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Bartkowiak A, Szczesny-Malysiak E, Dybas J. Tracking heme biology with resonance Raman spectroscopy. BIOCHIMICA ET BIOPHYSICA ACTA. PROTEINS AND PROTEOMICS 2025; 1873:141065. [PMID: 39999941 DOI: 10.1016/j.bbapap.2025.141065] [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: 11/28/2024] [Revised: 01/31/2025] [Accepted: 02/19/2025] [Indexed: 02/27/2025]
Abstract
Heme proteins are a large group of biomolecules with heme incorporated as a prosthetic group. Apart from cytochromes present in almost all cell types, many other specific heme proteins are expressed in different kinds of cells, e.g. hemoglobin in the erythrocytes, myoglobin (skeletal and vascular smooth muscle cells), cytoglobin (fibroblasts) and neuroglobin (neurons and retina). Among their wide and diverse biological functions, the most important is their unique ability to bind, store, and transport gaseous molecules, such as oxygen, carbon monoxide, and nitric oxide. Resonance Raman (RR) spectroscopy is an exceptional analytical tool that allows for qualitative and quantitative characterization of heme proteins in biological systems. Due to its high sensitivity, even subtle structural alterations of the heme group can be monitored and tracked during cellular processes. Resonance Raman excitation within the Soret absorption band (390-440 nm) provides rich information on the environment of heme's active site, allowing differentiation of the iron ion oxidation and spin states, and tracking the movement of the porphyrin ring plane in response to the changes in oxygenation status. Herein, we summarize and discuss recent developments in RR applications aimed to link the structure-function relationship of heme proteins within biological systems, connected, e.g., with the formation of hemoglobin (Hb) adducts (nitrosylhemoglobin, cyanhemoglobin, sulfhemoglobin), irreversible Hb alterations deteriorating oxygen binding and differentiation of heme proteins oxidation state within live cells in situ.
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Affiliation(s)
- Amanda Bartkowiak
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University 14 Bobrzyńskiego St., 30-348 Krakow, Poland
| | - Ewa Szczesny-Malysiak
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University 14 Bobrzyńskiego St., 30-348 Krakow, Poland
| | - Jakub Dybas
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University 14 Bobrzyńskiego St., 30-348 Krakow, Poland.
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Bünger V, Menk M, Hunsicker O, Krannich A, Balzer F, Spies CD, Kuebler WM, Weber-Carstens S, Graw JA. Carboxyhemoglobin and Methemoglobin as Biomarkers of Hemolysis and Mortality in Acute Respiratory Distress Syndrome Treated by Veno-Venous Extracorporeal Membrane Oxygenation. Anesth Analg 2025:00000539-990000000-01244. [PMID: 40163840 DOI: 10.1213/ane.0000000000007495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
BACKGROUND Critically ill patients who receive circulatory or respiratory assist using extracorporeal membrane oxygenation (ECMO) may develop hemolysis, which can complicate the delivery of supportive care and be a potential risk factor for increased morbidity and mortality. Clinically, hemolysis is often identified using laboratory markers such as cell-free hemoglobin (CFH) and haptoglobin (Hp). However, such measurements require photometry or enzyme-linked immunosorbent assay (ELISA) and are labor intensive. In contrast, metabolic downstream products of CFH, such as carboxyhemoglobin (CO-Hb) and methemoglobin (Met-Hb), can be regularly monitored via arterial blood gas analyses in the intensive care unit (ICU). We hypothesized that CO-Hb and Met-Hb values measured during ECMO would correlate with the presence of hemolytic events as measured by CFH values exceeding 50mg/dl. We further hypothesized that CO-Hb and Met-Hb levels would correlate with peri-ECMO mortality. METHODS Retrospective analysis of 435 patients with acute respiratory distress syndrome (ARDS) and veno-venous ECMO admitted to a tertiary ARDS referral center. Plasma concentrations of CO-Hb and Met-Hb were correlated with hemolytic events. Cutoff values of mean CO-Hb (mCO-Hb) and mean Met-Hb (mMet-Hb) associated with increased ICU mortality were calculated with recursive binary partitioning. Single and multivariable regression models for HE and ICU mortality were trained and compared. RESULTS Simple and multivariable models including potential confounders identified associations between Met-Hb and hemolytic events (adj. odds ratio [OR] 2.99 [95% confidence interval {CI}, 2.19-4.10], P < .001). A cutoff value with 90% specificity of a hemolytic event was estimated for Met-Hb (1.55%). Both, mean CO-Hb (OR 2.03 [95% CI, 1.60-2.61], P < .001) and Met-Hb (2.78 [1.59-5.09], P < .001) were associated with ICU mortality. Cutoff values for mortality were 2% for mean CO-Hb and 1.25% for mean Met-Hb. The multivariable regression model for mortality including the continuous markers mCO-Hb and mMet-Hb produced an area under the curve (AUC) of 0.803. CONCLUSIONS In patients with ARDS and ECMO, Met-Hb plasma concentrations were independently associated with hemolytic events. Both, mean CO-Hb and Met-Hb levels were associated with ICU mortality. These markers and their associated cutoff values might serve as a risk indicator in clinical practice.
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Affiliation(s)
- Victoria Bünger
- From the Department of Anesthesiology and Intensive Care Medicine, CCM/CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Mario Menk
- From the Department of Anesthesiology and Intensive Care Medicine, CCM/CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Department of Anesthesiology and Intensive Care Medicine, University Hospital "Carl Gustav Carus," Technische Universität Dresden, Dresden, Germany
| | - Oliver Hunsicker
- From the Department of Anesthesiology and Intensive Care Medicine, CCM/CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Alexander Krannich
- Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin, Berlin, Germany
- BioStats GmbH, Nauen, Germany
| | - Felix Balzer
- Institute of Medical Informatics, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Claudia D Spies
- From the Department of Anesthesiology and Intensive Care Medicine, CCM/CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Wolfgang M Kuebler
- Institute of Physiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Steffen Weber-Carstens
- From the Department of Anesthesiology and Intensive Care Medicine, CCM/CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Jan A Graw
- From the Department of Anesthesiology and Intensive Care Medicine, CCM/CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Department of Anesthesiology and Intensive Care Medicine, Universitätsklinikum Ulm, Ulm University, Ulm, Germany
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Liu X, Yang C, Zhang X, Ye R, Li X, Zhang Z, Jia S, Sun L, Meng Q, Chen X. Association between hemoglobin concentration and hypertension risk in native Tibetans at high altitude. J Clin Hypertens (Greenwich) 2024; 26:17-23. [PMID: 37724706 PMCID: PMC10795086 DOI: 10.1111/jch.14726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 09/03/2023] [Accepted: 09/04/2023] [Indexed: 09/21/2023]
Abstract
Previous studies examining the association between hemoglobin concentration and hypertension have yielded inconsistent results. There is still a lack of evidence regarding the association between hemoglobin concentration and hypertension risk in native Tibetans at high altitude. We performed this cross-sectional study in Luhuo County of Ganzi Tibetan Autonomous Prefecture (average altitude of 3500 m). In this study, we enrolled 1547 native Tibetans. The association between hemoglobin concentration and hypertension risk was examined by multivariate binary logistic regression and smooth curve fitting. Native Tibetans with hypertension had significantly higher hemoglobin concentrations than those without hypertension (165.9 ± 21.5 g/L vs. 157.7 ± 19.2 g/L, P < 0.001). An increase in hemoglobin concentration of 1 g/L was associated with hypertension (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01-1.02) after confounder adjustment. The highest hemoglobin concentration group (exceeding 173 g/L) was associated with an increased hypertension risk compared with the bottom quartile of hemoglobin concentration (OR 2.39, 95% CI 1.48-3.85). Hemoglobin concentration (per 1 g/L change) exceeding 176 g/L was significantly associated with an increased hypertension risk (OR 1.04, 95% CI 1.03-1.06). Additionally, high-altitude polycythemia significantly increased the hypertension risk compared with a normal hemoglobin concentration (OR 2.92, 95% CI 1.25-6.86). A similar result was observed for mild polycythemia (OR 1.74, 95% CI 1.29-2.34). In conclusion, hemoglobin concentration was associated with hypertension risk in native Tibetans. When the hemoglobin concentration exceeded a certain value (approximately 176 g/L), the risk of hypertension was significantly increased.
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Affiliation(s)
- Xueting Liu
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
| | - Changqiang Yang
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
| | - Xin Zhang
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
| | - Runyu Ye
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
| | - Xinran Li
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
| | - Zhipeng Zhang
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
| | - Shanshan Jia
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
| | - Lirong Sun
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
| | - Qingtao Meng
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
| | - Xiaoping Chen
- Department of CardiologyWest China Hospital of Sichuan UniversityChengduChina
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Hsia CCW. Tissue Perfusion and Diffusion and Cellular Respiration: Transport and Utilization of Oxygen. Semin Respir Crit Care Med 2023; 44:594-611. [PMID: 37541315 DOI: 10.1055/s-0043-1770061] [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: 08/06/2023]
Abstract
This article provides an overview of the journey of inspired oxygen after its uptake across the alveolar-capillary interface, and the interplay among tissue perfusion, diffusion, and cellular respiration in the transport and utilization of oxygen. The critical interactions between oxygen and its facilitative carriers (hemoglobin in red blood cells and myoglobin in muscle cells), and with other respiratory and vasoactive molecules (carbon dioxide, nitric oxide, and carbon monoxide), are emphasized to illustrate how this versatile system dynamically optimizes regional convective transport and diffusive gas exchange. The rates of reciprocal gas exchange in the lung and the periphery must be well-matched and sufficient for meeting the range of energy demands from rest to maximal stress but not excessive as to become toxic. The mobile red blood cells play a vital role in matching tissue perfusion and gas exchange by dynamically regulating the controlled uptake of oxygen and communicating regional metabolic signals across different organs. Intracellular oxygen diffusion and facilitation via myoglobin into the mitochondria, and utilization via electron transport chain and oxidative phosphorylation, are summarized. Physiological and pathophysiological adaptations are briefly described. Dysfunction of any component across this integrated system affects all other components and elicits corresponding structural and functional adaptation aimed at matching the capacities across the entire system and restoring equilibrium under normal and pathological conditions.
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Affiliation(s)
- Connie C W Hsia
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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Maia LB. Bringing Nitric Oxide to the Molybdenum World-A Personal Perspective. Molecules 2023; 28:5819. [PMID: 37570788 PMCID: PMC10420851 DOI: 10.3390/molecules28155819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/29/2023] [Accepted: 07/30/2023] [Indexed: 08/13/2023] Open
Abstract
Molybdenum-containing enzymes of the xanthine oxidase (XO) family are well known to catalyse oxygen atom transfer reactions, with the great majority of the characterised enzymes catalysing the insertion of an oxygen atom into the substrate. Although some family members are known to catalyse the "reverse" reaction, the capability to abstract an oxygen atom from the substrate molecule is not generally recognised for these enzymes. Hence, it was with surprise and scepticism that the "molybdenum community" noticed the reports on the mammalian XO capability to catalyse the oxygen atom abstraction of nitrite to form nitric oxide (NO). The lack of precedent for a molybdenum- (or tungsten) containing nitrite reductase on the nitrogen biogeochemical cycle contributed also to the scepticism. It took several kinetic, spectroscopic and mechanistic studies on enzymes of the XO family and also of sulfite oxidase and DMSO reductase families to finally have wide recognition of the molybdoenzymes' ability to form NO from nitrite. Herein, integrated in a collection of "personal views" edited by Professor Ralf Mendel, is an overview of my personal journey on the XO and aldehyde oxidase-catalysed nitrite reduction to NO. The main research findings and the path followed to establish XO and AO as competent nitrite reductases are reviewed. The evidence suggesting that these enzymes are probable players of the mammalian NO metabolism is also discussed.
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Affiliation(s)
- Luisa B Maia
- LAQV, REQUIMTE, Department of Chemistry, NOVA School of Science and Technology (FCT NOVA), 2829-516 Caparica, Portugal
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De Simone G, Varricchio R, Ruberto TF, di Masi A, Ascenzi P. Heme Scavenging and Delivery: The Role of Human Serum Albumin. Biomolecules 2023; 13:biom13030575. [PMID: 36979511 PMCID: PMC10046553 DOI: 10.3390/biom13030575] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Heme is the reactive center of several metal-based proteins that are involved in multiple biological processes. However, free heme, defined as the labile heme pool, has toxic properties that are derived from its hydrophobic nature and the Fe-atom. Therefore, the heme concentration must be tightly controlled to maintain cellular homeostasis and to avoid pathological conditions. Therefore, different systems have been developed to scavenge either Hb (i.e., haptoglobin (Hp)) or the free heme (i.e., high-density lipoproteins (HDL), low-density lipoproteins (LDL), hemopexin (Hx), and human serum albumin (HSA)). In the first seconds after heme appearance in the plasma, more than 80% of the heme binds to HDL and LDL, and only the remaining 20% binds to Hx and HSA. Then, HSA slowly removes most of the heme from HDL and LDL, and finally, heme transits to Hx, which releases it into hepatic parenchymal cells. The Hx:heme or HSA:heme complexes are internalized via endocytosis mediated by the CD91 and CD71 receptors, respectively. As heme constitutes a major iron source for pathogens, bacteria have evolved hemophores that can extract and uptake heme from host proteins, including HSA:heme. Here, the molecular mechanisms underlying heme scavenging and delivery from HSA are reviewed. Moreover, the relevance of HSA in disease states associated with increased heme plasma concentrations are discussed.
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Affiliation(s)
- Giovanna De Simone
- Department of Sciences, Section of Biomedical Sciences and Technologies, Roma Tre University, 00146 Roma, Italy
| | - Romualdo Varricchio
- Department of Sciences, Section of Biomedical Sciences and Technologies, Roma Tre University, 00146 Roma, Italy
| | - Tommaso Francesco Ruberto
- Department of Sciences, Section of Biomedical Sciences and Technologies, Roma Tre University, 00146 Roma, Italy
| | - Alessandra di Masi
- Department of Sciences, Section of Biomedical Sciences and Technologies, Roma Tre University, 00146 Roma, Italy
- Centro Linceo Interdisciplinare Beniamino Segre, Accademia Nazionale dei Lincei, 00165 Roma, Italy
| | - Paolo Ascenzi
- Department of Sciences, Section of Biomedical Sciences and Technologies, Roma Tre University, 00146 Roma, Italy
- Accademia Nazionale dei Lincei, 00165 Roma, Italy
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Pokidova OV, Novikova VO, Emel'yanova NS, Kormukhina AY, Kulikov AV, Utenyshev AN, Lazarenko VA, Ovanesyan NS, Starostina AA, Sanina NA. A nitrosyl iron complex with 3.4-dichlorothiophenolyl ligands: synthesis, structures and its reactions with targets - carriers of nitrogen oxide (NO) in vivo. Dalton Trans 2023; 52:2641-2662. [PMID: 36744818 DOI: 10.1039/d2dt04047f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
In this work, a new binuclear nitrosyl complex with 3.4-dichlorothiophenolyl ligands [Fe2(SC6H3Cl2)2(NO)4] has been synthesized. Nitrosyl iron complexes (NICs) are systems for the storage and delivery of NO in the body. There is a dynamic equilibrium between dinitrosyl iron units bound to low molecular weight ligands and high molecular weight (protein) ligands in vivo. From this point of view, the transformation of the studied complex in DMSO and buffer, as well as in biological systems, has been analyzed. In DMSO, it decomposes into mononuclear NICs, which quickly decay in buffer solutions with NO release. The high molecular weight product is formed as a result of the binding of the complex to bovine serum albumin (the Stern-Volmer constant is 2.1 × 105 M-1). In this case, the complex becomes a prolonged NO-donor. Such a long-term effect has been observed for the first time. Similarly, in a system with oxyhemoglobin, NO generation is slower; the UV-vis spectra show a gradual formation of methemoglobin. On the other hand, reduced glutathione has little effect on the NO-donor properties of the complex despite the fact that ligand substitution is observed in the system and a binuclear product is formed. Mucin binds the complex, and the decomposition mechanism is different from that for buffer solutions. Thus, these proteins and glutathione are able to participate in the transformation of the complex and modulate its properties as a potential drug.
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Affiliation(s)
- Olesya V Pokidova
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, prosp. Akad. Semenova, 1., 142432 Chernogolovka, Moscow region, Russian Federation.
| | - Veronika O Novikova
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, prosp. Akad. Semenova, 1., 142432 Chernogolovka, Moscow region, Russian Federation.
| | - Nina S Emel'yanova
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, prosp. Akad. Semenova, 1., 142432 Chernogolovka, Moscow region, Russian Federation.
| | - Alexandra Yu Kormukhina
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, prosp. Akad. Semenova, 1., 142432 Chernogolovka, Moscow region, Russian Federation. .,Faculty of Fundamental Physical and Chemical Engineering, Lomonosov Moscow State University M.V. Lomonosov, Leninskie gory, 1., 119991 Moscow, Russian Federation
| | - Alexander V Kulikov
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, prosp. Akad. Semenova, 1., 142432 Chernogolovka, Moscow region, Russian Federation. .,Faculty of Fundamental Physical and Chemical Engineering, Lomonosov Moscow State University M.V. Lomonosov, Leninskie gory, 1., 119991 Moscow, Russian Federation
| | - Andrey N Utenyshev
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, prosp. Akad. Semenova, 1., 142432 Chernogolovka, Moscow region, Russian Federation.
| | - Vladimir A Lazarenko
- National Research Center 'Kurchatov Institute', pl. Academician Kurchatov, 1, 123182, Moscow, Russian Federation
| | - Nikolai S Ovanesyan
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, prosp. Akad. Semenova, 1., 142432 Chernogolovka, Moscow region, Russian Federation.
| | - Arina A Starostina
- Faculty of Fundamental Physical and Chemical Engineering, Lomonosov Moscow State University M.V. Lomonosov, Leninskie gory, 1., 119991 Moscow, Russian Federation
| | - Natalya A Sanina
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, prosp. Akad. Semenova, 1., 142432 Chernogolovka, Moscow region, Russian Federation. .,Faculty of Fundamental Physical and Chemical Engineering, Lomonosov Moscow State University M.V. Lomonosov, Leninskie gory, 1., 119991 Moscow, Russian Federation.,Scientific and Educational Center "Medical Chemistry", Moscow State Regional Pedagogical University, st. Vera Voloshina, 24, 141014 Mytishchi, Moscow Region, Russian Federation
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De Simone G, di Masi A, Ascenzi P. Strategies of Pathogens to Escape from NO-Based Host Defense. Antioxidants (Basel) 2022; 11:2176. [PMID: 36358549 PMCID: PMC9686644 DOI: 10.3390/antiox11112176] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 10/27/2022] [Indexed: 06/22/2024] Open
Abstract
Nitric oxide (NO) is an essential signaling molecule present in most living organisms including bacteria, fungi, plants, and animals. NO participates in a wide range of biological processes including vasomotor tone, neurotransmission, and immune response. However, NO is highly reactive and can give rise to reactive nitrogen and oxygen species that, in turn, can modify a broad range of biomolecules. Much evidence supports the critical role of NO in the virulence and replication of viruses, bacteria, protozoan, metazoan, and fungi, thus representing a general mechanism of host defense. However, pathogens have developed different mechanisms to elude the host NO and to protect themselves against oxidative and nitrosative stress. Here, the strategies evolved by viruses, bacteria, protozoan, metazoan, and fungi to escape from the NO-based host defense are overviewed.
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Affiliation(s)
| | | | - Paolo Ascenzi
- Laboratorio Interdipartimentale di Microscopia Elettronica, Via della Vasca Navale 79, 00146 Roma, Italy
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Siervo M, Babateen A, Alharbi M, Stephan B, Shannon O. Dietary nitrate and brain health. Too much ado about nothing or a solution for dementia prevention? Br J Nutr 2022; 128:1130-1136. [PMID: 36688430 DOI: 10.1017/s0007114522002434] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Dementia is a significant public health priority with approximately 55 million cases worldwide, and this number is predicted to quadruple by 2050. Adherence to a healthy diet and achieving optimal nutritional status are vital strategies to improve brain health. The importance of this area of research has been consolidated into the new term ‘nutritional psychiatry’. Dietary nitrate, closely associated with the intake of fruits and vegetables, is a compound that is increased in dietary patterns such as the Mediterranean and MIND diets and has protective effects on cognition and brain health. Nitrate is characterised by a complex metabolism and is the precursor of the nitrate–nitrite–nitric oxide (NO) pathway contributing to systemic NO generation. A higher intake of dietary nitrate has been linked to protective effects on vascular outcomes including blood pressure and endothelial function. However, the current evidence supporting the protective effects of dietary nitrate on brain health is less convincing. This article aims to provide a critical appraisal of the current evidence for dietary nitrate supplementation for improving brain health and provide suggestions for future research.
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Affiliation(s)
- Mario Siervo
- School of Life Sciences, The University of Nottingham, Medical School, Nottingham, UK
| | - Abrar Babateen
- Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
- Faculty of Applied Medical Sciences, Clinical Nutrition Department, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mushari Alharbi
- School of Life Sciences, The University of Nottingham, Medical School, Nottingham, UK
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Blossom Stephan
- Institute of Mental Health, The University of Nottingham Medical School, Nottingham, UK
| | - Oliver Shannon
- Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
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Effects of Prolonged Exposure to Hypobaric Hypoxia on Oxidative Stress: Overwintering in Antarctic Concordia Station. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4430032. [PMID: 35535360 PMCID: PMC9078816 DOI: 10.1155/2022/4430032] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/25/2022] [Accepted: 04/09/2022] [Indexed: 12/14/2022]
Abstract
Concordia Station is the permanent, research station on the Antarctic Plateau at 3230 m. During the eleventh winter-over campaign (DC11-2015; February 2015 to November 2015) at Antarctic Concordia Station, 13 healthy team members were studied and blood samples were collected at six different time points: baseline measurements (T0), performed at sea level before the departure, and during the campaign at 3, 7, 20, 90, and 300 days after arrival at Concordia Station. Reducing the partial pressure of O2 as barometric pressure falls, hypobaric hypoxia (HH) triggers several physiological adaptations. Among the others, increased oxidative stress and enhanced generation of reactive oxygen/nitrogen species (ROS/RNS), resulting in severe oxidative damage, were observed, which can share potential physiopathological mechanisms associated with many diseases. This study characterized the extent and time-course changes after acute and chronic HH exposure, elucidating possible fundamental mechanisms of adaptation. ROS, oxidative stress biomarkers, nitric oxide, and proinflammatory cytokines significantly increased (range 24-135%) during acute and chronic hypoxia exposure (peak 20th day) with a decrease in antioxidant capacity (peak 90th day: -52%). Results suggest that the adaptive response of oxidative stress balance to HH requires a relatively long time, more than 300th days, as all the observed variables do not return to the preexposition level. These findings may also be relevant to patients in whom oxygen availability is limited through disease (i.e., chronic heart and lung and/or kidney disease) and/or during long-duration space missions.
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Medical Gas Plasma—A Potent ROS-Generating Technology for Managing Intraoperative Bleeding Complications. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12083800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cold medical gas plasmas are under pre-clinical investigation concerning their hemostatic activity and could be applied for intra-operative bleeding control in the future. The technological leap innovation was their generation at body temperature, thereby causing no thermal harm to the tissue and ensuring tissue integrity. This directly contrasts with current techniques such as electrocautery, which induces hemostasis by carbonizing the tissue using a heated electrode. However, the necrotized tissue is prone to fall, raising the risk of post-operative complications such as secondary bleedings or infection. In recent years, various studies have reported on the ability of medical gas plasmas to induce blood coagulation, including several suggestions concerning their mode of action. As non-invasive and gentle hemostatic agents, medical gas plasmas could be particularly eligible for vulnerable tissues, e.g., colorectal surgery and neurosurgery. Further, their usage could be beneficial regarding the prevention of post-operative bleedings due to the absence or sloughing of eschar. However, no clinical trials or individual healing attempts for medical gas plasmas have been reported to pave the way for clinical approvement until now, despite promising results in experimental animal models. In this light, the present mini-review aims to emphasize the potential of medical gas plasmas to serve as a hemostatic agent in clinical procedures. Providing a detailed overview of the current state of knowledge, feasible application fields are discussed, and possible obstacles are addressed.
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12
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Trends in biomedical analysis of red blood cells – Raman spectroscopy against other spectroscopic, microscopic and classical techniques. Trends Analyt Chem 2022. [DOI: 10.1016/j.trac.2021.116481] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Lehnert N, Kim E, Dong HT, Harland JB, Hunt AP, Manickas EC, Oakley KM, Pham J, Reed GC, Alfaro VS. The Biologically Relevant Coordination Chemistry of Iron and Nitric Oxide: Electronic Structure and Reactivity. Chem Rev 2021; 121:14682-14905. [PMID: 34902255 DOI: 10.1021/acs.chemrev.1c00253] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Nitric oxide (NO) is an important signaling molecule that is involved in a wide range of physiological and pathological events in biology. Metal coordination chemistry, especially with iron, is at the heart of many biological transformations involving NO. A series of heme proteins, nitric oxide synthases (NOS), soluble guanylate cyclase (sGC), and nitrophorins, are responsible for the biosynthesis, sensing, and transport of NO. Alternatively, NO can be generated from nitrite by heme- and copper-containing nitrite reductases (NIRs). The NO-bearing small molecules such as nitrosothiols and dinitrosyl iron complexes (DNICs) can serve as an alternative vehicle for NO storage and transport. Once NO is formed, the rich reaction chemistry of NO leads to a wide variety of biological activities including reduction of NO by heme or non-heme iron-containing NO reductases and protein post-translational modifications by DNICs. Much of our understanding of the reactivity of metal sites in biology with NO and the mechanisms of these transformations has come from the elucidation of the geometric and electronic structures and chemical reactivity of synthetic model systems, in synergy with biochemical and biophysical studies on the relevant proteins themselves. This review focuses on recent advancements from studies on proteins and model complexes that not only have improved our understanding of the biological roles of NO but also have provided foundations for biomedical research and for bio-inspired catalyst design in energy science.
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Affiliation(s)
- Nicolai Lehnert
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Eunsuk Kim
- Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
| | - Hai T Dong
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Jill B Harland
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Andrew P Hunt
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Elizabeth C Manickas
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Kady M Oakley
- Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
| | - John Pham
- Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
| | - Garrett C Reed
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
| | - Victor Sosa Alfaro
- Department of Chemistry and Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
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14
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Pillars and Gaps of S-Nitrosylation-Dependent Epigenetic Regulation in Physiology and Cancer. Life (Basel) 2021; 11:life11121424. [PMID: 34947954 PMCID: PMC8704633 DOI: 10.3390/life11121424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 11/17/2022] Open
Abstract
Nitric oxide (NO) is a diffusible signaling molecule produced by three isoforms of nitric oxide synthase, which release NO during the metabolism of the amino acid arginine. NO participates in pathophysiological responses of many different tissues, inducing concentration-dependent effect. Indeed, while low NO levels generally have protective effects, higher NO concentrations induce cytotoxic/cytostatic actions. In recent years, evidences have been accumulated unveiling S-nitrosylation as a major NO-dependent post-translational mechanism ruling gene expression. S-nitrosylation is a reversible, highly regulated phenomenon in which NO reacts with one or few specific cysteine residues of target proteins generating S-nitrosothiols. By inducing this chemical modification, NO might exert epigenetic regulation through direct effects on both DNA and histones as well as through indirect actions affecting the functions of transcription factors and transcriptional co-regulators. In this light, S-nitrosylation may also impact on cancer cell gene expression programs. Indeed, it affects different cell pathways and functions ranging from the impairment of DNA damage repair to the modulation of the activity of signal transduction molecules, oncogenes, tumor suppressors, and chromatin remodelers. Nitrosylation is therefore a versatile tool by which NO might control gene expression programs in health and disease.
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15
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Zhang R, Hausladen A, Qian Z, Liao X, Premont RT, Stamler JS. Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation. JCI Insight 2021; 7:155234. [PMID: 34914637 PMCID: PMC8855790 DOI: 10.1172/jci.insight.155234] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/15/2021] [Indexed: 11/25/2022] Open
Abstract
Systemic hypoxia is characterized by peripheral vasodilation and pulmonary vasoconstriction. However, the system-wide mechanism for signaling hypoxia remains unknown. Accumulating evidence suggests that hemoglobin (Hb) in RBCs may serve as an O2 sensor and O2-responsive NO signal transducer to regulate systemic and pulmonary vascular tone, but this remains unexamined at the integrated system level. One residue invariant in mammalian Hbs, β-globin cysteine93 (βCys93), carries NO as vasorelaxant S-nitrosothiol (SNO) to autoregulate blood flow during O2 delivery. βCys93Ala mutant mice thus exhibit systemic hypoxia despite transporting O2 normally. Here, we show that βCys93Ala mutant mice had reduced S-nitrosohemoglobin (SNO-Hb) at baseline and upon targeted SNO repletion and that hypoxic vasodilation by RBCs was impaired in vitro and in vivo, recapitulating hypoxic pathophysiology. Notably, βCys93Ala mutant mice showed marked impairment of hypoxic peripheral vasodilation and developed signs of pulmonary hypertension with age. Mutant mice also died prematurely with cor pulmonale (pulmonary hypertension with right ventricular dysfunction) when living under low O2. Altogether, we identify a major role for RBC SNO in clinically relevant vasodilatory responses attributed previously to endothelial NO. We conclude that SNO-Hb transduces the integrated, system-wide response to hypoxia in the mammalian respiratory cycle, expanding a core physiological principle.
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Affiliation(s)
- Rongli Zhang
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, United States of America
| | - Alfred Hausladen
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, United States of America
| | - Zhaoxia Qian
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, United States of America
| | - Xudong Liao
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, United States of America
| | - Richard T Premont
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, United States of America
| | - Jonathan S Stamler
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, United States of America
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16
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Kosmachevskaya OV, Nasybullina EI, Shumaev KB, Topunov AF. Expressed Soybean Leghemoglobin: Effect on Escherichia coli at Oxidative and Nitrosative Stress. Molecules 2021; 26:7207. [PMID: 34885789 PMCID: PMC8659191 DOI: 10.3390/molecules26237207] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 11/17/2022] Open
Abstract
Leghemoglobin (Lb) is an oxygen-binding plant hemoglobin of legume nodules, which participates in the symbiotic nitrogen fixation process. Another way to obtain Lb is its expression in bacteria, yeasts, or other organisms. This is promising for both obtaining Lb in the necessary quantity and scrutinizing it in model systems, e.g., its interaction with reactive oxygen (ROS) and nitrogen (RNS) species. The main goal of the work was to study how Lb expression affected the ability of Escherichia coli cells to tolerate oxidative and nitrosative stress. The bacterium E. coli with the embedded gene of soybean leghemoglobin a contains this protein in an active oxygenated state. The interaction of the expressed Lb with oxidative and nitrosative stress inducers (nitrosoglutathione, tert-butyl hydroperoxide, and benzylviologen) was studied by enzymatic methods and spectrophotometry. Lb formed NO complexes with heme-nitrosylLb or nonheme iron-dinitrosyl iron complexes (DNICs). The formation of Lb-bound DNICs was also detected by low-temperature electron paramagnetic resonance spectroscopy. Lb displayed peroxidase activity and catalyzed the reduction of organic peroxides. Despite this, E. coli-synthesized Lb were more sensitive to stress inducers. This might be due to the energy demand required by the Lb synthesis, as an alien protein consumes bacterial resources and thereby decreases adaptive potential of E. coli.
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Affiliation(s)
| | | | | | - Alexey F. Topunov
- Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 119071 Moscow, Russia; (O.V.K.); (E.I.N.); (K.B.S.)
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17
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Piknova B, Schechter AN, Park JW, Vanhatalo A, Jones AM. Skeletal Muscle Nitrate as a Regulator of Systemic Nitric Oxide Homeostasis. Exerc Sport Sci Rev 2021; 50:2-13. [PMID: 34669624 DOI: 10.1249/jes.0000000000000272] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
ABSTRACT Non-enzymatic nitric oxide (NO) generation via the reduction of nitrate and nitrite ions, along with remarkably high levels of nitrate ions in skeletal muscle, have been recently described. Skeletal muscle nitrate storage may be critical for maintenance of NO homeostasis in healthy ageing and nitrate supplementation may be useful for treatment of specific pathophysiologies as well as enhancing normal functions.
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Affiliation(s)
- Barbora Piknova
- Molecular Medicine Branch, NIDDK, National Institutes of Health,Bethesda, MD 20892, U.S. Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK
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18
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Zhang Q, Meyerhoff ME. Nitric Oxide Release for Enhanced Biocompatibility and Analytical Performance of Implantable Electrochemical Sensors. ELECTROANAL 2021. [DOI: 10.1002/elan.202100174] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Qi Zhang
- Department of Chemistry University of Michigan Ann Arbor MI 48109 USA
| | - Mark E. Meyerhoff
- Department of Chemistry University of Michigan Ann Arbor MI 48109 USA
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19
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Bhatia V, Elnagary L, Dakshinamurti S. Tracing the path of inhaled nitric oxide: Biological consequences of protein nitrosylation. Pediatr Pulmonol 2021; 56:525-538. [PMID: 33289321 DOI: 10.1002/ppul.25201] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/28/2020] [Accepted: 11/29/2020] [Indexed: 12/12/2022]
Abstract
Nitric oxide (NO) is a comprehensive regulator of vascular and airway tone. Endogenous NO produced by nitric oxide synthases regulates multiple signaling cascades, including activation of soluble guanylate cyclase to generate cGMP, relaxing smooth muscle cells. Inhaled NO is an established therapy for pulmonary hypertension in neonates, and has been recently proposed for the treatment of hypoxic respiratory failure and acute respiratory distress syndrome due to COVID-19. In this review, we summarize the effects of endogenous and exogenous NO on protein S-nitrosylation, which is the selective and reversible covalent attachment of a nitrogen monoxide group to the thiol side chain of cysteine. This posttranslational modification targets specific cysteines based on the acid/base sequence of surrounding residues, with significant impacts on protein interactions and function. S-nitrosothiol (SNO) formation is tightly compartmentalized and enzymatically controlled, but also propagated by nonenzymatic transnitrosylation of downstream protein targets. Redox-based nitrosylation and denitrosylation pathways dynamically regulate the equilibrium of SNO-proteins. We review the physiological roles of SNO proteins, including nitrosohemoglobin and autoregulation of blood flow through hypoxic vasodilation, and pathological effects of nitrosylation including inhibition of critical vasodilator enzymes; and discuss the intersection of NO source and dose with redox environment, in determining the effects of protein nitrosylation.
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Affiliation(s)
- Vikram Bhatia
- Biology of Breathing Group, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
| | - Lara Elnagary
- Biology of Breathing Group, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
| | - Shyamala Dakshinamurti
- Biology of Breathing Group, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada.,Section of Neonatology, Departments of Pediatrics and Physiology, University of Manitoba, Winnipeg, Canada
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20
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Lichota A, Szewczyk EM, Gwozdzinski K. Factors Affecting the Formation and Treatment of Thrombosis by Natural and Synthetic Compounds. Int J Mol Sci 2020; 21:E7975. [PMID: 33121005 PMCID: PMC7663413 DOI: 10.3390/ijms21217975] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022] Open
Abstract
Venous thromboembolism (VTE) refers to deep vein thrombosis (DVT), whose consequence may be a pulmonary embolism (PE). Thrombosis is associated with significant morbidity and mortality and is the third most common cardiovascular disease after myocardial infarction and stroke. DVT is associated with the formation of a blood clot in a deep vein in the body. Thrombosis promotes slowed blood flow, hypoxia, cell activation, and the associated release of many active substances involved in blood clot formation. All thrombi which adhere to endothelium consist of fibrin, platelets, and trapped red and white blood cells. In this review, we summarise the impact of various factors affecting haemostatic disorders leading to blood clot formation. The paper discusses the causes of thrombosis, the mechanism of blood clot formation, and factors such as hypoxia, the involvement of endothelial cells (ECs), and the activation of platelets and neutrophils along with the effects of bacteria and reactive oxygen species (ROS). Mechanisms related to the action of anticoagulants affecting coagulation factors including antiplatelet drugs have also been discussed. However, many aspects related to the pathogenesis of thrombosis still need to be clarified. A review of the drugs used to treat and prevent thrombosis and natural anticoagulants that occur in the plant world and are traditionally used in Far Eastern medicine has also been carried out.
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Affiliation(s)
- Anna Lichota
- Department of Pharmaceutical Microbiology and Microbiological Diagnostic, Faculty of Pharmacy, Medical University of Lodz, 90-235 Lodz, Poland; (A.L.); (E.M.S.)
| | - Eligia M. Szewczyk
- Department of Pharmaceutical Microbiology and Microbiological Diagnostic, Faculty of Pharmacy, Medical University of Lodz, 90-235 Lodz, Poland; (A.L.); (E.M.S.)
| | - Krzysztof Gwozdzinski
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
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21
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Durnin L, Kurahashi M, Sanders KM, Mutafova-Yambolieva VN. Extracellular metabolism of the enteric inhibitory neurotransmitter β-nicotinamide adenine dinucleotide (β-NAD) in the murine colon. J Physiol 2020; 598:4509-4521. [PMID: 32735345 DOI: 10.1113/jp280051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/20/2020] [Indexed: 12/16/2022] Open
Abstract
KEY POINTS β-Nicotinamide adenine dinucleotide (β-NAD) is a key inhibitory neurotransmitter in the colon. The neuroeffector junction in the gut consists of enteric motor neurons and SIP syncytium, including smooth muscle cells (SMCs), interstitial cells of Cajal (ICC), and cells expressing platelet-derived growth factor receptor α (PDGFRα+ cells). Measuring metabolism of 1,N6 -etheno-NAD (eNAD) in colonic tunica muscularis and in SMCs, ICC and PDGFRα+ cells with HPLC-FLD, we report that (1) in tissues, eNAD is degraded to eADP-ribose, eAMP and e-adenosine (eADO) by CD38, ENPP1 and NT5E, (2) with SMCs and PDGFRα+ cells, eNAD is metabolized to eADO by ENPP1 and NT5E, (3) eNAD is not metabolized by ICC, (4) NT5E is expressed chiefly by SMCs and moderately by PDGFRα+ cells, (5) SIP cells are not the primary location of CD38. These data argue that the duration and strength of purinergic neurotransmission can be modulated by targeting multiple enzymes with specialized cellular distribution in the colon. ABSTRACT Prior studies suggest that β-nicotinamide adenine dinucleotide (β-NAD) is an important inhibitory motor neurotransmitter in the enteric nervous system. Metabolism of β-NAD at the neuroeffector junction (NEJ) is likely to be necessary for terminating inhibitory neurotransmission and may also produce bioactive metabolites. The enteric NEJ consists of enteric neurons and postjunctional cells of the SIP syncytium, including smooth muscle cells (SMCs), interstitial cells of Cajal (ICC), and cells expressing platelet-derived growth factor receptor α (PDGFRα+ cells). We examined possible specialized functions of the NEJ in β-NAD metabolism by determining the degradation of 1,N6 -etheno-NAD (eNAD) in colonic tunica muscularis of wild-type, Cd38-/- , Nt5e-/- , Enpp1-/- and Cd38-/- /Nt5e-/- mice and in SIP cells from mice expressing cell-specific fluorescent reporters purified by fluorescence activated cell sorting (FACS). We measured eNAD and its metabolites eADP-ribose (eADPR), eAMP and e-adenosine (eADO) from tissues and sorted SIP cells using liquid chromatography. eNAD exposed to colonic muscularis of wild-type mice produced eADPR, eAMP and eADO. CD38 mediated the conversion of eNAD to eADPR, whereas ENPP1 mediated degradation of eNAD and eADPR to eAMP. NT5E (aka CD73) was the primary enzyme forming eADO from eAMP. PDGFRα+ cells and SMCs were involved in production of eADO from eNAD, and ICC were not involved in extracellular metabolism of eNAD. CD38 mediated the eNAD metabolism in whole tissues, but CD38 did not appear to be functionally expressed by SMCs or ICC. NT5E was expressed in SMCs > PDGFRα+ cells. Our data show that extracellular metabolism of β-NAD in the colon is mediated by multiple enzymes with cell-specific expression.
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Affiliation(s)
- Leonie Durnin
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, Reno, NV, 89557, USA
| | - Masaaki Kurahashi
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, Reno, NV, 89557, USA
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, Reno, NV, 89557, USA
| | - Violeta N Mutafova-Yambolieva
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, Reno, NV, 89557, USA
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22
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Haselden WD, Kedarasetti RT, Drew PJ. Spatial and temporal patterns of nitric oxide diffusion and degradation drive emergent cerebrovascular dynamics. PLoS Comput Biol 2020; 16:e1008069. [PMID: 32716940 PMCID: PMC7410342 DOI: 10.1371/journal.pcbi.1008069] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 08/06/2020] [Accepted: 06/17/2020] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) is a gaseous signaling molecule that plays an important role in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle surrounding cerebral arterioles, driving vasodilation. However, the rate of NO degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how this might impact NO signaling dynamics is not completely understood. We used simulations to investigate how the spatial and temporal patterns of NO generation and degradation impacted dilation of a penetrating arteriole in cortex. We found that the spatial location of NO production and the size of the vessel both played an important role in determining its responsiveness to NO. The much higher rate of NO degradation and scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. Large vasodilation events could be followed by post-stimulus constrictions driven by the increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations could also be generated. We found that these dynamics could be enhanced by elevation of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle cell anemia, or following blood transfusions. Finally, we show that changes in blood flow during hypoxia or hyperoxia could be explained by altered NO degradation in the parenchyma. Our simulations suggest that many common vascular dynamics may be emergent phenomena generated by NO degradation by the blood or parenchyma.
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Affiliation(s)
- William Davis Haselden
- Neuroscience Graduate Program, MD/PhD Medical Scientist Training Program, Pennsylvania State University, University Park, Pennsylvania, United States of America
- Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Ravi Teja Kedarasetti
- Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Patrick J. Drew
- Neuroscience Graduate Program, MD/PhD Medical Scientist Training Program, Pennsylvania State University, University Park, Pennsylvania, United States of America
- Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, Pennsylvania, United States of America
- Departments of Biomedical Engineering and Neurosurgery, Pennsylvania State University, University Park, Pennsylvania, United States of America
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23
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V. Pinto R, Antunes F, Pires J, Silva-Herdade A, Pinto ML. A Comparison of Different Approaches to Quantify Nitric Oxide Release from NO-Releasing Materials in Relevant Biological Media. MOLECULES (BASEL, SWITZERLAND) 2020; 25:molecules25112580. [PMID: 32498254 PMCID: PMC7321377 DOI: 10.3390/molecules25112580] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/25/2020] [Accepted: 05/29/2020] [Indexed: 01/08/2023]
Abstract
The development of solid materials that deliver nitric oxide (NO) are of interest for several therapeutic applications. Nevertheless, due to NO’s reactive nature, rapid diffusion and short half-life, reporting their NO delivery characteristics is rather complex. The full knowledge of this parameter is fundamental to discuss the therapeutic utility of these materials, and thus, the NO quantification strategy must be carefully considered according to the NO-releasing scaffold type, to the expected NO-releasing amounts and to the medium of quantification. In this work, we explore and discuss three different ways of quantifying the release of NO in different biological fluids: haemoglobin assay, Griess assay and NO electrochemical detection. For these measurements, different porous materials, namely zeolites and titanosilicates were used as models for NO-releasing platforms. The oxyhaemoglobin assay offers great sensitivity (nanomolar levels), but it is only possible to monitor the NO release while oxyhaemoglobin is not fully converted. On the other hand, Griess assay has low sensitivity in complex biological media, namely in blood, and interferences with media make NO measurements questionable. Nevertheless, this method can measure micromolar amounts of NO and may be useful for an initial screening for long-term release performance. The electrochemical sensor enabled real-time measurements in a variety of biological settings. However, measured NO is critically low in oxygenated and complex media, giving transient signals, which makes long-term quantification impossible. Despite the disadvantages of each method, the combination of all the results provided a more comprehensive NO release profile for these materials, which will help to determine which formulations are most promising for specific therapeutic applications. This study highlights the importance of using appropriate NO quantification tools to provide accurate reports.
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Affiliation(s)
- Rosana V. Pinto
- CERENA. Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal;
- Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal; (F.A.); (J.P.)
| | - Fernando Antunes
- Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal; (F.A.); (J.P.)
| | - João Pires
- Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal; (F.A.); (J.P.)
| | - Ana Silva-Herdade
- Instituto de Bioquímica, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;
| | - Moisés L. Pinto
- CERENA. Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal;
- Correspondence:
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24
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Zhang Q, Stachelek SJ, Inamdar VV, Alferiev I, Nagaswami C, Weisel JW, Hwang JH, Meyerhoff ME. Studies of combined NO-eluting/CD47-modified polyurethane surfaces for synergistic enhancement of biocompatibility. Colloids Surf B Biointerfaces 2020; 192:111060. [PMID: 32450498 PMCID: PMC7572543 DOI: 10.1016/j.colsurfb.2020.111060] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 03/15/2020] [Accepted: 04/13/2020] [Indexed: 12/22/2022]
Abstract
The blood compatibility of various intravascular (IV) devices (e.g., catheters, sensors, etc.) is compromised by activation of platelets that can cause thrombus formation and device failure. Such devices also carry a high risk of microbial infection. Recently, nitric oxide (NO) releasing polymers/devices have been proposed to reduce these clinical problems. CD47, a ubiquitously expressed transmembrane protein with proven anti-inflammation/anti-platelet properties when immobilized on polymeric surfaces, is a good candidate to complement NO release in both effectiveness and longevity. In this work, we successfully appended CD47 peptides (pepCD47) to the surface of biomedical grade polyurethane (PU) copolymers. SIRPα binding and THP-1 cell attachment experiments strongly suggested that the pepCD47 retains its biological properties when bound to PU films. In spite of the potentially high reactivity of NO toward various amino acid residues in CD47, the efficacy of surface-immobilized pepCD47 to prevent inflammatory cell attachment was not inhibited after being subjected to a high flux of NO for three days, demonstrating excellent compatibility of the two species. We further constructed a CD47 surface immobilized silicone tubing filled with NO releasing S-nitrosoglutathione/ascorbic acid (GSNO/AA) solution for synergistic biocompatibility evaluation. Via an ex vivo Chandler loop model, we demonstrate for the first time that NO release and CD47 modification could function synergistically at the blood/material interface and produce greatly enhanced anti-inflammatory/anti-platelet effects. This concept should be readily implementable to create a new generation of thromboresistant/antimicrobial implantable devices.
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Affiliation(s)
- Qi Zhang
- Department of Chemistry, The University of Michigan, Ann Arbor, MI 48109-1055, United States
| | - Stanley J Stachelek
- Division of Cardiology-Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States; Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, 19104, United States
| | - Vaishali V Inamdar
- Division of Cardiology-Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States; Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, 19104, United States
| | - Ivan Alferiev
- Division of Cardiology-Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States; Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, 19104, United States
| | - Chandrasekaran Nagaswami
- Department of Cell and Developmental Biology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, 19104, United States
| | - John W Weisel
- Department of Cell and Developmental Biology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, 19104, United States
| | - Jeong Hyun Hwang
- Department of Chemistry, The University of Michigan, Ann Arbor, MI 48109-1055, United States
| | - Mark E Meyerhoff
- Department of Chemistry, The University of Michigan, Ann Arbor, MI 48109-1055, United States
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25
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Pokidova O, Rudneva T, Tretyakov B, Kotelnikova R, Kotelnikov A, Aldoshin S. Influence of hemoglobin and albumin on the NO donation effect of tetranitrosyl iron complex with thiosulfate. Nitric Oxide 2020; 94:69-72. [PMID: 31678147 DOI: 10.1016/j.niox.2019.10.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/15/2019] [Accepted: 10/29/2019] [Indexed: 01/15/2023]
Abstract
The effects of deoxyhemoglobin (Hb) and albumin on the NO-donor activity of the anionic tetranitrosyl iron complex with thiosulfate ligands (1) were studied for the first time. It was shown that Hb significantly stabilizes complex 1; in its presence, NO generation from the complex proceeds at a noticeably slower rate. A similar effect is observed when complex 1 is bound to albumin, in which case complex 1 decomposes 27 times slower than in the absence of albumin in the solution. The observed effects provide a prolonged action of complex 1 as NO-donor, which may enhance its potential pharmacological efficacy.
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Affiliation(s)
- Olesya Pokidova
- Institute of Problems of Chemical Physics of the RAS, Chernogolovka, Moscow Region, 142432, Russian Federation.
| | - Tatiana Rudneva
- Institute of Problems of Chemical Physics of the RAS, Chernogolovka, Moscow Region, 142432, Russian Federation
| | - Bogdan Tretyakov
- Lomonosov Moscow State University, Moscow, 119991, Russian Federation
| | - Raisa Kotelnikova
- Institute of Problems of Chemical Physics of the RAS, Chernogolovka, Moscow Region, 142432, Russian Federation
| | - Alexander Kotelnikov
- Institute of Problems of Chemical Physics of the RAS, Chernogolovka, Moscow Region, 142432, Russian Federation; Lomonosov Moscow State University, Moscow, 119991, Russian Federation
| | - Sergey Aldoshin
- Institute of Problems of Chemical Physics of the RAS, Chernogolovka, Moscow Region, 142432, Russian Federation; Lomonosov Moscow State University, Moscow, 119991, Russian Federation
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26
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Schmitt G, Birke J, Jendrossek D. Towards the understanding of the enzymatic cleavage of polyisoprene by the dihaem-dioxygenase RoxA. AMB Express 2019; 9:166. [PMID: 31624946 PMCID: PMC6797691 DOI: 10.1186/s13568-019-0888-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 09/28/2019] [Indexed: 12/27/2022] Open
Abstract
Utilization of polyisoprene (natural rubber) as a carbon source by Steroidobacter cummioxidans 35Y (previously Xanthomonas sp. strain 35Y) depends on the formation and secretion of rubber oxygenase A (RoxA). RoxA is a dioxygenase that cleaves polyisoprene to 12-oxo-4,8-dimethyl-trideca-4,8-diene-1-al (ODTD), a suitable growth substrate for S. cummioxidans. RoxA harbours two non-equivalent, spectroscopically distinguishable haem centres. A dioxygen molecule is bound to the N-terminal haem of RoxA and identifies this haem as the active site. In this study, we provide insights into the nature of this unusually stable dioxygen-haem coordination of RoxA by a re-evaluation of previously published together with newly obtained biophysical data on the cleavage of polyisoprene by RoxA. In combination with the meanwhile available structure of RoxA we are now able to explain several uncommon and previously not fully understood features of RoxA, the prototype of rubber oxygenases in Gram-negative rubber-degrading bacteria.
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Affiliation(s)
- Georg Schmitt
- Institute of Microbiology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Jakob Birke
- Institute of Microbiology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
- Institute of Applied Biotechnology, University of Applied Sciences Biberach, Hubertus-Liebrecht-Strasse 35, 88400, Biberach, Germany
| | - Dieter Jendrossek
- Institute of Microbiology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
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Premont RT, Reynolds JD, Zhang R, Stamler JS. Role of Nitric Oxide Carried by Hemoglobin in Cardiovascular Physiology: Developments on a Three-Gas Respiratory Cycle. Circ Res 2019; 126:129-158. [PMID: 31590598 DOI: 10.1161/circresaha.119.315626] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A continuous supply of oxygen is essential for the survival of multicellular organisms. The understanding of how this supply is regulated in the microvasculature has evolved from viewing erythrocytes (red blood cells [RBCs]) as passive carriers of oxygen to recognizing the complex interplay between Hb (hemoglobin) and oxygen, carbon dioxide, and nitric oxide-the three-gas respiratory cycle-that insures adequate oxygen and nutrient delivery to meet local metabolic demand. In this context, it is blood flow and not blood oxygen content that is the main driver of tissue oxygenation by RBCs. Herein, we review the lines of experimentation that led to this understanding of RBC function; from the foundational understanding of allosteric regulation of oxygen binding in Hb in the stereochemical model of Perutz, to blood flow autoregulation (hypoxic vasodilation governing oxygen delivery) observed by Guyton, to current understanding that centers on S-nitrosylation of Hb (ie, S-nitrosohemoglobin; SNO-Hb) as a purveyor of oxygen-dependent vasodilatory activity. Notably, hypoxic vasodilation is recapitulated by native S-nitrosothiol (SNO)-replete RBCs and by SNO-Hb itself, whereby SNO is released from Hb and RBCs during deoxygenation, in proportion to the degree of Hb deoxygenation, to regulate vessels directly. In addition, we discuss how dysregulation of this system through genetic mutation in Hb or through disease is a common factor in oxygenation pathologies resulting from microcirculatory impairment, including sickle cell disease, ischemic heart disease, and heart failure. We then conclude by identifying potential therapeutic interventions to correct deficits in RBC-mediated vasodilation to improve oxygen delivery-steps toward effective microvasculature-targeted therapies. To the extent that diseases of the heart, lungs, and blood are associated with impaired tissue oxygenation, the development of new therapies based on the three-gas respiratory system have the potential to improve the well-being of millions of patients.
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Affiliation(s)
- Richard T Premont
- From the Institute for Transformative Molecular Medicine (R.T.P., J.D.R., R.Z., J.S.S.), Case Western Reserve University School of Medicine, OH.,Harrington Discovery Institute (R.T.P., J.D.R., J.S.S.), University Hospitals Cleveland Medical Center, OH
| | - James D Reynolds
- From the Institute for Transformative Molecular Medicine (R.T.P., J.D.R., R.Z., J.S.S.), Case Western Reserve University School of Medicine, OH.,Department of Anesthesiology and Perioperative Medicine (J.D.R.), Case Western Reserve University School of Medicine, OH.,Harrington Discovery Institute (R.T.P., J.D.R., J.S.S.), University Hospitals Cleveland Medical Center, OH
| | - Rongli Zhang
- From the Institute for Transformative Molecular Medicine (R.T.P., J.D.R., R.Z., J.S.S.), Case Western Reserve University School of Medicine, OH.,Department of Medicine, Cardiovascular Research Institute (R.Z., J.S.S.), Case Western Reserve University School of Medicine, OH
| | - Jonathan S Stamler
- From the Institute for Transformative Molecular Medicine (R.T.P., J.D.R., R.Z., J.S.S.), Case Western Reserve University School of Medicine, OH.,Department of Medicine, Cardiovascular Research Institute (R.Z., J.S.S.), Case Western Reserve University School of Medicine, OH.,Harrington Discovery Institute (R.T.P., J.D.R., J.S.S.), University Hospitals Cleveland Medical Center, OH
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Vishwakarma A, Wany A, Pandey S, Bulle M, Kumari A, Kishorekumar R, Igamberdiev AU, Mur LAJ, Gupta KJ. Current approaches to measure nitric oxide in plants. JOURNAL OF EXPERIMENTAL BOTANY 2019; 70:4333-4343. [PMID: 31106826 PMCID: PMC6736158 DOI: 10.1093/jxb/erz242] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Accepted: 05/14/2019] [Indexed: 05/20/2023]
Abstract
Nitric oxide (NO) is now established as an important signalling molecule in plants where it influences growth, development, and responses to stress. Despite extensive research, the most appropriate methods to measure and localize these signalling radicals are debated and still need investigation. Many confounding factors such as the presence of other reactive intermediates, scavenging enzymes, and compartmentation influence how accurately each can be measured. Further, these signalling radicals have short half-lives ranging from seconds to minutes based on the cellular redox condition. Hence, it is necessary to use sensitive and specific methods in order to understand the contribution of each signalling molecule to various biological processes. In this review, we summarize the current knowledge on NO measurement in plant samples, via various methods. We also discuss advantages, limitations, and wider applications of each method.
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Affiliation(s)
| | - Aakanksha Wany
- National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India
| | - Sonika Pandey
- National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India
| | - Mallesham Bulle
- National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India
| | - Aprajita Kumari
- National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India
| | - Reddy Kishorekumar
- National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India
| | - Abir U Igamberdiev
- Department of Biology, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Luis A J Mur
- Institute of Environmental and Rural Science, Aberystwyth University, Edward Llwyd Building, Aberystwyth, UK
| | - Kapuganti Jagadis Gupta
- National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India
- Correspondence:
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Oxygen dissociation from ferrous oxygenated human hemoglobin:haptoglobin complexes confirms that in the R-state α and β chains are functionally heterogeneous. Sci Rep 2019; 9:6780. [PMID: 31043649 PMCID: PMC6494993 DOI: 10.1038/s41598-019-43190-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 04/15/2019] [Indexed: 01/25/2023] Open
Abstract
The adverse effects of extra-erythrocytic hemoglobin (Hb) are counterbalanced by several plasma proteins devoted to facilitate the clearance of free heme and Hb. In particular, haptoglobin (Hp) traps the αβ dimers of Hb, which are delivered to the reticulo-endothelial system by CD163 receptor-mediated endocytosis. Since Hp:Hb complexes show heme-based reactivity, kinetics of O2 dissociation from the ferrous oxygenated human Hp1-1:Hb and Hp2-2:Hb complexes (Hp1-1:Hb(II)-O2 and Hp2-2:Hb(II)-O2, respectively) have been determined. O2 dissociation from Hp1-1:Hb(II)-O2 and Hp2-2:Hb(III)-O2 follows a biphasic process. The relative amplitude of the fast and slow phases ranges between 0.47 and 0.53 of the total amplitude, with values of koff1 (ranging between 25.6 ± 1.4 s-1 and 29.1 ± 1.3 s-1) being about twice faster than those of koff2 (ranging between 13.8 ± 1.6 s-1 and 16.1 ± 1.2 s-1). Values of koff1 and koff2 are essentially the same independently on whether O2 dissociation has been followed after addition of a dithionite solution or after O2 displacement by a CO solution in the presence of dithionite. They correspond to those reported for the dissociation of the first O2 molecule from tetrameric Hb(II)-O2, indicating that in the R-state α and β chains are functionally heterogeneous and the tetramer and the dimer behave identically. Accordingly, the structural conformation of the α and β chains of the Hb dimer bound to Hp corresponds to that of the subunits of the Hb tetramer in the R-state.
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30
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Dybas J, Berkowicz P, Proniewski B, Dziedzic-Kocurek K, Stanek J, Baranska M, Chlopicki S, Marzec KM. Spectroscopy-based characterization of Hb-NO adducts in human red blood cells exposed to NO-donor and endothelium-derived NO. Analyst 2019; 143:4335-4346. [PMID: 30109873 DOI: 10.1039/c8an00302e] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The work presents the complementary approach to characterize the formation of various Hb species inside isolated human RBCs exposed to NO, with a focus on the formed Hb-NO adducts. This work presents a complementary approach based on Resonance Raman Spectroscopy (RRS) supported by Blood Gas Analysis, Electron Paramagnetic Resonance Spectroscopy, UV-Vis Absorption Spectroscopy and Mössbauer Spectroscopy to characterize the formation of various Hb species, with a focus on the Hb-NO adducts formed inside isolated human RBCs exposed to NO, under the experimental conditions of low and high levels of oxygen Hb saturation. In the present work, we induced Hb-NO adducts using PAPA-NONOate, a NO-donor with known chemistry and kinetics of NO release, and confirmed the formation of Hb-NO adducts in RBCs incubated with Human Aortic Endothelial Cells (HAECs) stimulated to produce NO. Our results provide a new insight into the formation of Hb-NO adducts after the exposure of RBCs with high oxyHb content to exogenous NO with special attention to the formation of LSHbIIINO in addition to LSHbIINO and metHb (HS/LSHbIIIH2O). We also point out that reliable characterization of Hb-NO adducts requires complementary techniques. Among them, RRS, as a label-free and non-destructive tool, appears to be an important discrimination technique in the studies of Hb-NO adducts inside intact RBCs.
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Affiliation(s)
- Jakub Dybas
- Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland
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31
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Goodwin JM, Chrestensen CA, Moomaw EW. Detection of Nitric Oxide by Membrane Inlet Mass Spectrometry. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2019; 1747:35-47. [PMID: 29600449 DOI: 10.1007/978-1-4939-7695-9_4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Membrane inlet mass spectrometry (MIMS) is a reproducible and reliable method for the measurement of nitric oxide in aqueous solution with a lower limit of detection of 10 nM and a linear response to 50 μM. MIMS utilizes a semipermeable membrane to partition analytes based on physicochemical properties from the bulk sample into the mass spectrometer. Silastic tubing allows the introduction of small gaseous molecules including nitric oxide (NO) into the high vacuum of a mass spectrometer. We describe the measurement of NO generated chemically from nitrite and MAHMA NONOate as well as enzymatically by nitric oxide synthase (NOS).
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Affiliation(s)
- John M Goodwin
- Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA, USA
| | - Carol A Chrestensen
- Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA, USA
| | - Ellen W Moomaw
- Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA, USA.
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32
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Khirfan G, Ahmed MK, Faulx MD, Dakkak W, Dweik RA, Tonelli AR. Gasometric gradients between blood obtained from the pulmonary artery wedge and pulmonary artery positions in pulmonary arterial hypertension. Respir Res 2019; 20:6. [PMID: 30621691 PMCID: PMC6325872 DOI: 10.1186/s12931-018-0969-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 12/20/2018] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Little is known on the pulmonary gradients of oxyhemoglobin, carboxyhemoglobin and methemoglobin in pulmonary arterial hypertension (PAH). We sought to determine these gradients in group 1 PAH and assess their association with disease severity and survival. METHODS During right heart catheterization (RHC) we obtained blood from pulmonary artery (PA) and pulmonary artery wedge (PAW) positions and used co-oximetry to test their gasometric differences. RESULTS We included a total of 130 patients, 65 had group 1 PAH, 40 had pulmonary hypertension (PH) from groups 2-5 and 25 had no PH during RHC. In all groups, PAW blood had higher pH, carboxyhemoglobin and lactate as well as lower pCO2 than PA blood. In group 1 PAH (age 58 ± 15 years, 72% females), methemoglobin in the PAW was lower than in the PA blood (0.83% ± 0.43 vs 0.95% ± 0.50, p = 0.03) and was directly associated with the degree of change in pulmonary vascular resistance (R = 0.35, p = 0.02) during inhaled nitric oxide test. Oxyhemoglobin in PA (HR (95%CI): 0.90 (0.82-0.99), p = 0.04) and PAW (HR (95%CI): 0.91 (0.84-0.98), p = 0.003) blood was associated with adjusted survival in PAH. CONCLUSIONS Marked differences were observed in the gasometric determinations between PAW and PA blood. The pulmonary gradient of methemoglobin was lower in PAH patients compared to controls and a higher PAW blood methemoglobin was associated with a more pronounced pulmonary vascular response to inhaled nitric oxide. Pulmonary artery and PAW oxyhemoglobin tracked with disease severity and survival in PAH.
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Affiliation(s)
- Ghaleb Khirfan
- Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A-90, Cleveland, OH 44195 USA
| | - Mostafa K. Ahmed
- Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A-90, Cleveland, OH 44195 USA
- Department of Chest Diseases, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Michael D. Faulx
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH USA
| | - Wael Dakkak
- Department of Internal Medicine, John H. Stroger Jr. Hospital of Cook County, Chicago, IL USA
| | - Raed A. Dweik
- Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A-90, Cleveland, OH 44195 USA
| | - Adriano R. Tonelli
- Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A-90, Cleveland, OH 44195 USA
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Maia LB, Moura JJG. Putting xanthine oxidoreductase and aldehyde oxidase on the NO metabolism map: Nitrite reduction by molybdoenzymes. Redox Biol 2018; 19:274-289. [PMID: 30196191 PMCID: PMC6129670 DOI: 10.1016/j.redox.2018.08.020] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 08/23/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide radical (NO) is a signaling molecule involved in several physiological and pathological processes and a new nitrate-nitrite-NO pathway has emerged as a physiological alternative to the "classic" pathway of NO formation from L-arginine. Since the late 1990s, it has become clear that nitrite can be reduced back to NO under hypoxic/anoxic conditions and exert a significant cytoprotective action in vivo under challenging conditions. To reduce nitrite to NO, mammalian cells can use different metalloproteins that are present in cells to perform other functions, including several heme proteins and molybdoenzymes, comprising what we denominated as the "non-dedicated nitrite reductases". Herein, we will review the current knowledge on two of those "non-dedicated nitrite reductases", the molybdoenzymes xanthine oxidoreductase and aldehyde oxidase, discussing the in vitro and in vivo studies to provide the current picture of the role of these enzymes on the NO metabolism in humans.
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Affiliation(s)
- Luisa B Maia
- LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.
| | - José J G Moura
- LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
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Ascenzi P, Coletta M. Peroxynitrite Detoxification by Human Haptoglobin:Hemoglobin Complexes: A Comparative Study. J Phys Chem B 2018; 122:11100-11107. [DOI: 10.1021/acs.jpcb.8b05340] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Paolo Ascenzi
- Interdepartmental Laboratory for Electron Microscopy, Roma Tre University, Via della Vasca Navale 79, I-00146 Roma, Italy
| | - Massimo Coletta
- Department of Clinical Sciences and Translational Medicine, University of Roma “Tor Vergata”, Via Montpellier 1, I-00133 Roma, Italy
- Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, Via Celso Ulpiani 27, I-70126 Bari, Italy
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35
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Bender D, Schwarz G. Nitrite-dependent nitric oxide synthesis by molybdenum enzymes. FEBS Lett 2018; 592:2126-2139. [DOI: 10.1002/1873-3468.13089] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 05/02/2018] [Indexed: 01/07/2023]
Affiliation(s)
- Daniel Bender
- Department of Chemistry; Institute for Biochemistry; University of Cologne; Germany
- Center for Molecular Medicine Cologne (CMMC); University of Cologne; Germany
| | - Guenter Schwarz
- Department of Chemistry; Institute for Biochemistry; University of Cologne; Germany
- Center for Molecular Medicine Cologne (CMMC); University of Cologne; Germany
- Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD); University of Cologne; Germany
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36
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Eilertsen M, Allin SM, Pearson RJ. New 4-aryl-1,3,2-oxathiazolylium-5-olates: Chemical synthesis and photochemical stability of a novel series of S-nitrosothiols. Bioorg Med Chem Lett 2018; 28:1106-1110. [PMID: 29482942 DOI: 10.1016/j.bmcl.2018.01.059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 01/25/2018] [Accepted: 01/27/2018] [Indexed: 01/12/2023]
Abstract
S-nitrosothiols (RSNOs) remain one of the most popular classes of NO-donating compounds due to their ability to release nitric oxide (NO) under non-enzymatic means whilst producing an inert disulphide by-product. However, alligning these compounds to the different biological fields of NO research has proved to be problematic due to the inherent instability of such compounds under a variety of conditions including heat, light and the presence of copper ions. 1,3,2-Oxathiazolylium-5-olates (OZOs) represent an interesting subclass of S-nitrosothiols that lock the -SNO moiety into a five membered heterocyclic ring in an attempt to improve the compound's overall stability. The synthesis of a novel series of halogen-containing OZOs was comprehensively studied resulting in a seven-step route and overall yields ranging between 21 and 37%. The photochemical stability of these compounds was assessed to determine if S-nitrosothiols locked within these mesoionic ring systems can offer greater stability and thereby release NO in a more controllable fashion than their non-cyclic counterparts.
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Affiliation(s)
- Monica Eilertsen
- School of Pharmacy, Keele University, Hornbeam Building, Keele, Staffordshire ST5 5BG, UK
| | - Steve M Allin
- Department of Chemistry and Forensics, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
| | - Russell J Pearson
- School of Pharmacy, Keele University, Hornbeam Building, Keele, Staffordshire ST5 5BG, UK.
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Ascenzi P, De Simone G, Polticelli F, Gioia M, Coletta M. Reductive nitrosylation of ferric human hemoglobin bound to human haptoglobin 1-1 and 2-2. J Biol Inorg Chem 2018; 23:437-445. [PMID: 29605886 DOI: 10.1007/s00775-018-1551-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 03/09/2018] [Indexed: 12/22/2022]
Abstract
Haptoglobin (Hp) sequesters hemoglobin (Hb) preventing the Hb-based damage occurring upon its physiological release into plasma. Here, reductive nitrosylation of ferric human hemoglobin [Hb(III)] bound to human haptoglobin (Hp) 1-1 and 2-2 [Hp1-1:Hb(III) and Hp2-2:Hb(III), respectively] has been investigated between pH 7.5 and 9.5, at T=20.0 °C. Over the whole pH range explored, only one process is detected reflecting NO binding to Hp1-1:Hb(III) and Hp2-2:Hb(III). Values of the pseudo-first-order rate constant for Hp1-1:Hb(III) and Hp2-2:Hb(III) nitrosylation (k) do not depend linearly on the ligand concentration but tend to level off. The conversion of Hp1-1:Hb(III)-NO to Hp1-1:Hb(II)-NO and of Hp2-2:Hb(III)-NO to Hp2-2:Hb(II)-NO is limited by the OH-- and H2O-based catalysis. In fact, bimolecular NO binding to Hp1-1:Hb(III), Hp2-2:Hb(III), Hp1-1:Hb(II), and Hp2-2:Hb(II) proceeds very rapidly. The analysis of data allowed to determine the values of the dissociation equilibrium constant for Hp1-1:Hb(III) and Hp2-2:Hb(III) nitrosylation [K = (1.2 ± 0.1) × 10-4 M], which is pH-independent, and of the first-order rate constant for Hp1-1:Hb(III) and Hp2-2:Hb(III) conversion to Hp1-1:Hb(II)-NO and Hp2-2:Hb(II)-NO, respectively (k'). From the dependence of k' on [OH-], values of hOH- [(4.9 ± 0.6) × 103 M-1 s-1 and (6.79 ± 0.7) × 103 M-1 s-1, respectively] and of [Formula: see text] [(2.6 ± 0.3) × 10-3 s-1] were determined. Values of kinetic and thermodynamic parameters for Hp1-1:Hb(III) and Hp2-2:Hb(III) reductive nitrosylation match well with those of the Hb R-state, which is typical of the αβ dimers of Hb bound to Hp.
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Affiliation(s)
- Paolo Ascenzi
- Interdepartmental Laboratory of Electron Microscopy, Roma Tre University, Via Della Vasca Navale 79, 00146, Rome, Italy.
| | - Giovanna De Simone
- Department of Sciences, Roma Tre University, Viale Guglielmo Marconi 446, 00146, Rome, Italy
| | - Fabio Polticelli
- Department of Sciences, Roma Tre University, Viale Guglielmo Marconi 446, 00146, Rome, Italy.,Roma Tre Section, National Institute of Nuclear Physics, Via Della Vasca Navale 84, 00146, Rome, Italy
| | - Magda Gioia
- Department of Clinical Sciences and Translational Medicine, University of Roma "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.,Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, Via Celso Ulpiani 27, 70126, Bari, Italy
| | - Massimo Coletta
- Department of Clinical Sciences and Translational Medicine, University of Roma "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.,Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, Via Celso Ulpiani 27, 70126, Bari, Italy
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Das AK, Meuwly M. Kinetic Analysis and Structural Interpretation of Competitive Ligand Binding for NO Dioxygenation in Truncated Hemoglobin N. Angew Chem Int Ed Engl 2018; 57:3509-3513. [PMID: 29356324 DOI: 10.1002/anie.201711445] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Indexed: 11/06/2022]
Abstract
The conversion of nitric oxide (NO) into nitrate (NO3- ) by dioxygenation protects cells from lethal NO. Starting from NO-bound heme, the first step in converting NO into benign NO3- is the ligand exchange reaction FeNO+O2 →FeO2 +NO, which is still poorly understood at a molecular level. For wild-type (WT) truncated hemoglobin N (trHbN) and its Y33A mutant, the calculated barriers for the exchange reaction differ by 1.5 kcal mol-1 , compared with 1.7 kcal mol-1 from experiment. It is directly confirmed that the ligand exchange reaction is rate-limiting in trHbN and that entropic contributions account for 75 % of the difference between the WT and the mutant. Residues Tyr 33, Phe 46, Val 80, His 81, and Gln 82 surrounding the active site are expected to control the reaction path. By comparison with electronic structure calculations, the transition state separating the two ligand-bound states was assigned to a 2 A state.
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Affiliation(s)
- Akshaya Kumar Das
- Department of Chemistry, University of Basel, Klingelbergstrasse 80, Basel, Switzerland
| | - Markus Meuwly
- Department of Chemistry, University of Basel, Klingelbergstrasse 80, Basel, Switzerland
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39
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Kinetische Analyse und strukturelle Interpretation der kompetitiven Ligandenbindung für Denitrifikation in gekürztem Hämoglobin N. Angew Chem Int Ed Engl 2018. [DOI: 10.1002/ange.201711445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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40
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Ghosh S, Deka H, Dangat YB, Saha S, Gogoi K, Vanka K, Mondal B. Reductive nitrosylation of nickel(ii) complex by nitric oxide followed by nitrous oxide release. Dalton Trans 2018; 45:10200-8. [PMID: 27230278 DOI: 10.1039/c6dt00826g] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Ni(ii) complex of ligand ( = bis(2-ethyl-4-methylimidazol-5-yl)methane) in methanol solution reacts with an equivalent amount of NO resulting in a corresponding Ni(i) complex. Adding further NO equivalent affords a Ni(i)-nitrosyl intermediate with the {NiNO}(10) configuration. This nitrosyl intermediate upon subsequent reaction with additional NO results in the release of N2O and formation of a Ni(ii)-nitrito complex. Crystallographic characterization of the nitrito complex revealed a symmetric η(2)-O,O-nitrito bonding to the metal ion. This study demonstrates the reductive nitrosylation of a Ni(ii) center followed by N2O release in the presence of excess NO.
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Affiliation(s)
- Somnath Ghosh
- Department of Chemsitry, Indian Institute of Technology Guwahati, Assam 781039, India.
| | - Hemanta Deka
- Department of Chemsitry, Indian Institute of Technology Guwahati, Assam 781039, India.
| | - Yuvraj B Dangat
- Academy of Scientific and Innovative Research, National Chemical Laboratory, Pune 411008, Maharashtra, India
| | - Soumen Saha
- Department of Chemsitry, Indian Institute of Technology Guwahati, Assam 781039, India.
| | - Kuldeep Gogoi
- Department of Chemsitry, Indian Institute of Technology Guwahati, Assam 781039, India.
| | - Kumar Vanka
- Academy of Scientific and Innovative Research, National Chemical Laboratory, Pune 411008, Maharashtra, India
| | - Biplab Mondal
- Department of Chemsitry, Indian Institute of Technology Guwahati, Assam 781039, India.
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41
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Gell DA. Structure and function of haemoglobins. Blood Cells Mol Dis 2017; 70:13-42. [PMID: 29126700 DOI: 10.1016/j.bcmd.2017.10.006] [Citation(s) in RCA: 140] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 10/29/2017] [Accepted: 10/30/2017] [Indexed: 12/18/2022]
Abstract
Haemoglobin (Hb) is widely known as the iron-containing protein in blood that is essential for O2 transport in mammals. Less widely recognised is that erythrocyte Hb belongs to a large family of Hb proteins with members distributed across all three domains of life-bacteria, archaea and eukaryotes. This review, aimed chiefly at researchers new to the field, attempts a broad overview of the diversity, and common features, in Hb structure and function. Topics include structural and functional classification of Hbs; principles of O2 binding affinity and selectivity between O2/NO/CO and other small ligands; hexacoordinate (containing bis-imidazole coordinated haem) Hbs; bacterial truncated Hbs; flavohaemoglobins; enzymatic reactions of Hbs with bioactive gases, particularly NO, and protection from nitrosative stress; and, sensor Hbs. A final section sketches the evolution of work on the structural basis for allosteric O2 binding by mammalian RBC Hb, including the development of newer kinetic models. Where possible, reference to historical works is included, in order to provide context for current advances in Hb research.
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Affiliation(s)
- David A Gell
- School of Medicine, University of Tasmania, TAS 7000, Australia.
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42
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Qadri SM, Bissinger R, Solh Z, Oldenborg PA. Eryptosis in health and disease: A paradigm shift towards understanding the (patho)physiological implications of programmed cell death of erythrocytes. Blood Rev 2017; 31:349-361. [PMID: 28669393 DOI: 10.1016/j.blre.2017.06.001] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 05/05/2017] [Accepted: 06/15/2017] [Indexed: 12/19/2022]
Abstract
During the course of their natural ageing and upon injury, anucleate erythrocytes can undergo an unconventional apoptosis-like cell death, termed eryptosis. Eryptotic erythrocytes display a plethora of morphological alterations including volume reduction, membrane blebbing and breakdown of the membrane phospholipid asymmetry resulting in phosphatidylserine externalization which, in turn, mediates their phagocytic recognition and clearance from the circulation. Overall, the eryptosis machinery is tightly orchestrated by a wide array of endogenous mediators, ion channels, membrane receptors, and a host of intracellular signaling proteins. Enhanced eryptosis shortens the lifespan of circulating erythrocytes and confers a procoagulant phenotype; this phenomenon has been tangibly implicated in the pathogenesis of anemia, deranged microcirculation, and increased prothrombotic risk associated with a multitude of clinical conditions. Herein, we reviewed the molecular mechanisms dictating eryptosis and erythrophagocytosis and critically analyzed the current evidence leading to the pathophysiological ramifications of eryptotic cell death in the context of human disease.
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Affiliation(s)
- Syed M Qadri
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; Centre for Innovation, Canadian Blood Services, Hamilton, ON, Canada.
| | - Rosi Bissinger
- Department of Internal Medicine, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Ziad Solh
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; Medical Services and Innovation, Canadian Blood Services, Hamilton, ON, Canada
| | - Per-Arne Oldenborg
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
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43
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Parikh J, Kapela A, Tsoukias NM. Can endothelial hemoglobin-α regulate nitric oxide vasodilatory signaling? Am J Physiol Heart Circ Physiol 2017; 312:H854-H866. [PMID: 28130333 DOI: 10.1152/ajpheart.00315.2016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 01/24/2017] [Accepted: 01/24/2017] [Indexed: 11/22/2022]
Abstract
We used mathematical modeling to investigate nitric oxide (NO)-dependent vasodilatory signaling in the arteriolar wall. Detailed continuum cellular models of calcium (Ca2+) dynamics and membrane electrophysiology in smooth muscle and endothelial cells (EC) were coupled with models of NO signaling and biotransport in an arteriole. We used this theoretical approach to examine the role of endothelial hemoglobin-α (Hbα) as a modulator of NO-mediated myoendothelial feedback, as previously suggested in Straub et al. (Nature 491: 473-477, 2012). The model considers enriched expression of inositol 1,4,5-triphosphate receptors (IP3Rs), endothelial nitric oxide synthase (eNOS) enzyme, Ca2+-activated potassium (KCa) channels and Hbα in myoendothelial projections (MPs) between the two cell layers. The model suggests that NO-mediated myoendothelial feedback is plausible if a significant percentage of eNOS is localized within or near the myoendothelial projection. Model results show that the ability of Hbα to regulate the myoendothelial feedback is conditional to its colocalization with eNOS near MPs at concentrations in the high nanomolar range (>0.2 μM or 24,000 molecules). Simulations also show that the effect of Hbα observed in in vitro experimental studies may overestimate its contribution in vivo, in the presence of blood perfusion. Thus, additional experimentation is required to quantify the presence and spatial distribution of Hbα in the EC, as well as to test that the strong effect of Hbα on NO signaling seen in vitro, translates also into a physiologically relevant response in vivo.NEW & NOTEWORTHY Mathematical modeling shows that although regulation of nitric oxide signaling by hemoglobin-α (Hbα) is plausible, it is conditional to its presence in significant concentrations colocalized with endothelial nitric oxide synthase in myoendothelial projections. Additional experimentation is required to test that the strong effect of Hbα seen in vitro translates into a physiologically relevant response in vivo.
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Affiliation(s)
- Jaimit Parikh
- Department of Biomedical Engineering, Florida International University, Miami, Florida; and
| | - Adam Kapela
- Department of Biomedical Engineering, Florida International University, Miami, Florida; and
| | - Nikolaos M Tsoukias
- Department of Biomedical Engineering, Florida International University, Miami, Florida; and .,School of Chemical Engineering, National Technical University of Athens, Athens, Greece
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44
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Bailey DM, Rasmussen P, Overgaard M, Evans KA, Bohm AM, Seifert T, Brassard P, Zaar M, Nielsen HB, Raven PB, Secher NH. Nitrite and
S
-Nitrosohemoglobin Exchange Across the Human Cerebral and Femoral Circulation. Circulation 2017; 135:166-176. [DOI: 10.1161/circulationaha.116.024226] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 11/02/2016] [Indexed: 12/22/2022]
Abstract
Background:
The mechanisms underlying red blood cell (RBC)–mediated hypoxic vasodilation remain controversial, with separate roles for nitrite (
) and
S
-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O
2
tension and blood flow.
Methods:
Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O
2
) and hypoxic (10% O
2
) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle.
Results:
Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (
P
<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (
P
<0.05 versus rest) in proportion to the reduction in RBC oxygenation (
r
=0.680–0.769,
P
<0.001). Plasma
gradients reflecting consumption (arterial>venous;
P
<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial;
P
<0.05) at rest in normoxia, during hypoxia (
P
<0.05 versus normoxia), and especially during exercise (
P
<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (
P
<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma
S
-nitrosothiols (
P
>0.05).
Conclusions:
These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated
reduction identified as the dominant mechanism underlying hypoxic vasodilation.
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Affiliation(s)
- Damian M. Bailey
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Peter Rasmussen
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Morten Overgaard
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Kevin A. Evans
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Aske M. Bohm
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Thomas Seifert
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Patrice Brassard
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Morten Zaar
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Henning B. Nielsen
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Peter B. Raven
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
| | - Niels H. Secher
- From Faculty of Medicine, Reichwald Health Sciences Centre, University of British Columbia–Okanagan, Kelowna, BC, Canada (D.M.B.); Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Glamorgan, UK (K.A.E.); Department of Anesthesia, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (P.R., M.D., A.M.B., T.S., P.B., M.Z., H.B.N., N.H.S.); Université Laval, Québec, QC, Canada (P.B.); and Department of Integrative Physiology and Anatomy,
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45
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Immunological properties of oxygen-transport proteins: hemoglobin, hemocyanin and hemerythrin. Cell Mol Life Sci 2016; 74:293-317. [PMID: 27518203 PMCID: PMC5219038 DOI: 10.1007/s00018-016-2326-7] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 07/17/2016] [Accepted: 08/03/2016] [Indexed: 01/22/2023]
Abstract
It is now well documented that peptides with enhanced or alternative functionality (termed cryptides) can be liberated from larger, and sometimes inactive, proteins. A primary example of this phenomenon is the oxygen-transport protein hemoglobin. Aside from respiration, hemoglobin and hemoglobin-derived peptides have been associated with immune modulation, hematopoiesis, signal transduction and microbicidal activities in metazoans. Likewise, the functional equivalents to hemoglobin in invertebrates, namely hemocyanin and hemerythrin, act as potent immune effectors under certain physiological conditions. The purpose of this review is to evaluate the true extent of oxygen-transport protein dynamics in innate immunity, and to impress upon the reader the multi-functionality of these ancient proteins on the basis of their structures. In this context, erythrocyte-pathogen antibiosis and the immune competences of various erythroid cells are compared across diverse taxa.
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46
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Tian S, Liu J, Cowley RE, Hosseinzadeh P, Marshall NM, Yu Y, Robinson H, Nilges MJ, Blackburn NJ, Solomon EI, Lu Y. Reversible S-nitrosylation in an engineered azurin. Nat Chem 2016; 8:670-7. [PMID: 27325093 PMCID: PMC4918514 DOI: 10.1038/nchem.2489] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 03/02/2016] [Indexed: 12/20/2022]
Abstract
S-Nitrosothiols are known as reagents for NO storage and transportation and as regulators in many physiological processes. Although the S-nitrosylation catalysed by haem proteins is well known, no direct evidence of S-nitrosylation in copper proteins has been reported. Here, we report reversible insertion of NO into a copper-thiolate bond in an engineered copper centre in Pseudomonas aeruginosa azurin by rational design of the primary coordination sphere and tuning its reduction potential by deleting a hydrogen bond in the secondary coordination sphere. The results not only provide the first direct evidence of S-nitrosylation of Cu(II)-bound cysteine in metalloproteins, but also shed light on the reaction mechanism and structural features responsible for stabilizing the elusive Cu(I)-S(Cys)NO species. The fast, efficient and reversible S-nitrosylation reaction is used to demonstrate its ability to prevent NO inhibition of cytochrome bo3 oxidase activity by competing for NO binding with the native enzyme under physiologically relevant conditions.
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Affiliation(s)
- Shiliang Tian
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Jing Liu
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Ryan E. Cowley
- Department of Chemistry, Stanford University, Stanford, California 94305, USA
| | - Parisa Hosseinzadeh
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Nicholas M. Marshall
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Yang Yu
- Center of Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Howard Robinson
- Department of Biology, Brookhaven National Laboratory, Upton, New York 11973, USA
| | - Mark J. Nilges
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Ninian J. Blackburn
- Institute of Environmental Health, Oregon Health & Sciences University, Portland, Oregon 97239, USA
| | - Edward I. Solomon
- Department of Chemistry, Stanford University, Stanford, California 94305, USA
| | - Yi Lu
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Center of Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
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47
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Dumitrescu SD, Meszaros AT, Puchner S, Weidinger A, Boros M, Redl H, Kozlov AV. EPR analysis of extra- and intracellular nitric oxide in liver biopsies. Magn Reson Med 2016; 77:2372-2380. [PMID: 27368066 DOI: 10.1002/mrm.26291] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 05/08/2016] [Accepted: 05/09/2016] [Indexed: 01/26/2023]
Abstract
PURPOSE To develop an assay that can enable the quantification of intra- and extracellular nitric oxide (NO) levels in liver biopsies without application of potentially harmful exogenous NO traps. THEORY Electron paramagnetic resonance (EPR) spectroscopy is currently the most appropriate method of measuring NO in biological samples due to the outstanding specificity resulting from the interaction of NO with exogenous NO traps. Because such traps are not allowed in clinical settings, we tested the reliability of endogenous NO traps for the determination of NO levels in blood and liver compartments. METHODS Rats were injected with 0-8 mg/kg lipopolysaccharide (LPS) to gradually induce a systemic inflammatory response. Specific features of NO-hemoglobin and NO-Fe EPR signals were quantified using a specifically developed calibration procedure. RESULTS Whereas both NO-hemoglobin (NO-HbLIVER BLOOD ) and NO-Fe (NO-FeLIVER ) complexes were detected in nonperfused liver tissue, only NO-Fe complexes were detected in perfused tissue and only NO-Hb complexes were detected in blood (NO-HbBLOOD ). The NO concentrations increased in the sequence NO-HbBLOOD < NO-FeLIVER < NO-HbLIVER BLOOD (9.4, 18.5, 27.9 nmol/cm3 , respectively at 2.5 mg/kg LPS). The detection limit of the method was 0.61 nmol/cm3 for NO-Hb and 0.52 nmol/cm3 for NO-Fe. CONCLUSION The assay reported here does not influence natural NO pathways and enables the quantification of NO distribution in two liver compartments using a single liver biopsy. Magn Reson Med 77:2372-2380, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
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Affiliation(s)
- Sergiu D Dumitrescu
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
| | - Andras T Meszaros
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Institute of Surgical Research, University of Szeged, Szeged, Hungary
| | - Stefan Puchner
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
| | - Adelheid Weidinger
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
| | - Mihaly Boros
- Institute of Surgical Research, University of Szeged, Szeged, Hungary
| | - Heinz Redl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
| | - Andrey V Kozlov
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
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48
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Zajda J, Crist NR, Malinowska E, Meyerhoff ME. Asymmetric Anion-selective Membrane Electrode for Determining Nitric Oxide Release Rates from Ppolymeric Films/Electrochemical Devices. ELECTROANAL 2015. [DOI: 10.1002/elan.201500395] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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49
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50
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Triggers, inhibitors, mechanisms, and significance of eryptosis: the suicidal erythrocyte death. BIOMED RESEARCH INTERNATIONAL 2015; 2015:513518. [PMID: 25821808 PMCID: PMC4364016 DOI: 10.1155/2015/513518] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 01/12/2015] [Accepted: 01/15/2015] [Indexed: 12/13/2022]
Abstract
Suicidal erythrocyte death or eryptosis is characterized by erythrocyte shrinkage, cell membrane blebbing, and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca(2+) entry, ceramide formation, stimulation of caspases, calpain activation, energy depletion, oxidative stress, and dysregulation of several kinases. Eryptosis is triggered by a wide variety of xenobiotics. It is inhibited by several xenobiotics and endogenous molecules including NO and erythropoietin. The susceptibility of erythrocytes to eryptosis increases with erythrocyte age. Phosphatidylserine exposing erythrocytes adhere to the vascular wall by binding to endothelial CXC-Motiv-Chemokin-16/Scavenger-receptor for phosphatidylserine and oxidized low density lipoprotein (CXCL16). Phosphatidylserine exposing erythrocytes are further engulfed by phagocytosing cells and are thus rapidly cleared from circulating blood. Eryptosis eliminates infected or defective erythrocytes thus counteracting parasitemia in malaria and preventing detrimental hemolysis of defective cells. Excessive eryptosis, however, may lead to anemia and may interfere with microcirculation. Enhanced eryptosis contributes to the pathophysiology of several clinical disorders including metabolic syndrome and diabetes, malignancy, cardiac and renal insufficiency, hemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose 6-phosphate dehydrogenase deficiency, and Wilson's disease. Facilitating or inhibiting eryptosis may be a therapeutic option in those disorders.
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