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Bauer N, Mao Q, Vashistha A, Seshadri A, Nancy Du YC, Otterbein L, Tan C, de Caestecker MP, Wang B. Compelling Evidence: A Critical Update on the Therapeutic Potential of Carbon Monoxide. Med Res Rev 2025. [PMID: 40302550 DOI: 10.1002/med.22116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 04/08/2025] [Accepted: 04/11/2025] [Indexed: 05/02/2025]
Abstract
Carbon monoxide (CO) is an endogenous signaling molecule. It is produced via heme degradation by heme oxygenase (HMOX), releasing stoichiometric amounts of CO, iron, and biliverdin (then bilirubin). The HMOX-CO axis has long been shown to offer beneficial effects by modulating inflammation, proliferation and cell death as they relate to tissue and organ protection. Recent years have seen a large number of studies examining CO pharmacology, its molecular targets, cellular mechanisms of action, pharmacokinetics, and detection methods using various delivery modalities including inhaled CO gas, CO solutions, and various types of CO donors. Unfortunately, one widely used donor type includes four commercially available carbonyl complexes with metal or borane, CORM-2 (Ru2+), CORM-3 (Ru2+), CORM-A1 (BH3), and CORM-401 (Mn+), which have been shown to have minimal and/or unpredictable CO production and extensive CO-independent chemical reactivity and biological activity. As a result, not all "CO biological activities" in the literature can be attributed to CO. In this review, we summarize key findings based on CO gas and CO in solution for the certainty of the active principal and to avoid data contamination resulting from the confirmed or potential reactivities and activities of the "carrier" portion of CORMs. Along a similar line, we discuss interesting potential research areas of CO in the brain including a newly proposed CO/HMOX/dopamine axis and the role of CO in cognitive stimulation and circadian rhythm. This review is critical for the future development of the CO field by steering clear of complications caused by chemically reactive donor molecules.
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Affiliation(s)
- Nicola Bauer
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Qiyue Mao
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Aditi Vashistha
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Anupamaa Seshadri
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Yi-Chieh Nancy Du
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, New York, USA
| | - Leo Otterbein
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Chalet Tan
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Mark P de Caestecker
- Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Binghe Wang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
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Zhang JJ, Ye XR, Liu XS, Zhang HL, Qiao Q. Impact of sodium-glucose cotransporter-2 inhibitors on pulmonary vascular cell function and arterial remodeling. World J Cardiol 2025; 17:101491. [PMID: 39866213 PMCID: PMC11755123 DOI: 10.4330/wjc.v17.i1.101491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/02/2024] [Accepted: 12/17/2024] [Indexed: 01/21/2025] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a cutting-edge class of oral antidiabetic therapeutics that operate through selective inhibition of glucose reabsorption in proximal renal tubules, consequently augmenting urinary glucose excretion and attenuating blood glucose levels. Extensive clinical investigations have demonstrated their profound cardiovascular efficacy. Parallel basic science research has elucidated the mechanistic pathways through which diverse SGLT-2 inhibitors beneficially modulate pulmonary vascular cells and arterial remodeling. Specifically, these inhibitors exhibit promising potential in enhancing pulmonary vascular endothelial cell function, suppressing pulmonary smooth muscle cell proliferation and migration, reversing pulmonary arterial remodeling, and maintaining hemodynamic equilibrium. This comprehensive review synthesizes current literature to delineate the mechanisms by which SGLT-2 inhibitors enhance pulmonary vascular cell function and reverse pulmonary remodeling, thereby offering novel therapeutic perspectives for pulmonary vascular diseases.
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Affiliation(s)
- Jing-Jing Zhang
- Chinese Academy Medical Sciences, Fuwai Yunnan Hospital, Kunming 650000, Yunnan Province, China
- Kunming Medical University, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming 650000, Yunnan Province, China
| | - Xue-Rui Ye
- Chinese Academy Medical Sciences, Fuwai Yunnan Hospital, Kunming 650000, Yunnan Province, China
- Kunming Medical University, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming 650000, Yunnan Province, China
| | - Xue-Song Liu
- Department of Biochemistry, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Qian Qiao
- Chinese Academy Medical Sciences, Fuwai Yunnan Hospital, Kunming 650000, Yunnan Province, China
- Kunming Medical University, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming 650000, Yunnan Province, China.
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Hwang H, Lee S, Heo YW, Ha WS, Kim KM, Cha YS. Carbon monoxide poisoning is associated with increased risk of migraine in the long term: a nationwide population-based cohort study. FRONTIERS IN TOXICOLOGY 2025; 7:1532584. [PMID: 39917277 PMCID: PMC11794217 DOI: 10.3389/ftox.2025.1532584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Objective Carbon monoxide poisoning can cause migraine-like attacks. However, the association between carbon monoxide poisoning and the risk of migraine has not been thoroughly studied. This study aimed to investigate the long-term risk of migraine in patients with carbon monoxide poisoning. Methods This nationwide, population-based cohort study was conducted using the administrative database of the National Health Insurance Service of Korea from 2002 to 2021. Patients with carbon monoxide poisoning with at least one visit documented according to the International Classification of Diseases, 10th Revision code T58 were included. Patients were only included if they had the same diagnostic code at two or more outpatient clinic visits. The primary outcome of this study was the incidence of migraine after carbon monoxide poisoning. Results The overall risk of migraine was higher in the carbon monoxide poisoning group regardless of age, sex, or use of hyperbaric oxygen therapy (adjusted hazard ratio, 1.37; 95% confidence interval, 1.28-1.48). The carbon monoxide poisoning group had a persistently higher cumulative incidence of migraine during the observation period than the control group. Conclusion Carbon monoxide poisoning was associated with an increased overall risk of developing migraine during long-term follow-up.
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Affiliation(s)
- Heewon Hwang
- Department of Neurology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Solam Lee
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Yeon-Woo Heo
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Woo-Seok Ha
- Department of Neurology, Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyung Min Kim
- Department of Neurology, Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Sung Cha
- Department of Emergency Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
- Research Institute of Hyperbaric Medicine and Science, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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Zhang H, Li M, Hu CJ, Stenmark KR. Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms. Cells 2024; 13:914. [PMID: 38891046 PMCID: PMC11171669 DOI: 10.3390/cells13110914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing and remodeling extracellular matrixes and organizing functional tissue networks, which are essential for tissue homeostasis and various human diseases. Pulmonary hypertension (PH) is a devastating syndrome with high mortality, characterized by remodeling of the pulmonary vasculature and significant cellular and structural changes within the intima, media, and adventitia layers. Most research on PH has focused on alterations in the intima (endothelial cells) and media (smooth muscle cells). However, research over the past decade has provided strong evidence of the critical role played by pulmonary artery adventitial fibroblasts in PH. These fibroblasts exhibit the earliest, most dramatic, and most sustained proliferative, apoptosis-resistant, and inflammatory responses to vascular stress. This review examines the aberrant phenotypes of PH fibroblasts and their role in the pathogenesis of PH, discusses potential molecular signaling pathways underlying these activated phenotypes, and highlights areas of research that merit further study to identify promising targets for the prevention and treatment of PH.
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Affiliation(s)
- Hui Zhang
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Min Li
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Cheng-Jun Hu
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Craniofacial Biology, University of Colorado School of Dental Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kurt R. Stenmark
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
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Sun Q, He D, Zhang L, Li Z, Qu L, Sun Y. Coumarin-hemicyanine-based far-red to near-infrared fluorescent probes: A new generation of fluorescent probe design platform. Trends Analyt Chem 2023; 167:117272. [DOI: 10.1016/j.trac.2023.117272] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Meservey A, Krishnan G, Green CL, Morrison S, Rackley CR, Kraft BD. U-Shaped Association Between Carboxyhemoglobin and Mortality in Patients With Acute Respiratory Distress Syndrome on Venovenous Extracorporeal Membrane Oxygenation. Crit Care Explor 2023; 5:e0957. [PMID: 37614802 PMCID: PMC10443764 DOI: 10.1097/cce.0000000000000957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023] Open
Abstract
Background Carbon monoxide (CO) is an endogenous signaling molecule that activates cytoprotective programs implicated in the resolution of acute respiratory distress syndrome (ARDS) and survival of critical illness. Because CO levels can be measured in blood as carboxyhemoglobin, we hypothesized that carboxyhemoglobin percent (COHb%) may associate with mortality. OBJECTIVES To examine the relationship between COHb% and outcomes in patients with ARDS requiring venovenous extracorporeal membrane oxygenation (ECMO), a condition where elevated COHb% is commonly observed. DESIGN Retrospective cohort study. SETTING Academic medical center ICU. PATIENTS Patients were included that had ARDS on venovenous ECMO. MEASUREMENTS AND MAIN RESULTS We examined the association between COHb% and mortality using a Cox proportional hazards model. Secondary outcomes including ECMO duration, ventilator weaning, and hospital and ICU length of stay were examined using both subdistribution and causal-specific hazard models for competing risks. We identified 109 consecutive patients for analysis. Mortality significantly decreased per 1 U increase in COHb% below 3.25% (hazard ratio [HR], 0.35; 95% CI, 0.15-0.80; p = 0.013) and increased per 1 U increase above 3.25% (HR, 4.7; 95% CI, 1.5-14.7; p = 0.007) reflecting a nonlinear association (p = 0.006). Each unit increase in COHb% was associated with reduced likelihood of liberation from ECMO and mechanical ventilation, and increased time to hospital and ICU discharge (all p < 0.05). COHb% was significantly associated with hemolysis but not with initiation of hemodialysis or blood transfusions. CONCLUSIONS In patients with ARDS on venovenous ECMO, COHb% is a novel biomarker for mortality exhibiting a U-shaped pattern. Our findings suggest that too little CO (perhaps due to impaired host signaling) or excess CO (perhaps due to hemolysis) is associated with higher mortality. Patients with low COHb% may exhibit the most benefit from future therapies targeting anti-oxidant and anti-inflammatory pathways such as low-dose inhaled CO gas.
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Affiliation(s)
- Amber Meservey
- Department of Medicine, Duke University School of Medicine, Durham, NC
| | - Govind Krishnan
- Department of Medicine, Duke University School of Medicine, Durham, NC
| | - Cynthia L Green
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC
| | - Samantha Morrison
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC
| | - Craig R Rackley
- Department of Medicine, Duke University School of Medicine, Durham, NC
| | - Bryan D Kraft
- Department of Medicine, Duke University School of Medicine, Durham, NC
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Hou L, Yang X, Liu C, Guo J, Shi Y, Sun T, Feng X, Zhou J, Liu J. Heme Oxygenase-1 and Its Metabolites Carbon Monoxide and Biliverdin, but Not Iron, Exert Antiviral Activity against Porcine Circovirus Type 3. Microbiol Spectr 2023; 11:e0506022. [PMID: 37140466 PMCID: PMC10269822 DOI: 10.1128/spectrum.05060-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/11/2023] [Indexed: 05/05/2023] Open
Abstract
Porcine circovirus type 3 (PCV3) is a newly discovered pathogen that causes porcine dermatitis and nephropathy syndrome (PDNS)-like clinical signs, multisystemic inflammation, and reproductive failure. Heme oxygenase-1 (HO-1), a stress-inducible enzyme, exerts protective functions by converting heme into carbon monoxide (CO), biliverdin (BV), and iron. However, the effects of HO-1 and its metabolites on PCV3 replication remain unknown. In this study, experiments involving specific inhibitors, lentivirus transduction, and small interfering RNA (siRNA) transfection revealed that active PCV3 infection reduced HO-1 expression and that the expression of HO-1 negatively regulated virus replication in cultured cells, depending on its enzymatic activity. Subsequently, the effects of the HO-1 metabolites (CO, BV, and iron) on PCV3 infection were investigated. The CO inducers (cobalt protoporphyrin IX [CoPP] or tricarbonyl dichloro ruthenium [II] dimer [CORM-2]) mediate PCV3 inhibition by generating CO, and this inhibition is reversed by hemoglobin (Hb; a CO scavenger). The inhibition of PCV3 replication by BV depended on BV-mediated reactive oxygen species (ROS) reduction, as N-acetyl-l-cysteine affected PCV3 replication while reducing ROS production. The reduction product of BV, bilirubin (BR), specifically promoted nitric oxide (NO) generation and further activated the cyclic GMP/protein kinase G (cGMP/PKG) pathway to attenuate PCV3 infection. Both the iron provided by FeCl3 and the iron chelated by deferoxamine (DFO) with CoPP treatment failed to affect PCV3 replication. Our data demonstrate that the HO-1-CO-cGMP/PKG, HO-1-BV-ROS, and HO-1-BV-BR-NO-cGMP/PKG pathways contribute crucially to the inhibition of PCV3 replication. These results provide important insights regarding preventing and controlling PCV3 infection. IMPORTANCE The regulation of host protein expression by virus infection is the key to facilitating self-replication. As an important emerging pathogen of swine, clarification of the interaction between PCV3 infection and the host enables us to understand the viral life cycle and pathogenesis better. Heme oxygenase-1 (HO-1) and its metabolites carbon monoxide (CO), biliverdin (BV), and iron have been demonstrated to involve a wealth of viral replications. Here, we, for the first time, demonstrated that HO-1 expression decreases in PCV3-infected cells and negatively regulates PCV3 replication and that the HO-1 metabolic products CO and BV inhibit PCV3 replication by the CO- or BV/BR/NO-dependent cGMP/PKG pathway or BV-mediated ROS reduction, but the iron (the third metabolic product) does not. Specifically, PCV3 infection maintains normal proliferation by downregulating HO-1 expression. These findings clarify the mechanism by which HO-1 modulates PCV3 replication in cells and provide important targets for preventing and controlling PCV3 infection.
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Affiliation(s)
- Lei Hou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Xiaoyu Yang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Changzhe Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Jinshuo Guo
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Yongyan Shi
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Tong Sun
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Xufei Feng
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Jianwei Zhou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Jue Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
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Sun J, Wang W, Hu X, Zhang X, Zhu C, Hu J, Ma R. Local delivery of gaseous signaling molecules for orthopedic disease therapy. J Nanobiotechnology 2023; 21:58. [PMID: 36810201 PMCID: PMC9942085 DOI: 10.1186/s12951-023-01813-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/13/2023] [Indexed: 02/24/2023] Open
Abstract
Over the past decade, a proliferation of research has used nanoparticles to deliver gaseous signaling molecules for medical purposes. The discovery and revelation of the role of gaseous signaling molecules have been accompanied by nanoparticle therapies for their local delivery. While most of them have been applied in oncology, recent advances have demonstrated their considerable potential in diagnosing and treating orthopedic diseases. Three of the currently recognized gaseous signaling molecules, nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), are highlighted in this review along with their distinctive biological functions and roles in orthopedic diseases. Moreover, this review summarizes the progress in therapeutic development over the past ten years with a deeper discussion of unresolved issues and potential clinical applications.
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Affiliation(s)
- Jiaxuan Sun
- Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Wenzhi Wang
- Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Xianli Hu
- Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Xianzuo Zhang
- Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Chen Zhu
- Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.
| | - Jinming Hu
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, 230001, Anhui, China.
| | - Ruixiang Ma
- Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.
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Canagliflozin Inhibits Human Endothelial Cell Inflammation through the Induction of Heme Oxygenase-1. Int J Mol Sci 2022; 23:ijms23158777. [PMID: 35955910 PMCID: PMC9369341 DOI: 10.3390/ijms23158777] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). Studies have also shown that canagliflozin directly acts on endothelial cells (ECs). Since heme oxygenase-1 (HO-1) is an established modulator of EC function, we investigated if canagliflozin regulates the endothelial expression of HO-1, and if this enzyme influences the biological actions of canagliflozin in these cells. Treatment of human ECs with canagliflozin stimulated a concentration- and time-dependent increase in HO-1 that was associated with a significant increase in HO activity. Canagliflozin also evoked a concentration-dependent blockade of EC proliferation, DNA synthesis, and migration that was unaffected by inhibition of HO-1 activity and/or expression. Exposure of ECs to a diabetic environment increased the adhesion of monocytes to ECs, and this was attenuated by canagliflozin. Knockdown of HO-1 reduced the anti-inflammatory effect of canagliflozin which was restored by bilirubin but not carbon monoxide. In conclusion, this study identified canagliflozin as a novel inducer of HO-1 in human ECs. It also found that HO-1-derived bilirubin contributed to the anti-inflammatory action of canagliflozin, but not the anti-proliferative and antimigratory effects of the drug. The ability of canagliflozin to regulate HO-1 expression and EC function may contribute to the clinical profile of the drug.
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Tadelle A. QT Interval Prolongation in Cirrhotic Cardiomyopathy. RESEARCH REPORTS IN CLINICAL CARDIOLOGY 2022. [DOI: 10.2147/rrcc.s371615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Ross RL, Mavria G, Del Galdo F, Elies J. Downregulation of Vascular Hemeoxygenase-1 Leads to Vasculopathy in Systemic Sclerosis. Front Physiol 2022; 13:900631. [PMID: 35600300 PMCID: PMC9117635 DOI: 10.3389/fphys.2022.900631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 04/12/2022] [Indexed: 11/13/2022] Open
Abstract
Systemic sclerosis (SSc) is a terminal disease characterized by vasculopathy, tissue fibrosis, and autoimmunity. Although the exact etiology of SSc remains unknown, endothelial dysfunction, oxidative stress, and calcium handling dysregulation have been associated with a large number of SSc-related complications such as neointima formation, vasculogenesis, pulmonary arterial hypertension, impaired angiogenesis, and cardiac arrhythmias. Hemeoxygenase-1 (HO-1) is an antioxidant enzyme involved in multiple biological actions in the cardiovascular system including vascular tone, angiogenesis, cellular proliferation, apoptosis, and oxidative stress. The aim of this work was to investigate the physiological role of HO-1 and its relevance in the cardiovascular complications occurring in SSc. We found that, in early phases of SSc, the expression of HO-1 in dermal fibroblast is lower compared to those isolated from healthy control individuals. This is particularly relevant as reduction of the HO-1/CO signaling pathway is associated with endothelial dysfunction and vasculopathy. We show evidence of the role of HO-1/carbon monoxide (CO) signaling pathway in calcium handling. Using an in vitro model of pulmonary arterial hypertension (PAH) we investigated the role of HO-1 in Ca2+ mobilization from intracellular stores. Our results indicate that HO-1 regulates calcium release from intracellular stores of human pulmonary arterial endothelial cells. We interrogated the activity of HO-1 in angiogenesis using an organotypic co-culture of fibroblast-endothelial cell. Inhibition of HO-1 significantly reduced the ability of endothelial cells to form tubules. We further investigated if this could be associated with cell motility or migration of endothelial cells into the extracellular matrix synthesized by fibroblasts. By mean of holographic imaging, we studied the morphological and functional features of endothelial cells in the presence of an HO-1 activator and selective inhibitors. Our results demonstrate that inhibition of HO-1 significantly reduces cell proliferation and cell motility (migration) of cultured endothelial cells, whilst activation of HO-1 does not modify either morphology, proliferation or motility. In addition, we investigated the actions of CO on the Kv7.1 (KCQN1) channel current, an important component of the cardiac action potential repolarization. Using electrophysiology (whole-cell patch-clamp in a recombinant system overexpressing the KCQN1 channel), we assessed the regulation of KCQN1 by CO. CORM-2, a CO donor, significantly reduced the Kv7.1 current, suggesting that HO-1/CO signaling may play a role in the modulation of the cardiac action potential via regulation of this ion channel. In summary, our results indicate a clear link between: 1) downregulation of HO-1/CO signaling; and 2) pathophysiological processes occurring in early phases of SSc, such as calcium homeostasis dysregulation, impaired angiogenesis and cardiac arrhythmias. A better understanding of the canonical actions (mainly due to the biological actions of CO), and non-canonical actions of HO-1, as well as the interaction of HO-1/CO signaling with other gasotransmitters in SSc will contribute to the development of novel therapeutic approaches.
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Affiliation(s)
- Rebecca L Ross
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
- Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, United Kingdom
| | - Georgia Mavria
- Signal Transduction and Tumour Microenvironment Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Francesco Del Galdo
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
- Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, United Kingdom
| | - Jacobo Elies
- Cardiovascular Research Group, Faculty of Life Sciences, University of Bradford, Bradford, United Kingdom
- *Correspondence: Jacobo Elies,
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Amorim MR, Foresti R, Benrahla DE, Motterlini R, Branco LGS. CORM-401, an orally active carbon monoxide-releasing molecule, increases body temperature by activating non-shivering thermogenesis in rats. Temperature (Austin) 2022; 9:310-317. [PMID: 36339088 PMCID: PMC9629103 DOI: 10.1080/23328940.2022.2061270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Thermoregulation is critical in health and disease and is tightly controlled to maintain body temperature homeostasis. Carbon monoxide (CO), an endogenous gasotransmitter produced during heme degradation by heme oxygenases, has been suggested to play a role in body core temperature (Tb) regulation. However, a direct involvement of CO in thermoregulation has not been confirmed and its mechanism(s) of action remain largely unknown. In the present study we characterized the effects of systemic delivery of CO by administration of an orally active CO-releasing molecule (CORM-401) on Tb regulation in conscious freely moving rats. Specifically, we evaluated the main thermo effectors in rats treated with CORM-401 by assessing: (i) non-shivering thermogenesis, i.e. the increased metabolism of brown fat measured through oxygen consumption and (ii) the rate of heat loss from the tail through calculations of heat loss index. We found that oral administration of CORM-401 (30 mg/kg) resulted in augmented CO delivery into the blood circulation as evidenced a by significant increase in carbon monoxy hemoglobin levels(COHb). In addition, treatment with CORM-401 increased Tb, which was caused by an elevated non-shivering thermogenesis indicated by increased oxygen consumption without significant changes in the tail heat loss. On the other hand, CORM-401 did not affect blood pressure, but significantly decreased heart rate. In summary, the findings of the present study reveal that increased circulating CO levels lead to a rise in Tb, which could have important implications in the emerging role of CO in the modulation of energetic metabolism.
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Affiliation(s)
- Mateus R. Amorim
- Dental School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Roberta Foresti
- Faculty of Health, University Paris Est Créteil, INSERM, IMRB, Créteil, France
| | | | - Roberto Motterlini
- Faculty of Health, University Paris Est Créteil, INSERM, IMRB, Créteil, France
| | - Luiz G. S. Branco
- Dental School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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13
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Shi B, Zhou T, Lv S, Wang M, Chen S, Heidari AA, Huang X, Chen H, Wang L, Wu P. An evolutionary machine learning for pulmonary hypertension animal model from arterial blood gas analysis. Comput Biol Med 2022; 146:105529. [PMID: 35594682 DOI: 10.1016/j.compbiomed.2022.105529] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/11/2022] [Accepted: 04/13/2022] [Indexed: 11/03/2022]
Abstract
Pulmonary hypertension (PH) is a rare and fatal condition that leads to right heart failure and death. The pathophysiology of PH and potential therapeutic approaches are yet unknown. PH animal models' development and proper evaluation are critical to PH research. This work presents an effective analysis technology for PH from arterial blood gas analysis utilizing an evolutionary kernel extreme learning machine with multiple strategies integrated slime mould algorithm (MSSMA). In MSSMA, two efficient bee-foraging learning operators are added to the original slime mould algorithm, ensuring a suitable trade-off between intensity and diversity. The proposed MSSMA is evaluated on thirty IEEE benchmarks and the statistical results show that the search performance of the MSSMA is significantly improved. The MSSMA is utilised to develop a kernel extreme learning machine (MSSMA-KELM) on PH from arterial blood gas analysis. Comprehensively, the proposed MSSMA-KELM can be used as an effective analysis technology for PH from arterial Blood gas analysis with an accuracy of 93.31%, Matthews coefficient of 90.13%, Sensitivity of 91.12%, and Specificity of 90.73%. MSSMA-KELM can be treated as an effective approach for evaluating mouse PH models.
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Affiliation(s)
- Beibei Shi
- Affiliated People's Hospital of Jiangsu University, 8 Dianli Road, Zhenjiang, Jiangsu, 212000, China.
| | - Tao Zhou
- The First Clinical College, Wenzhou Medical University, Wenzhou, 325000, China.
| | - Shushu Lv
- The First Clinical College, Wenzhou Medical University, Wenzhou, 325000, China.
| | - Mingjing Wang
- College of Computer Science and Artificial Intelligence, Wenzhou University, Wenzhou, 325035, China.
| | - Siyuan Chen
- Affiliated People's Hospital of Jiangsu University, 8 Dianli Road, Zhenjiang, Jiangsu, 212000, China.
| | - Ali Asghar Heidari
- School of Surveying and Geospatial Engineering, College of Engineering, University of Tehran, Tehran, Iran; Department of Computer Science, School of Computing, National University of Singapore, Singapore, Singapore.
| | - Xiaoying Huang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Huiling Chen
- College of Computer Science and Artificial Intelligence, Wenzhou University, Wenzhou, 325035, China.
| | - Liangxing Wang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Peiliang Wu
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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14
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Lu W, Yang X, Wang B. Carbon monoxide signaling and soluble guanylyl cyclase: Facts, myths, and intriguing possibilities. Biochem Pharmacol 2022; 200:115041. [PMID: 35447132 DOI: 10.1016/j.bcp.2022.115041] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/12/2022]
Abstract
The endogenous signaling roles of carbon monoxide (CO) have been firmly established at the pathway level. For CO's molecular mechanism(s) of actions, hemoproteins are generally considered as possible targets. Importantly, soluble guanylyl cyclase (sGC) is among the most widely referenced molecular targets. However, the affinity of CO for sGC (Kd: 240 μM) is much lower than for other highly abundant hemoproteins in the body, such as myoglobin (Kd: 29 nM) and hemoglobin (Kd: 0.7 nM-4.5 μM), which serve as CO reservoirs. Further, most of the mechanistic studies involving sGC activation by CO were based on in-vitro or ex-vivo studies using CO concentrations not readily attenable in vivo and in the absence of hemoglobin as a competitor in binding. As such, whether such in-vitro/ex-vivo results can be directly extrapolated to in-vivo studies is not clear because of the need for CO to be transferred from a high-affinity binder (e.g., hemoglobin) to a low-affinity target if sGC is to be activated in vivo. In this review, we discuss literature findings of sGC activation by CO and the experimental conditions; examine the myths in the disconnect between the low affinity of sGC for CO and the reported activation of sGC by CO; and finally present several possibilities that may lead to additional studies to improve our understanding of this direct CO-sGC axis, which is yet to be convincingly established as playing generally critical roles in CO signaling in vivo.
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Affiliation(s)
- Wen Lu
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
| | - Xiaoxiao Yang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
| | - Binghe Wang
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
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15
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Sun HJ, Wang ZC, Nie XW, Bian JS. Therapeutic potential of carbon monoxide in hypertension-induced vascular smooth muscle cell damage revisited: from physiology and pharmacology. Biochem Pharmacol 2022; 199:115008. [PMID: 35318039 DOI: 10.1016/j.bcp.2022.115008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/13/2022] [Accepted: 03/15/2022] [Indexed: 01/14/2023]
Abstract
As a chronic and progressive disorder, hypertension remains to be a serious public health problem around the world. Among the different types of hypertension, pulmonary arterial hypertension (PAH) is a devastating disease associated with pulmonary arteriole remodeling, right ventricular failure and death. The contemporary management of systemic hypertension and PAH has substantially grown since more therapeutic targets and/or agents have been developed. Evolving treatment strategies targeting the vascular remodeling lead to improving outcomes in patients with hypertension, nevertheless, significant advancement opportunities for developing better antihypertensive drugs remain. Carbon monoxide (CO), an active endogenous gasotransmitter along with hydrogen sulfide (H2S) and nitric oxide (NO), is primarily generated by heme oxygenase (HO). Cumulative evidence suggests that CO is considered as an important signaling molecule under both physiological and pathological conditions. Studies have shown that CO confers a number of biological and pharmacological properties, especially its involvement in the pathological process and treatment of hypertension-related vascular remodeling. This review will critically outline the roles of CO in hypertension-associated vascular remodeling and discuss the underlying mechanisms for the protective effects of CO against hypertension and vascular remodeling. In addition, we will propose the challenges and perspectives of CO in hypertensive vascular remodeling. It is expected that a comprehensive understanding of CO in the vasculature might be essential to translate CO to be a novel pharmacological agent for hypertension-induced vascular remodeling.
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Affiliation(s)
- Hai-Jian Sun
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Zi-Chao Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Xiao-Wei Nie
- Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518055, China.
| | - Jin-Song Bian
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu 215000, China.
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16
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Lang E, Abdou H, Edwards J, Patel N, Morrison JJ. State-of-the-Art Review: Sex Hormone Therapy in Trauma-Hemorrhage. Shock 2022; 57:317-326. [PMID: 34618728 DOI: 10.1097/shk.0000000000001871] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT Trauma-hemorrhage is the leading cause of prehospital and early in-hospital deaths, while also significantly contributing to the later development of multisystem organ dysfunction/failure and sepsis. Common and advanced resuscitative methods would potentially demonstrate benefits in the prehospital setting; however, they face a variety of barriers to application and implementation. Thus, a dialogue around a novel adjunct has arisen, sex hormone therapy. Proposed candidates include estradiol and its derivatives, metoclopramide hydrochloride/prolactin, dehydroepiandrosterone, and flutamide; with each having demonstrated a range of salutary effects in several animal model studies. Several retrospective analyses have observed a gender-based dimorphism in mortality following trauma-hemorrhage, thus suggesting that estrogens contribute to this pattern. Trauma-hemorrhage animal models have shown estrogens offer protective effects to the cardiovascular, pulmonary, hepatic, gastrointestinal, and immune systems. Additionally, a series of survival studies utilizing 17α-ethinylestradiol-3-sulfate, a potent, water-soluble synthetic estrogen, have demonstrated a significant survival benefit and beneficial effects on cardiovascular function. This review presents the findings of retrospective clinical studies, preclinical animal studies, and discusses how and why 17α-ethinylestradiol-3-sulfate should be considered for investigation within a prospective clinical trial.
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Affiliation(s)
- Eric Lang
- R Adams Cowley Shock Trauma Center, University of Maryland Medical System, Baltimore, Maryland
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17
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Beck KF, Pfeilschifter J. The Pathophysiology of H2S in Renal Glomerular Diseases. Biomolecules 2022; 12:biom12020207. [PMID: 35204708 PMCID: PMC8961591 DOI: 10.3390/biom12020207] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/12/2022] [Accepted: 01/22/2022] [Indexed: 02/06/2023] Open
Abstract
Renal glomerular diseases such as glomerulosclerosis and diabetic nephropathy often result in the loss of glomerular function and consequently end-stage renal disease. The glomerulus consists of endothelial cells, mesangial cells and glomerular epithelial cells also referred to as podocytes. A fine-tuned crosstalk between glomerular cells warrants control of growth factor synthesis and of matrix production and degradation, preserving glomerular structure and function. Hydrogen sulfide (H2S) belongs together with nitric oxide (NO) and carbon monoxide (CO) to the group of gasotransmitters. During the last three decades, these higher concentration toxic gases have been found to be produced in mammalian cells in a well-coordinated manner. Recently, it became evident that H2S and the other gasotransmitters share common targets as signalling devices that trigger mainly protective pathways. In several animal models, H2S has been demonstrated as a protective factor in the context of kidney disorders, in particular of diabetic nephropathy. Here, we focus on the synthesis and action of H2S in glomerular cells, its beneficial effects in the glomerulus and its action in the context of the other gaseous signalling molecules NO and CO.
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18
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Kim MJ, Hwang YH, Hwang JW, Alam Z, Lee DY. Heme oxygenase-1 gene delivery for altering high mobility group box-1 protein in pancreatic islet. J Control Release 2022; 343:326-337. [PMID: 35085698 DOI: 10.1016/j.jconrel.2022.01.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 01/14/2022] [Accepted: 01/19/2022] [Indexed: 10/19/2022]
Abstract
Pancreatic islet transplantation is a promising strategy for the treatment of type I diabetes. High-mobility group box-1 (HMGB1), highly expressed in islet cells, is a potent immune stimulator in immune rejection. Heme oxygenase-1 (HO1) gene therapy can modulate the release of HMGB1 by altering intracellular molecules for successful cell transplantation. After delivery of the heme oxygenase-1 (HO1) gene to islet cells using an adeno-associated viral vector (AAV), it was evaluated the changes in cytoplasmic Ca2+ ions and calcineurin activity as well as histone acetyltransferase (HAT) and Poly(ADP) ribose polymerase-1 (PARP-1). Inhibition of HMGB1 release was evaluated through altering these intracellular molecules. Then, after transplantation of HO1-transduced islets, the therapeutic effect of them was evaluated through measuring blood glucose level to diabetic mice and through immunohistochemical analysis. The transduced HO1 gene significantly inhibited HMGB1 release in islets that was under the cell damage by hypoxia exposure. It was confirmed that this result was initially due to the decrease in cytoplasmic Ca2+ ion concentration and calcineurin activity. In addition, the delivered HO1 gene simultaneously reduced the activity of HAT and PARP-1, which are involved in the translocation of HMGB1 from the nucleus to the cytoplasm. As a result, when the HO1 gene-transduced islets were transplanted into diabetic mice, the treatment efficiency of diabetes was effectively improved by increasing the survival rate of the islets. Collectively, these results suggest that HO1 gene transfer can be used for successful islet transplantation by altering the activity of intracellular signal molecules and reducing HMGB1 release.
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Affiliation(s)
- Min Jun Kim
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul 04763, Republic of Korea
| | - Yong Hwa Hwang
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul 04763, Republic of Korea
| | - Jin Wook Hwang
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul 04763, Republic of Korea
| | - Zahid Alam
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul 04763, Republic of Korea
| | - Dong Yun Lee
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul 04763, Republic of Korea; Institute of Nano Science & Technology (INST), Hanyang University, Seoul 04763, Republic of Korea; Elixir Pharmatech Inc., Seoul 04763, Republic of Korea.
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19
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Dent MR, DeMartino AW, Tejero J, Gladwin MT. Endogenous Hemoprotein-Dependent Signaling Pathways of Nitric Oxide and Nitrite. Inorg Chem 2021; 60:15918-15940. [PMID: 34313417 PMCID: PMC9167621 DOI: 10.1021/acs.inorgchem.1c01048] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Interdisciplinary research at the interface of chemistry, physiology, and biomedicine have uncovered pivotal roles of nitric oxide (NO) as a signaling molecule that regulates vascular tone, platelet aggregation, and other pathways relevant to human health and disease. Heme is central to physiological NO signaling, serving as the active site for canonical NO biosynthesis in nitric oxide synthase (NOS) enzymes and as the highly selective NO binding site in the soluble guanylyl cyclase receptor. Outside of the primary NOS-dependent biosynthetic pathway, other hemoproteins, including hemoglobin and myoglobin, generate NO via the reduction of nitrite. This auxiliary hemoprotein reaction unlocks a "second axis" of NO signaling in which nitrite serves as a stable NO reservoir. In this Forum Article, we highlight these NO-dependent physiological pathways and examine complex chemical and biochemical reactions that govern NO and nitrite signaling in vivo. We focus on hemoprotein-dependent reaction pathways that generate and consume NO in the presence of nitrite and consider intermediate nitrogen oxides, including NO2, N2O3, and S-nitrosothiols, that may facilitate nitrite-based signaling in blood vessels and tissues. We also discuss emergent therapeutic strategies that leverage our understanding of these key reaction pathways to target NO signaling and treat a wide range of diseases.
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Affiliation(s)
- Matthew R Dent
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Anthony W DeMartino
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Jesús Tejero
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Mark T Gladwin
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
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20
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Zhang H, He H, Cui Y, Yu S, Li S, Afedo SY, Wang Y, Bai X, He J. Regulatory effects of HIF-1α and HO-1 in hypoxia-induced proliferation of pulmonary arterial smooth muscle cells in yak. Cell Signal 2021; 87:110140. [PMID: 34478827 DOI: 10.1016/j.cellsig.2021.110140] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/24/2021] [Accepted: 08/29/2021] [Indexed: 01/13/2023]
Abstract
Hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1) are important transcription regulators in hypoxic cells and for maintaining cellular homeostasis, but it is unclear whether they participate in hypoxia-induced excessive proliferation of yak pulmonary artery smooth muscle cells (PASMCs). In this study, we identified distribution of HIF-1α and HO-1 in yak lungs. Immunohistochemistry and immunofluorescence results revealed that both HIF-1α and HO-1 were mainly concentrated in the medial layer of small pulmonary arteries. Furthermore, under induced-hypoxic conditions, we investigated HIF-1α and HO-1 protein expression and studied their potential involvement in yak PASMCs proliferation and apoptosis. Western blot results also showed that both factors significantly increased in age-dependent manner and upregulated in hypoxic PASMCs (which exhibited obvious proliferation and anti-apoptosis phenomena). HIF-1α up-regulation by DMOG increased the proliferation and anti-apoptosis of PASMCs, while HIF-1α down-regulation by LW6 decreased proliferation and promoted apoptosis. More so, treatment with ZnPP under hypoxic conditions down-regulated HO-1 expression, stimulated proliferation, and resisted apoptosis in yak PASMCs. Taken together, our study demonstrated that both HIF-1α and HO-1 participated in PASMCs proliferation and apoptosis, suggesting that HO-1 is important for inhibition of yak PASMCs proliferation while HIF-1α promoted hypoxia-induced yak PASMCs proliferation.
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Affiliation(s)
- Huizhu Zhang
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Honghong He
- Gansu Province Livestock Embryo Engineering Research Center, Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Yan Cui
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; Gansu Province Livestock Embryo Engineering Research Center, Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China.
| | - Sijiu Yu
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; Gansu Province Livestock Embryo Engineering Research Center, Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Shijie Li
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Seth Yaw Afedo
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Yali Wang
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Xuefeng Bai
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Junfeng He
- Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
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21
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Reyes-Ramos CA, Gaxiola-Robles R, Vázquez-Medina JP, Ramírez-Jirano LJ, Bitzer-Quintero OK, Zenteno-Savín T. In silico Characterization of the Heme Oxygenase 1 From Bottlenose Dolphin ( Tursiops truncatus): Evidence of Changes in the Active Site and Purifying Selection. Front Physiol 2021; 12:711645. [PMID: 34456750 PMCID: PMC8388933 DOI: 10.3389/fphys.2021.711645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/12/2021] [Indexed: 11/13/2022] Open
Abstract
Cetacea is a clade well-adapted to the aquatic lifestyle, with diverse adaptations and physiological responses, as well as a robust antioxidant defense system. Serious injuries caused by boats and fishing nets are common in bottlenose dolphins (Tursiops truncatus); however, these animals do not show signs of serious infections. Evidence suggests an adaptive response to tissue damage and associated infections in cetaceans. Heme oxygenase (HO) is a cytoprotective protein that participates in the anti-inflammatory response. HO catalyzes the first step in the oxidative degradation of the heme group. Various stimuli, including inflammatory mediators, regulate the inducible HO-1 isoform. This study aims to characterize HO-1 of the bottlenose dolphin in silico and compare its structure to the terrestrial mammal protein. Upstream HO-1 sequence of the bottlenose dolphin was obtained from NCBI and Ensemble databases, and the gene structure was determined using bioinformatics tools. Five exons and four introns were identified, and proximal regulatory elements were detected in the upstream region. The presence of 10 α-helices, three 310 helices, the heme group lodged between the proximal and distal helices, and a histidine-25 in the proximal helix serving as a ligand to the heme group were inferred for T. truncatus. Amino acid sequence alignment suggests HO-1 is a conserved protein. The HO-1 "fingerprint" and histidine-25 appear to be fully conserved among all species analyzed. Evidence of positive selection within an α-helix configuration without changes in protein configuration and evidence of purifying selection were found, indicating evolutionary conservation of the coding sequence structure.
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Affiliation(s)
- Carlos A. Reyes-Ramos
- Centro de Investigaciones Biológicas del Noroeste, S.C. Planeación Ambiental y Conservación, La Paz, Mexico
| | - Ramón Gaxiola-Robles
- Centro de Investigaciones Biológicas del Noroeste, S.C. Planeación Ambiental y Conservación, La Paz, Mexico
- Hospital General de Zona No. 1, Instituto Mexicano del Seguro Social, La Paz, Mexico
| | | | - Luis Javier Ramírez-Jirano
- Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico
| | - Oscar Kurt Bitzer-Quintero
- Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico
| | - Tania Zenteno-Savín
- Centro de Investigaciones Biológicas del Noroeste, S.C. Planeación Ambiental y Conservación, La Paz, Mexico
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22
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Impact of Hypoxia over Human Viral Infections and Key Cellular Processes. Int J Mol Sci 2021; 22:ijms22157954. [PMID: 34360716 PMCID: PMC8347150 DOI: 10.3390/ijms22157954] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/16/2021] [Accepted: 07/20/2021] [Indexed: 01/01/2023] Open
Abstract
Oxygen is essential for aerobic cells, and thus its sensing is critical for the optimal maintenance of vital cellular and tissue processes such as metabolism, pH homeostasis, and angiogenesis, among others. Hypoxia-inducible factors (HIFs) play central roles in oxygen sensing. Under hypoxic conditions, the α subunit of HIFs is stabilized and forms active heterodimers that translocate to the nucleus and regulate the expression of important sets of genes. This process, in turn, will induce several physiological changes intended to adapt to these new and adverse conditions. Over the last decades, numerous studies have reported a close relationship between viral infections and hypoxia. Interestingly, this relation is somewhat bidirectional, with some viruses inducing a hypoxic response to promote their replication, while others inhibit hypoxic cellular responses. Here, we review and discuss the cellular responses to hypoxia and discuss how HIFs can promote a wide range of physiological and transcriptional changes in the cell that modulate numerous human viral infections.
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23
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Choi YK, Kim YM. Regulation of Endothelial and Vascular Functions by Carbon Monoxide via Crosstalk With Nitric Oxide. Front Cardiovasc Med 2021; 8:649630. [PMID: 33912601 PMCID: PMC8071856 DOI: 10.3389/fcvm.2021.649630] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/16/2021] [Indexed: 12/21/2022] Open
Abstract
Carbon monoxide (CO), generated by heme oxygenase (HO), has been considered a signaling molecule in both the cardiovascular and central nervous systems. The biological function of the HO/CO axis is mostly related to other gaseous molecules, including nitric oxide (NO), which is synthesized by nitric oxide synthase (NOS). Healthy blood vessels are essential for the maintenance of tissue homeostasis and whole-body metabolism; however, decreased or impaired vascular function is a high-risk factor of cardiovascular and neuronal diseases. Accumulating evidence supports that the interplay between CO and NO plays a crucial role in vascular homeostasis and regeneration by improving endothelial function. Moreover, endothelial cells communicate with neighboring cells, such as, smooth muscle cells, immune cells, pericytes, and astrocytes in the periphery and neuronal vascular systems. Endogenous CO could mediate the cell-cell communication and improve the physiological functions of the cardiovascular and neurovascular systems via crosstalk with NO. Thus, a forward, positive feedback circuit between HO/CO and NOS/NO pathways can maintain cardiovascular and neurovascular homeostasis and prevent various human diseases. We discussed the crucial role of CO-NO crosstalk in the cardiovascular and neurovascular systems.
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Affiliation(s)
- Yoon Kyung Choi
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, South Korea
| | - Young-Myeong Kim
- Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea
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Gautam K, Negi S, Saini V. Targeting endogenous gaseous signaling molecules as novel host-directed therapies against tuberculosis infection. Free Radic Res 2021; 55:655-670. [PMID: 33641567 DOI: 10.1080/10715762.2021.1892091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Tuberculosis (TB) is a chronic pulmonary disease caused by Mycobacterium tuberculosis which is a major cause of morbidity and mortality worldwide. Due to the complexity of disease and its continuous global spread, there is an urgent need to improvise the strategies for prevention, diagnosis, and treatment. The current anti-TB regimen lasts for months and warrants strict compliance to clear infection and to minimize the risk of development of multi drug-resistant tuberculosis. This underscores the need to have new and improved therapeutics for TB treatment. Several studies have highlighted the unique ability of Mycobacterium tuberculosis to exploit host factors to support its survival inside the intracellular environment. One of the key players to mycobacterial disease susceptibility and infection are endogenous gases such as oxygen, nitric oxide, carbon monoxide and hydrogen sulfide. Nitric oxide and carbon monoxide as the physiological gaseous messengers are considered important to the outcome of Mycobacterium tuberculosis infection. The role of hydrogen sulfide in human tuberculosis is yet not fully elucidated, but this gas has been shown to play a significant role in bacterial respiration, growth and pathogenesis. This review will focus on the host factors majorly endogenous gaseous signaling molecules which contributes to Mycobacterium tuberculosis survival inside the intracellular environment and highlight the potential therapeutic targets.
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Affiliation(s)
- Kamini Gautam
- Laboratory of Infection Biology and Translational Research, Department of Biotechnology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Sheetal Negi
- Laboratory of Infection Biology and Translational Research, Department of Biotechnology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Vikram Saini
- Laboratory of Infection Biology and Translational Research, Department of Biotechnology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
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25
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Bukowska-Strakova K, Włodek J, Pitera E, Kozakowska M, Konturek-Cieśla A, Cieśla M, Gońka M, Nowak W, Wieczorek A, Pawińska-Wąsikowska K, Józkowicz A, Siedlar M. Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia. Int J Mol Sci 2021; 22:ijms22030988. [PMID: 33498175 PMCID: PMC7863945 DOI: 10.3390/ijms22030988] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 01/15/2021] [Indexed: 12/17/2022] Open
Abstract
Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(−413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.
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Affiliation(s)
- Karolina Bukowska-Strakova
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 31-663 Kraków, Poland; (J.W.); (E.P.)
- Correspondence: (K.B.-S.); (A.J.); (M.S.); Tel.: +48-(12)-664-6411 (A.J.); +48-(12)-658-2486 (M.S.); Fax: +48-(12)-658-1756 (M.S.)
| | - Joanna Włodek
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 31-663 Kraków, Poland; (J.W.); (E.P.)
| | - Ewelina Pitera
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 31-663 Kraków, Poland; (J.W.); (E.P.)
| | - Magdalena Kozakowska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Anna Konturek-Cieśla
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Maciej Cieśla
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Monika Gońka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Witold Nowak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Aleksandra Wieczorek
- Pediatric, Oncology and Hematology Department, Institute of Pediatrics, Jagiellonian University Medical College, 30-387 Krakow, Poland; (A.W.); (K.P.-W.)
| | - Katarzyna Pawińska-Wąsikowska
- Pediatric, Oncology and Hematology Department, Institute of Pediatrics, Jagiellonian University Medical College, 30-387 Krakow, Poland; (A.W.); (K.P.-W.)
| | - Alicja Józkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
- Correspondence: (K.B.-S.); (A.J.); (M.S.); Tel.: +48-(12)-664-6411 (A.J.); +48-(12)-658-2486 (M.S.); Fax: +48-(12)-658-1756 (M.S.)
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 31-663 Kraków, Poland; (J.W.); (E.P.)
- Correspondence: (K.B.-S.); (A.J.); (M.S.); Tel.: +48-(12)-664-6411 (A.J.); +48-(12)-658-2486 (M.S.); Fax: +48-(12)-658-1756 (M.S.)
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26
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Yang Q, Zhou L, Peng L, Yuan G, Ding H, Tan L, Zhou Y. A smart mitochondria-targeting TP-NIR fluorescent probe for the selective and sensitive sensing of H 2S in living cells and mice. NEW J CHEM 2021. [DOI: 10.1039/d1nj00840d] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hydrogen sulfide (H2S) is one of the important gaseous signalling molecules, which plays key roles in various critical biological processes.
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Affiliation(s)
- Qiaomei Yang
- Hunan Key Laboratory of Processed Food for Special Medical Purpose
- National Engineering Laboratory for Deep Process of Rice and Byproducts
- College of Food Science and Engineering
- Central South University of Forestry and Technology
- Changsha
| | - Liyi Zhou
- Hunan Key Laboratory of Processed Food for Special Medical Purpose
- National Engineering Laboratory for Deep Process of Rice and Byproducts
- College of Food Science and Engineering
- Central South University of Forestry and Technology
- Changsha
| | - Longpeng Peng
- Hunan Key Laboratory of Processed Food for Special Medical Purpose
- National Engineering Laboratory for Deep Process of Rice and Byproducts
- College of Food Science and Engineering
- Central South University of Forestry and Technology
- Changsha
| | - Gangqiang Yuan
- Hunan Key Laboratory of Processed Food for Special Medical Purpose
- National Engineering Laboratory for Deep Process of Rice and Byproducts
- College of Food Science and Engineering
- Central South University of Forestry and Technology
- Changsha
| | - Haiyuan Ding
- Hunan Key Laboratory of Processed Food for Special Medical Purpose
- National Engineering Laboratory for Deep Process of Rice and Byproducts
- College of Food Science and Engineering
- Central South University of Forestry and Technology
- Changsha
| | - Libin Tan
- Hunan Key Laboratory of Processed Food for Special Medical Purpose
- National Engineering Laboratory for Deep Process of Rice and Byproducts
- College of Food Science and Engineering
- Central South University of Forestry and Technology
- Changsha
| | - Yizhuang Zhou
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation
- Guilin Medical University
- Guilin
- China
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27
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Solár P, Brázda V, Levin S, Zamani A, Jančálek R, Dubový P, Joukal M. Subarachnoid Hemorrhage Increases Level of Heme Oxygenase-1 and Biliverdin Reductase in the Choroid Plexus. Front Cell Neurosci 2020; 14:593305. [PMID: 33328892 PMCID: PMC7732689 DOI: 10.3389/fncel.2020.593305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/04/2020] [Indexed: 11/18/2022] Open
Abstract
Subarachnoid hemorrhage is a specific, life-threatening form of hemorrhagic stroke linked to high morbidity and mortality. It has been found that the choroid plexus of the brain ventricles forming the blood-cerebrospinal fluid barrier plays an important role in subarachnoid hemorrhage pathophysiology. Heme oxygenase-1 and biliverdin reductase are two of the key enzymes of the hemoglobin degradation cascade. Therefore, the aim of present study was to investigate changes in protein levels of heme oxygenase-1 and biliverdin reductase in the rat choroid plexus after experimental subarachnoid hemorrhage induced by injection of non-heparinized autologous blood to the cisterna magna. Artificial cerebrospinal fluid of the same volume as autologous blood was injected to mimic increased intracranial pressure in control rats. Immunohistochemical and Western blot analyses were used to monitor changes in the of heme oxygenase-1 and biliverdin reductase levels in the rat choroid plexus after induction of subarachnoid hemorrhage or artificial cerebrospinal fluid application for 1, 3, and 7 days. We found increased levels of heme oxygenase-1 and biliverdin reductase protein in the choroid plexus over the entire period following subarachnoid hemorrhage induction. The level of heme oxygenase-1 was the highest early (1 and 3 days) after subarachnoid hemorrhage indicating its importance in hemoglobin degradation. Increased levels of heme oxygenase-1 were also observed in the choroid plexus epithelial cells at all time points after application of artificial cerebrospinal fluid. Biliverdin reductase protein was detected mainly in the choroid plexus epithelial cells, with levels gradually increasing during subarachnoid hemorrhage. Our results suggest that heme oxygenase-1 and biliverdin reductase are involved not only in hemoglobin degradation but probably also in protecting choroid plexus epithelial cells and the blood-cerebrospinal fluid barrier from the negative effects of subarachnoid hemorrhage.
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Affiliation(s)
- Peter Solár
- Department of Anatomy, Faculty of Medicine, Cellular and Molecular Neurobiology Research Group, Masaryk University, Brno, Czechia.,Department of Neurosurgery - St. Anne's University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czechia.,Department of Neurosurgery, St. Anne's University Hospital Brno, Brno, Czechia
| | - Václav Brázda
- Department of Anatomy, Faculty of Medicine, Cellular and Molecular Neurobiology Research Group, Masaryk University, Brno, Czechia.,Institute of Biophysics of the Czech Academy of Sciences, Brno, Czechia
| | - Shahaf Levin
- Department of Anatomy, Faculty of Medicine, Cellular and Molecular Neurobiology Research Group, Masaryk University, Brno, Czechia
| | - Alemeh Zamani
- Department of Anatomy, Faculty of Medicine, Cellular and Molecular Neurobiology Research Group, Masaryk University, Brno, Czechia
| | - Radim Jančálek
- Department of Neurosurgery - St. Anne's University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czechia.,Department of Neurosurgery, St. Anne's University Hospital Brno, Brno, Czechia
| | - Petr Dubový
- Department of Anatomy, Faculty of Medicine, Cellular and Molecular Neurobiology Research Group, Masaryk University, Brno, Czechia
| | - Marek Joukal
- Department of Anatomy, Faculty of Medicine, Cellular and Molecular Neurobiology Research Group, Masaryk University, Brno, Czechia
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Zhao X, Zhang L, Bai J, Wu P, Li Y, Liang L, Xie L, Wang J. A copper-based metal-organic framework for ratiometric detection of hydrogen sulfide with high sensitivity and fast response. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2020; 243:118794. [PMID: 32799192 DOI: 10.1016/j.saa.2020.118794] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/21/2020] [Accepted: 07/24/2020] [Indexed: 06/11/2023]
Abstract
Metal-organic framework (MOF) is a class of crystalline porous solid materials which could be designed as sensors for bioactive molecules. In this study, charge transition between the ligand and the metal ions related emission and the ligand-based emission were formed simultaneously within a novel luminescent MOF with the copper reactive site as nodes. It can serve as a rare example of MOFs implicated ratiometric sensor for selective luminescent detection of H2S. The luminescent detection limitations for H2S is 0.21 μM, and it possesses a fast response of 30 s. The sensing mechanism is also discussed.
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Affiliation(s)
- Xiaoli Zhao
- School of Chemistry and Materials Science & Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China
| | - Lijiao Zhang
- School of Chemistry and Materials Science & Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China
| | - Jianguo Bai
- School of Chemistry and Materials Science & Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China
| | - Pengyan Wu
- School of Chemistry and Materials Science & Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China..
| | - Yang Li
- School of Chemistry and Materials Science & Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China
| | - Lili Liang
- School of Chemistry and Materials Science & Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China
| | - Liheng Xie
- School of Chemistry and Materials Science & Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China
| | - Jian Wang
- School of Chemistry and Materials Science & Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China..
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29
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Beck KF, Pfeilschifter J. Gasotransmitter synthesis and signalling in the renal glomerulus. Implications for glomerular diseases. Cell Signal 2020; 77:109823. [PMID: 33152441 DOI: 10.1016/j.cellsig.2020.109823] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 01/19/2023]
Abstract
Glomerular injury is a hallmark of kidney diseases such as diabetic nephropathy, IgA nephropathy or other forms of glomerulonephritis. Glomerular endothelial cells, mesangial cells, glomerular epithelial cells (podocytes) and, in an inflammatory context, infiltrating immune cells crosstalk to mediate signalling processes in the glomerulus. Under physiological conditions, mesangial cells act by the control of extracellular matrix production and degradation, by the synthesis of growth factors and by preserving a well-defined crosstalk with glomerular podocytes and endothelial cells to regulate glomerular structure and function. It is well known that mesangial cells are able to amplify an inflammatory process by the formation of cytokines, reactive oxygen species (ROS) and nitric oxide (NO). This exaggerated reaction may result in a vicious cycle with subsequent damage of neighboured podocytes and endothelial cells, loss of the filtration barrier and, finally destruction of the whole glomerulus. Unfortunately, all efforts to develop new therapies for the treatment of glomerular diseases by controlling unbridled ROS or NO production directly had so far no success. However, on-going research on ROS and NO defined these autacoids more as important signalling molecules than as endogenously produced cytotoxic compounds. New findings on signalling activities of ROS, NO but also hydrogen sulfide (H2S) and carbon monoxide (CO) supported this paradigm shift. Because of their similar chemical properties and their similar signal transduction capacities, NO, H2S and CO are meanwhile designated as the group of gasotransmitters. In this review, we describe the current knowledge of the signalling properties of gasotransmitters with a focus on glomerular cells and their role in glomerular diseases.
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Affiliation(s)
- Karl-Friedrich Beck
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main, Germany.
| | - Josef Pfeilschifter
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main, Germany
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30
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Robson JA, Kubánková M, Bond T, Hendley RA, White AJP, Kuimova MK, Wilton‐Ely JDET. Simultaneous Detection of Carbon Monoxide and Viscosity Changes in Cells. Angew Chem Int Ed Engl 2020. [DOI: 10.1002/ange.202008224] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Jonathan A. Robson
- Department of Chemistry Molecular Sciences Research Hub Imperial College London White City Campus London W12 0BZ UK
| | - Markéta Kubánková
- Department of Chemistry Molecular Sciences Research Hub Imperial College London White City Campus London W12 0BZ UK
| | - Tamzin Bond
- Department of Chemistry Molecular Sciences Research Hub Imperial College London White City Campus London W12 0BZ UK
| | - Rian A. Hendley
- Department of Chemistry Molecular Sciences Research Hub Imperial College London White City Campus London W12 0BZ UK
| | - Andrew J. P. White
- Department of Chemistry Molecular Sciences Research Hub Imperial College London White City Campus London W12 0BZ UK
| | - Marina K. Kuimova
- Department of Chemistry Molecular Sciences Research Hub Imperial College London White City Campus London W12 0BZ UK
| | - James D. E. T. Wilton‐Ely
- Department of Chemistry Molecular Sciences Research Hub Imperial College London White City Campus London W12 0BZ UK
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31
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Robson JA, Kubánková M, Bond T, Hendley RA, White AJP, Kuimova MK, Wilton-Ely JDET. Simultaneous Detection of Carbon Monoxide and Viscosity Changes in Cells. Angew Chem Int Ed Engl 2020; 59:21431-21435. [PMID: 32686308 PMCID: PMC7756414 DOI: 10.1002/anie.202008224] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/14/2020] [Indexed: 12/11/2022]
Abstract
A new family of robust, non‐toxic, water‐compatible ruthenium(II) vinyl probes allows the rapid, selective and sensitive detection of endogenous carbon monoxide (CO) in live mammalian cells under normoxic and hypoxic conditions. Uniquely, these probes incorporate a viscosity‐sensitive BODIPY fluorophore that allows the measurement of microscopic viscosity in live cells via fluorescence lifetime imaging microscopy (FLIM) while also monitoring CO levels. This is the first example of a probe that can simultaneously detect CO alongside small viscosity changes in organelles of live cells.
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Affiliation(s)
- Jonathan A Robson
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, London, W12 0BZ, UK
| | - Markéta Kubánková
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, London, W12 0BZ, UK
| | - Tamzin Bond
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, London, W12 0BZ, UK
| | - Rian A Hendley
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, London, W12 0BZ, UK
| | - Andrew J P White
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, London, W12 0BZ, UK
| | - Marina K Kuimova
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, London, W12 0BZ, UK
| | - James D E T Wilton-Ely
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, London, W12 0BZ, UK
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Wu Q, Huo F, Wang J, Yin C. Fluorescent probe for detecting hydrogen sulfide based on disulfide nucleophilic substitution-addition. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2020; 238:118437. [PMID: 32388415 DOI: 10.1016/j.saa.2020.118437] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 04/24/2020] [Accepted: 04/29/2020] [Indexed: 06/11/2023]
Abstract
In view of the importance of hydrogen sulfide (H2S) in the organism, a fast, noninvasive method for the detection of H2S in situ is needed. Fluorescent probes based on disulfide-bond nucleophilic substitution-addition can selectively detect H2S in vivo, which is very popular because it allows quick response for H2S, thus it will be a useful tool for monitoring H2S in the vivo. We developed a dicyanoisopentanone-based H2S fluorescent probe (EW-H) that used a disulfide group as a self-destructive linker reaction site. Under the nucleophilic substitution of H2S, the disulfide bond of EW-H was cleaved, and then nucleophilic addition took place intramolecularly to release the fluorophore (at 580 nm). The response to H2S, EW-H had high sensitivity (86 nM of the detection limit), large Stokes shift (155 nm) and a fast response time. More importantly, the probe was also applied for bioimaging in HepG2 cells, indicating its potential applications in biological organism.
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Affiliation(s)
- Qing Wu
- Department of Chemistry, Xinzhou Teachers University, Xinzhou 034000, Shanxi, China; Research Institute of Applied Chemistry, Shanxi University, Taiyuan 030006, China
| | - Fangjun Huo
- Department of Chemistry, Xinzhou Teachers University, Xinzhou 034000, Shanxi, China; Research Institute of Applied Chemistry, Shanxi University, Taiyuan 030006, China
| | - Junping Wang
- Institute of Molecular Science, Shanxi University, Taiyuan 030006, China
| | - Caixia Yin
- Department of Chemistry, Xinzhou Teachers University, Xinzhou 034000, Shanxi, China; Institute of Molecular Science, Shanxi University, Taiyuan 030006, China.
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Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease. Antioxidants (Basel) 2020; 9:antiox9090829. [PMID: 32899732 PMCID: PMC7554957 DOI: 10.3390/antiox9090829] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 02/06/2023] Open
Abstract
Heme oxygenase-1 (HO-1) catalyzes the degradation of heme into carbon monoxide (CO), iron, and biliverdin, which is rapidly metabolized to bilirubin. The activation of vascular smooth muscle cells (SMCs) plays a critical role in mediating the aberrant arterial response to injury and a number of vascular diseases. Pharmacological induction or gene transfer of HO-1 improves arterial remodeling in animal models of post-angioplasty restenosis, vascular access failure, atherosclerosis, transplant arteriosclerosis, vein grafting, and pulmonary arterial hypertension, whereas genetic loss of HO-1 exacerbates the remodeling response. The vasoprotection evoked by HO-1 is largely ascribed to the generation of CO and/or the bile pigments, biliverdin and bilirubin, which exert potent antioxidant and anti-inflammatory effects. In addition, these molecules inhibit vascular SMC proliferation, migration, apoptosis, and phenotypic switching. Several therapeutic strategies are currently being pursued that may allow for the targeting of HO-1 in arterial remodeling in various pathologies, including the use of gene delivery approaches, the development of novel inducers of the enzyme, and the administration of unique formulations of CO and bilirubin.
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Yang S, Kuang G, Zhang L, Wu S, Zhao Z, Wang B, Yin X, Gong X, Wan J. Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells. Front Immunol 2020; 11:285. [PMID: 32158448 PMCID: PMC7052129 DOI: 10.3389/fimmu.2020.00285] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 02/04/2020] [Indexed: 12/21/2022] Open
Abstract
Acute liver injury and its terminal phase, hepatic failure, trigger a series of complications, including hepatic encephalopathy, systematic inflammatory response syndrome, and multiorgan failure, with relatively high morbidity and mortality. Liver transplantation is the ultimate intervention, but the shortage of donor organs has limited clinical success. Mangiferin (MF), a xanthone glucoside, has been reported to have excellent anti-inflammatory efficacy. Here, a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury mouse model was established to investigate the protective role of MF and the underlying mechanisms of action. Pretreatment with MF improved survival, decreased serum aminotransferase activities, and inhibited hepatic TNF-α production in LPS/D-GalN-challenged mice. Through Kupffer cell (KC) deletion by GdCl3 and KC adoptive transfer, KCs were confirmed to be involved in these beneficial effects of MF. MF reduced LPS-mediated TNF-α production via the suppression of the TLR4/NF-κB signaling pathway in vitro. MF promoted HO-1 expression, but the knockdown of HO-1 prevented TNF-α inhibition, suggesting that the damage-resistance effects of HO-1 occurred via the suppression of TNF-α synthesis. When HO-1-silenced KCs were transferred to the liver with KC deletion, the protective effect of MF against LPS/D-GalN-induced acute liver injury was reduced, illustrating the role of KC-derived HO-1 in the anti-injury effects of MF. Collectively, MF attenuated acute liver injury induced by LPS/D-GalN via the inhibition of TNF-α production by promoting KCs to upregulate HO-1 expression.
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Affiliation(s)
- Sen Yang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Ge Kuang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Liangke Zhang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Shengwang Wu
- Department of Anatomy, Chongqing Medical University, Chongqing, China
| | - Zizuo Zhao
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bin Wang
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xinru Yin
- Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Xia Gong
- Department of Anatomy, Chongqing Medical University, Chongqing, China
| | - Jingyuan Wan
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
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35
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Wang A, Li X, Ju Y, Chen D, Lu J. Bioluminescence imaging of carbon monoxide in living cells based on a selective deiodination reaction. Analyst 2020; 145:550-556. [DOI: 10.1039/c9an02107h] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Modification of a heavy iodine atom for d-Luciferin was explored as a “turn-on” transduction scheme for CO detection. This new probe could image exogenous and endogenous CO in the luciferase-transfected cancer cells.
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Affiliation(s)
- Anni Wang
- School of Pharmacy
- Fudan University
- Shanghai
- China
| | - Xuewei Li
- School of Pharmacy
- Fudan University
- Shanghai
- China
| | - Yong Ju
- School of Pharmacy
- Fudan University
- Shanghai
- China
| | - Dongying Chen
- Shanghai Institute of Materia Medica
- Chinese Academy of Sciences
- Shanghai
- China
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36
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Zhang Y, Chen Y, Bai Y, Xue X, He W, Guo Z. FRET-based fluorescent ratiometric probes for the rapid detection of endogenous hydrogen sulphide in living cells. Analyst 2020; 145:4233-4238. [DOI: 10.1039/d0an00531b] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
FRET strategy was adopted for designing ratiometric fluorescent H2S sensors using Coumarin-derived merocyanine fluorophore.
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Affiliation(s)
- Yuming Zhang
- State Key Laboratory of Coordination Chemistry
- Coordination ChemistryInstitute
- School of Chemistry and Chemical Engineering
- Nanjing University
- Nanjing 210023
| | - Yuncong Chen
- State Key Laboratory of Coordination Chemistry
- Coordination ChemistryInstitute
- School of Chemistry and Chemical Engineering
- Nanjing University
- Nanjing 210023
| | - Yang Bai
- State Key Laboratory of Coordination Chemistry
- Coordination ChemistryInstitute
- School of Chemistry and Chemical Engineering
- Nanjing University
- Nanjing 210023
| | - Xuling Xue
- State Key Laboratory of Coordination Chemistry
- Coordination ChemistryInstitute
- School of Chemistry and Chemical Engineering
- Nanjing University
- Nanjing 210023
| | - Weijiang He
- State Key Laboratory of Coordination Chemistry
- Coordination ChemistryInstitute
- School of Chemistry and Chemical Engineering
- Nanjing University
- Nanjing 210023
| | - Zijian Guo
- State Key Laboratory of Coordination Chemistry
- Coordination ChemistryInstitute
- School of Chemistry and Chemical Engineering
- Nanjing University
- Nanjing 210023
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37
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Xie S, Fu T, He L, Qiu L, Liu H, Tan W. DNA-Capped Silver Nanoflakes as Fluorescent Nanosensor for Highly Sensitive Imaging of Endogenous H2S in Cell Division Cycles. Anal Chem 2019; 91:15404-15410. [DOI: 10.1021/acs.analchem.9b02527] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Sitao Xie
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Bio Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, and Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha 410082, China
| | - Ting Fu
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Bio Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, and Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha 410082, China
| | - Lei He
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Bio Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, and Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha 410082, China
| | - Liping Qiu
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Bio Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, and Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha 410082, China
| | - Honglin Liu
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Bio Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, and Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha 410082, China
- School of Food and Biological Engineering, Hefei University of Technology, Anhui 230009, China
| | - Weihong Tan
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Bio Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, and Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha 410082, China
- Department of Chemistry and Physiology and Functional Genomics, Center for Research at the Bio/Nano Interface, Shands Cancer Center, University of Florida, Gainesville, Florida 32611-7200, United States
- Institute of Molecular Medicine, Renji Hospital, School of Medicine and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
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38
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Wang X, Sun Q, Zhao L, Gong S, Xu L. Visualization of hydrogen polysulfides in living cells and in vivo via a near-infrared fluorescent probe. J Biol Inorg Chem 2019; 24:1077-1085. [PMID: 31515622 DOI: 10.1007/s00775-019-01718-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 08/29/2019] [Indexed: 11/24/2022]
Abstract
Hydrogen polysulfides (H2Sn, n > 1), as the oxidized forms of H2S, have attracted increasing attention these years due to their involvement in signaling transduction and cytoprotective processes. It is necessary to detect H2Sn in living systems for the study of their functions. In this work, we report a BODIPY-based near-infrared emitting fluorescence probe NIR-PHS1, with "turn-on" response, rapid response rate (within 10 min), outstanding selectivity and excellent sensitivity (detection limit = 12 nM) response towards H2Sn. The probe was successfully applied to the visualizing of endogenous H2Sn in living cells. Moreover, it can be used for near-infrared in vivo imaging of H2Sn in living mice. Therefore, NIR-PHS1 could be a potential imaging tool to study the biological roles of H2Sn in living systems.
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Affiliation(s)
- Xiaoqing Wang
- College of Science, Nanjing Forestry University, Nanjing, 210037, China.
| | - Qian Sun
- College of Science, Nanjing Forestry University, Nanjing, 210037, China
| | - Liming Zhao
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, China
| | - Shuwen Gong
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, China
| | - Li Xu
- College of Science, Nanjing Forestry University, Nanjing, 210037, China. .,Institute of Material Physics and Chemistry, Nanjing Forestry University, Nanjing, 210037, China.
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39
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Lignitto L, LeBoeuf SE, Homer H, Jiang S, Askenazi M, Karakousi TR, Pass HI, Bhutkar AJ, Tsirigos A, Ueberheide B, Sayin VI, Papagiannakopoulos T, Pagano M. Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1. Cell 2019; 178:316-329.e18. [PMID: 31257023 DOI: 10.1016/j.cell.2019.06.003] [Citation(s) in RCA: 401] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 03/19/2019] [Accepted: 06/03/2019] [Indexed: 01/01/2023]
Abstract
Approximately 30% of human lung cancers acquire mutations in either Keap1 or Nfe2l2, resulting in the stabilization of Nrf2, the Nfe2l2 gene product, which controls oxidative homeostasis. Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. In mouse models of lung cancers, loss of Keap1 or Fbxo22 induces metastasis in a Bach1-dependent manner. Pharmacological inhibition of Ho1 suppresses metastasis in a Fbxo22-dependent manner. Human metastatic lung cancer display high levels of Ho1 and Bach1. Bach1 transcriptional signature is associated with poor survival and metastasis in lung cancer patients. We propose that Nrf2 activates a metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.
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Affiliation(s)
- Luca Lignitto
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA
| | - Sarah E LeBoeuf
- Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Harrison Homer
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA
| | - Shaowen Jiang
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA
| | - Manor Askenazi
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Biomedical Hosting LLC, 33 Lewis Avenue, Arlington, MA 02474, USA
| | - Triantafyllia R Karakousi
- Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Harvey I Pass
- Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Cardiothoracic Surgery, New York University School of Medicine, New York, NY 10016, USA
| | - Arjun J Bhutkar
- Koch Institute for Integrative Cancer Research, MIT, 77 Massachusetts Ave. Building 76, Cambridge, MA 02139, USA
| | - Aristotelis Tsirigos
- Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Beatrix Ueberheide
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA
| | - Volkan I Sayin
- Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Thales Papagiannakopoulos
- Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
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40
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Abdalla MY, Ahmad IM, Rachagani S, Banerjee K, Thompson CM, Maurer HC, Olive KP, Bailey KL, Britigan BE, Kumar S. Enhancing responsiveness of pancreatic cancer cells to gemcitabine treatment under hypoxia by heme oxygenase-1 inhibition. Transl Res 2019; 207:56-69. [PMID: 30653942 DOI: 10.1016/j.trsl.2018.12.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 12/30/2018] [Accepted: 12/31/2018] [Indexed: 01/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and has one of the worst prognoses leading to a meager 5-year survival rate of ∼8%. Chemotherapy has had limited success in extending the life span of patients with advanced PDAC due to poor tumor perfusion and hypoxia-induced resistance. Hypoxia reprograms the gene expression profile and upregulates the expression of multiple genes including heme oxygenase-1 (HO-1), which provide survival advantage to PDAC cells. However, the relationships between HO-1, hypoxia, and response to chemotherapy is unclear. Our results showed that hypoxia upregulates the expression of HO-1 in PDAC cells, and HO-1 inhibition using the HO-1 inhibitors zinc protoporphyrin, tin protoporphyrin IX (SnPP), and HO-1 knockout using CRISPR/Cas9 suppresses the proliferation of PDAC cells under hypoxia and sensitize them to gemcitabine under in vitro conditions. Treating orthotopic tumors with SnPP, or SnPP in combination with gemcitabine, significantly reduced the weight of pancreatic tumors (P < 0.05), decreased metastasis and improved the efficacy of gemcitabine treatment (P < 0.05). Mechanistically, inhibition of HO-1 increased the production of reactive oxygen species as demonstrated by increased dihydroethidium, and Mitosox, disrupted glutathione cycle, and enhanced apoptosis. There was significant increase in cleaved caspase-3 staining in tumors after combined treatment with SnPP and gemcitabine comparing to control or gemcitabine alone. In addition, inhibiting HO-1 reduced expression of stemness markers (CD133, and CD44) as compared to control or gemcitabine. Overall, our study may present a novel therapeutic regimen that might be adopted for the treatment of PDAC patients.
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Affiliation(s)
- Maher Y Abdalla
- Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
| | - Iman M Ahmad
- Department of Medical Imaging and Therapeutic Sciences, University of Nebraska Medical Center, Omaha, Nebraska
| | - Satyanarayana Rachagani
- Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Kasturi Banerjee
- Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Christopher M Thompson
- Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - H Carlo Maurer
- Departments of Medicine and Pathology & Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Kenneth P Olive
- Departments of Medicine and Pathology & Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Katie L Bailey
- Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Bradley E Britigan
- Research Service, VA Medical Center, Nebraska/Western Iowa, Omaha, Nebraska; Department of Internal Medicine; University of Nebraska Medical Center, Omaha, Nebraska
| | - Sushil Kumar
- Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
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41
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Carvalho MVH, Kroll PC, Kroll RTM, Carvalho VN. Cirrhotic cardiomyopathy: the liver affects the heart. ACTA ACUST UNITED AC 2019; 52:e7809. [PMID: 30785477 PMCID: PMC6376321 DOI: 10.1590/1414-431x20187809] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 12/04/2018] [Indexed: 12/14/2022]
Abstract
Cirrhotic cardiomyopathy historically has been confused as alcoholic cardiomyopathy. The key points for diagnosis of cirrhotic cardiomyopathy have been well explained, however this entity was neglected for a long time. Nowadays the diagnosis of this entity has become important because it is a factor that contributes significantly to morbidity-mortality in cirrhotic patients. Characteristics of cirrhotic cardiomyopathy are a hyperdynamic circulatory state, altered diastolic relaxation, impaired contractility, and electrophysiological abnormalities, particularity QT interval prolongation. The pathogenesis includes impaired function of beta-receptors, altered transmembrane currents and overproduction of cardiodepressant factors, such as nitric oxide, cytokines and endogenous cannabinoids. In addition to physical signs of hyperdynamic state and heart failure under stress conditions, the diagnosis can be done with dosage of serum markers, electrocardiography, echocardiography and magnetic resonance. The treatment is mainly supportive, but orthotopic liver transplantation appears to improve this condition although the prognosis of liver transplantation in patients with cirrhotic cardiomyopathy is uncertain.
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Affiliation(s)
- M V H Carvalho
- Departamento de Cirurgia, Faculdade de Medicina de Jundiaí, Jundiaí, SP, Brasil
| | - P C Kroll
- Hospital de Transplante E.J. Zerbini, São Paulo, SP, Brasil
| | - R T M Kroll
- Instituto Dante Pazzanese de Cardiologia, São Paulo, SP, Brasil
| | - V N Carvalho
- Hospital Municipal Dr. Mario Gatti, Campinas, SP, Brasil
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42
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Yang C, Chen K, Chen M, Hu X, Huan SY, Chen L, Song G, Zhang XB. Nanoscale Metal–Organic Framework Based Two-Photon Sensing Platform for Bioimaging in Live Tissue. Anal Chem 2019; 91:2727-2733. [DOI: 10.1021/acs.analchem.8b04405] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Chan Yang
- Molecular Science and Biomedicine Laboratory, College of Chemistry and Chemical Engineering and College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, People’s Republic of China
| | - Kun Chen
- Molecular Science and Biomedicine Laboratory, College of Chemistry and Chemical Engineering and College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, People’s Republic of China
| | - Mei Chen
- College of Materials Science and Engineering, Hunan University, Changsha 410082, People’s Republic of China
| | - Xiaoxiao Hu
- Molecular Science and Biomedicine Laboratory, College of Chemistry and Chemical Engineering and College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, People’s Republic of China
| | - Shuang-Yan Huan
- Molecular Science and Biomedicine Laboratory, College of Chemistry and Chemical Engineering and College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, People’s Republic of China
| | - Lanlan Chen
- Shandong Provincial Key Laboratory of Detection Technology for Tumour Markers, College of Chemistry and Chemical Engineering, Linyi University, Linyi, Shandong 276005, People’s Republic of China
| | - Guosheng Song
- Molecular Science and Biomedicine Laboratory, College of Chemistry and Chemical Engineering and College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, People’s Republic of China
| | - Xiao-Bing Zhang
- Molecular Science and Biomedicine Laboratory, College of Chemistry and Chemical Engineering and College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, People’s Republic of China
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43
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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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44
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Fang Q, Xiong H, Yang L, Wang B, Song X. An instantaneous fluorescent probe for detecting hydrogen sulfide in biological systems. NEW J CHEM 2019. [DOI: 10.1039/c9nj02849h] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
An instantaneous (within seconds) fluorescent probe for detecting H2S was developed and successfully used for H2S imaging in living cells and zebrafish.
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Affiliation(s)
- Qian Fang
- College of Chemistry & Chemical Engineering
- Central South University
- Changsha
- China
| | - Haiqing Xiong
- College of Chemistry & Chemical Engineering
- Central South University
- Changsha
- China
| | - Lei Yang
- College of Chemistry & Chemical Engineering
- Central South University
- Changsha
- China
- Shandong Province Key Laboratory of Detection Technology for Tumor Markers
| | - Benhua Wang
- College of Chemistry & Chemical Engineering
- Central South University
- Changsha
- China
| | - Xiangzhi Song
- College of Chemistry & Chemical Engineering
- Central South University
- Changsha
- China
- Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety
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45
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Yan Y, Chen L, Liu R, Zheng Y, Wang S. A turn-on fluorescent probe with a dansyl fluorophore for hydrogen sulfide sensing. RSC Adv 2019; 9:27652-27658. [PMID: 35529213 PMCID: PMC9070855 DOI: 10.1039/c9ra04790e] [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: 06/25/2019] [Accepted: 08/21/2019] [Indexed: 12/21/2022] Open
Abstract
Hydrogen sulfide (H2S) is a biologically relevant molecule that has been newly identified as a gasotransmitter and is also a toxic gaseous pollutant. In this study, we report on a metal complex fluorescent probe to achieve the sensitive detection of H2S in a fluorescent “turn-on” mode. The probe bears a dansyl fluorophore with multidentate ligands for coordination with copper ions. The fluorescent “turn-on” mode is facilitated by the strong bonding between H2S and the Cu(ii) ions to form insoluble copper sulfide, which leads to the release of a strongly fluorescent product. The H2S limit of detection (LOD) for the proposed probe is estimated to be 11 nM in the aqueous solution, and the utilization of the probe is demonstrated for detecting H2S in actual lake and mineral water samples with good reproducibility. Furthermore, we designed detector vials and presented their successful application for the visual detection of gaseous H2S. H2S turn on the fluorescence of DNS–Cu complex probe.![]()
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Affiliation(s)
| | | | | | | | - Suhua Wang
- School of Environmental Science and Engineering
- North China Electric Power University
- Beijing 102206
- China
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46
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Abebe F, Sutton T, Perkins P, Shaw R. Two colorimetric fluorescent turn-on chemosensors for detection of Al 3+ and N 3 - : Synthesis, photophysical and computational studies. LUMINESCENCE 2018; 33:1194-1201. [PMID: 30091286 PMCID: PMC6727853 DOI: 10.1002/bio.3535] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 06/11/2018] [Accepted: 06/26/2018] [Indexed: 01/02/2023]
Abstract
Two new rhodamine derivative L1 and L2 bearing 2-methoxy-1-naphthaldehyde and 5-bromo-3-methoxy salicylaldehyde units were designed and synthesized using microwave-assisted organic synthesis and utilized towards sequential fluorescence detection of aluminum ion (Al3+ ) and azide (N3 - ) in aqueous acetonitrile solution. Aluminum ion (Al3+ ) triggers the formation of highly fluorescent ring-open spirolactam. The fluorescence and colorimetric response of the L1 -Al3+ and L2 -Al3+ complexes were quenched by the addition of N3 - , which extracting the Al3+ from the complexes and turn-off the sensors, confirming that the recognition process is reversible. The recognition ability of the sensors was investigated by fluorescence titration, Job's plot, 1 H-NMR spectroscopy and density functional theory (DFT) calculations.
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Affiliation(s)
- Fasil Abebe
- Department of Chemistry, Morgan State University, Baltimore, MD, USA
| | - Treshaun Sutton
- Department of Chemistry, Morgan State University, Baltimore, MD, USA
| | - Pierce Perkins
- Department of Chemistry, Morgan State University, Baltimore, MD, USA
| | - Roosevelt Shaw
- Department of Chemistry, Morgan State University, Baltimore, MD, USA
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47
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Gas Signaling Molecules and Mitochondrial Potassium Channels. Int J Mol Sci 2018; 19:ijms19103227. [PMID: 30340432 PMCID: PMC6214077 DOI: 10.3390/ijms19103227] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/15/2018] [Accepted: 10/16/2018] [Indexed: 12/27/2022] Open
Abstract
Recently, gaseous signaling molecules, such as carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), which were previously considered to be highly toxic, have been of increasing interest due to their beneficial effects at low concentrations. These so-called gasotransmitters affect many cellular processes, such as apoptosis, proliferation, cytoprotection, oxygen sensing, ATP synthesis, and cellular respiration. It is thought that mitochondria, specifically their respiratory complexes, constitute an important target for these gases. On the other hand, increasing evidence of a cytoprotective role for mitochondrial potassium channels provides motivation for the analysis of the role of gasotransmitters in the regulation of channel function. A number of potassium channels have been shown to exhibit activity within the inner mitochondrial membrane, including ATP-sensitive potassium channels, Ca2+-activated potassium channels, voltage-gated Kv potassium channels, and TWIK-related acid-sensitive K+ channel 3 (TASK-3). The effects of these channels include the regulation of mitochondrial respiration and membrane potential. Additionally, they may modulate the synthesis of reactive oxygen species within mitochondria. The opening of mitochondrial potassium channels is believed to induce cytoprotection, while channel inhibition may facilitate cell death. The molecular mechanisms underlying the action of gasotransmitters are complex. In this review, we focus on the molecular mechanisms underlying the action of H2S, NO, and CO on potassium channels present within mitochondria.
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Nrf2 in aging - Focus on the cardiovascular system. Vascul Pharmacol 2018; 112:42-53. [PMID: 30170173 DOI: 10.1016/j.vph.2018.08.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 08/09/2018] [Accepted: 08/20/2018] [Indexed: 02/07/2023]
Abstract
Aging is the most critical risk factor for the development of cardiovascular diseases and their complications. Therefore, the fine-tuning of cellular response to getting older is an essential target for prospective therapies in cardiovascular medicine. One of the most promising targets might be the transcription factor Nrf2, which drives the expression of cytoprotective and antioxidative genes. Importantly, Nrf2 expression correlates with potential lifespan in rodents. However, the effect of Nrf2 activity in vascular diseases might be ambiguous and strongly depend on the cell type. On the one hand, the Nrf2 activity may protect cells from oxidative stress and senescence, on the other hand, total lack of Nrf2 is protective against atherosclerosis development. Therefore, this review aims to discuss the current knowledge on the role played by the transcription factor Nrf2 in cardiovascular diseases and its potential effects on aging.
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Koçer G, Nasircilar Ülker S, Şentürk ÜK. The contribution of carbon monoxide to vascular tonus. Microcirculation 2018; 25:e12495. [PMID: 30040171 DOI: 10.1111/micc.12495] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 06/15/2018] [Accepted: 07/18/2018] [Indexed: 01/27/2023]
Abstract
OBJECTIVE The aim of this descriptive study was to examine the contribution of CO in the maintenance of vascular tonus in different organs and different vessel segments; the underlying mechanism of CO-induced vasodilation was investigated. METHODS Sixty Wistar albino rats, aged 6-8 months, were used in this study. Response to CO by isolated arteries from the thoracic and abdominal aorta and mesenteric, renal, gastrocnemius, and gracilis muscles as well as heart, lung, and brain vascular beds was endogenously and exogenously studied using organ baths or myograph. In addition, HO-2 protein expression was assessed using Western blot analysis in isolated vessel segments. RESULTS Although CO was shown to contribute to the regulation of vascular tonus in all feed arteries except those of the gracilis vascular bed, no effect was observed in the resistance arteries, with the sole exception of the pial artery. No relationship between HO-2 protein level and CO contribution to endogenous vascular tonus was observed. CONCLUSIONS While the vasodilator effect of CO in vessels smaller than 600 μm in diameter was found to be mediated via potassium channels, in vessels larger than 600 μm in diameter, the effect was through both the potassium channels and the cGMP pathway.
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Affiliation(s)
- Günnur Koçer
- Department of Physiology, Medical Faculty, Near East University, Nicosia, Cyprus
| | | | - Ümit Kemal Şentürk
- Department of Physiology, Medical Faculty, Akdeniz University, Antalya, Turkey
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Li QQ, Li LJ, Wang XY, Sun YY, Wu J. Research Progress in Understanding the Relationship Between Heme Oxygenase-1 and Intracerebral Hemorrhage. Front Neurol 2018; 9:682. [PMID: 30177908 PMCID: PMC6109777 DOI: 10.3389/fneur.2018.00682] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 07/30/2018] [Indexed: 01/14/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is a fatal acute cerebrovascular disease, with a high morbidity and mortality. Following ICH, erythrocytes release heme and several of its metabolites, thereby contributing to brain edema and secondary brain damage. Heme oxygenase is the initial and rate-limiting enzyme of heme catabolism, and the expression of heme oxygenase-1 (HO-1) is rapidly induced following acute brain injury. As HO-1 exerts it effects via various metabolites, its role during ICH remains complex. Therefore, in-depth studies regarding the role of HO-1 in secondary brain damage following ICH may provide a theoretical basis for neuroprotective function after ICH. The present review aims to summarize recent key studies regarding the effects of HO-1 following ICH, as well as its influence on ICH prognosis.
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Affiliation(s)
- Qian-Qian Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Lan-Jun Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xin-Yu Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yu-Ying Sun
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Jun Wu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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