals with therapeutic applications.
- Published
- 2013
14. Toward Carbon Monoxide-Based Therapeutics: Critical Drug Delivery and Developability Issues.
- Author
-
Ji X, Damera K, Zheng Y, Yu B, Otterbein LE, and Wang B
- Subjects
- Administration, Inhalation, Animals, Carbon Monoxide pharmacokinetics, Drug Delivery Systems trends, Drug Discovery trends, Humans, Prodrugs administration & dosage, Prodrugs chemistry, Prodrugs pharmacokinetics, Carbon Monoxide administration & dosage, Carbon Monoxide chemistry, Drug Delivery Systems methods, Drug Discovery methods
- Abstract
Carbon monoxide (CO) is an intrinsic signaling molecule with importance on par with that of nitric oxide. During the past decade, pharmacologic studies have amply demonstrated the therapeutic potential of carbon monoxide. However, such studies were mostly based on CO inhalation and metal-based CO-releasing molecules. The field is now at the stage that a major effort is needed to develop pharmaceutically acceptable forms of CO for delivery via various routes such as oral, injection, infusion, or topical applications. This review examines the state of the art, discusses the existing hurdles to overcome, and proposes developmental strategies necessary to address remaining drug delivery issues., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
15. Molecules
- Author
-
Ledger, Philip
- Published
- 2003
- Full Text
- View/download PDF
16. CORM-3, a water soluble CO-releasing molecule, uncouples mitochondrial respiration via interaction with the phosphate carrier.
- Author
-
Long R, Salouage I, Berdeaux A, Motterlini R, and Morin D
- Subjects
- Animals, Carbon Monoxide metabolism, Membrane Potential, Mitochondrial, Mitochondria physiology, Oxygen Consumption, Protons, Rats, Water chemistry, Cell Respiration physiology, Mitochondria metabolism, Mitochondria, Heart metabolism, Organometallic Compounds metabolism, Phosphate Transport Proteins metabolism
- Abstract
Carbon monoxide is continuously produced in small quantities in tissues and is an important signaling mediator in mammalian cells. We previously demonstrated that CO delivered to isolated rat heart mitochondria using a water-soluble CO-releasing molecule (CORM-3) is able to uncouple mitochondrial respiration. The aim of this study was to explore more in depth the mechanism(s) of this uncoupling effect. We found that acceleration of mitochondrial O2 consumption and decrease in membrane potential induced by CORM-3 were associated with an increase in mitochondrial swelling. This effect was independent of the opening of the mitochondrial transition pore as cyclosporine A was unable to prevent it. Interestingly, removal of phosphate from the incubation medium suppressed the effects mediated by CORM-3. Blockade of the dicarboxylate carrier, which exchanges dicarboxylate for phosphate, decreased the effects induced by CORM-3 while direct inhibition of the phosphate carrier with N-ethylmaleimide completely abolished the effects of CORM-3. In addition, CORM-3 was able to enhance the transport of phosphate into mitochondria as evidenced by changes in mitochondrial phosphate concentration and mitochondrial swelling that evaluates the activity of the phosphate carrier in de-energized conditions. These results indicate that CORM-3 activates the phosphate carrier leading to an increase in phosphate and proton transport inside mitochondria, both of which could contribute to the non-classical uncoupling effect mediated by CORM-3. The dicarboxylate carrier amplifies this effect by increasing intra-mitochondrial phosphate concentration., (© 2013.)
- Published
- 2014
- Full Text
- View/download PDF
17. Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells.
- Author
-
Foresti R, Bains SK, Pitchumony TS, de Castro Brás LE, Drago F, Dubois-Randé JL, Bucolo C, and Motterlini R
- Subjects
- Animals, Antioxidants metabolism, Bilirubin metabolism, Cell Line, Cell Survival drug effects, Gene Expression Regulation drug effects, Heme Oxygenase-1 genetics, Heme Oxygenase-1 immunology, Inflammation drug therapy, Inflammation immunology, Interferon-gamma immunology, Lipopolysaccharides immunology, Mice, Microglia cytology, Microglia immunology, Microglia metabolism, NF-E2-Related Factor 2 immunology, Heme metabolism, Heme Oxygenase-1 metabolism, Microglia drug effects, NF-E2-Related Factor 2 metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology
- Abstract
The nuclear factor erythroid derived 2-related factor 2 (Nrf2) and the antioxidant protein heme oxygenase-1 (HO-1) are crucial components of the cellular stress response. These two systems work together to combat oxidative stress and inflammation and are attractive drug targets for counteracting different pathologies, including neuroinflammation. We aimed to identify the most effective Nrf2/HO-1 activators that modulate the inflammatory response in microglia cells. In the present study, we searched the literature and selected 56 compounds reported to activate Nrf2 or HO-1 and analyzed them for HO-1 induction at 6 and 24h and cytotoxicity in BV2 microglial cells in vitro. Approximately 20 compounds up-regulated HO-1 at the concentrations tested (5-20 μM) with carnosol, supercurcumin, cobalt protoporphyrin-IX and dimethyl fumarate exhibiting the best induction/low cytotoxicity profile. Up-regulation of HO-1 by some compounds resulted in increased cellular bilirubin levels but did not augment the expression of proteins involved in heme synthesis (ALAS 1) or biliverdin reductase. Bilirubin production by HO-1 inducers correlated with their potency in inhibiting nitrite production after challenge with interferon-γ (INF-γ) or lipopolysaccharide (LPS). The compounds down-regulated the inflammatory response (TNF-α, PGE2 and nitrite) more strongly in cells challenged with INF-γ than LPS, and silencing HO-1 or Nrf2 with shRNA differentially affected the levels of inflammatory markers. These findings indicate that some small activators of Nrf2/HO-1 are effective modulators of microglia inflammation and highlight the chemical scaffolds that can serve for the synthesis of potent new derivatives to counteract neuroinflammation and neurodegeneration., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
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