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Sakhuja A, Bhattacharyya R, Katakia YT, Ramakrishnan SK, Chakraborty S, Jayakumar H, Tripathi SM, Pandya Thakkar N, Thakar S, Sundriyal S, Chowdhury S, Majumder S. S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis. Nat Commun 2025; 16:3953. [PMID: 40289112 PMCID: PMC12034783 DOI: 10.1038/s41467-025-59003-x] [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: 02/08/2024] [Accepted: 04/08/2025] [Indexed: 04/30/2025] Open
Abstract
Nitric oxide (NO), a versatile bio-active molecule modulates cellular functions through diverse mechanisms including S-nitrosylation of proteins. Herein, we report S-nitrosylation of selected cysteine residues of EZH2 in endothelial cells, which interplays with its stability and functions. We detect a significant reduction in H3K27me3 upon S-nitrosylation of EZH2 as contributed by the early dissociation of SUZ12 from the PRC2. Moreover, S-nitrosylation of EZH2 causes its cytosolic translocation, ubiquitination, and degradation. Further analysis reveal S-nitrosylation of cysteine 329 induces EZH2 instability, whereas S-nitrosylation of cysteine 700 abrogates its catalytic activity. We further show that S-nitrosylation-dependent regulation of EZH2 maintains endothelial homeostasis in both physiological and pathological settings. Molecular dynamics simulation reveals the inability of SUZ12 to efficiently bind to the SAL domain of EZH2 upon S-nitrosylation. Taken together, our study reports S-nitrosylation-dependent regulation of EZH2 and its associated PRC2 complex, thereby influencing the epigenetics of endothelial homeostasis.
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Affiliation(s)
- Ashima Sakhuja
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Ritobrata Bhattacharyya
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Yash Tushar Katakia
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Shyam Kumar Ramakrishnan
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Srinjoy Chakraborty
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Hariharan Jayakumar
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Shailesh Mani Tripathi
- Department of Pharmacy, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Niyati Pandya Thakkar
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Sumukh Thakar
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Sandeep Sundriyal
- Department of Pharmacy, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Shibasish Chowdhury
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India
| | - Syamantak Majumder
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Pilani Campus, Rajasthan, Pilani, India.
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Alahdad N, Hamidpour SK, Yazdanpanah MA, Amiri M, Alizadeh R, Rezayat SM, Tavakol S. Nitric oxide synthases: A delicate dance between bone regeneration and neuronal birth. Biomed Pharmacother 2025; 187:118105. [PMID: 40294491 DOI: 10.1016/j.biopha.2025.118105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 03/23/2025] [Accepted: 04/24/2025] [Indexed: 04/30/2025] Open
Abstract
Spinal cord injury (SCI) is a devastating condition resulting from traumatic or nontraumatic injury/chronic disorder. The pathogenesis of SCI necessitates a comprehensive approach, as it involves therapeutic strategies addressing both bone (spine) and neural (spinal cord) damage. This review centers on the pivotal role of nitric oxide (NO) and its synthesizing enzymes, nitric oxide synthases (NOS), in mediating the crosstalk between osteogenesis and neurogenesis. NO's effects are context-dependent, exhibiting a delicate balance between beneficial and detrimental actions. Reduced levels of nitric oxide (NO), primarily derived from endothelial NOS (eNOS), tipically stimulate osteoblast activity and promote neurogenesis by influencing neural stem cell (NSC) migration and differentiation. Conversely, elevated NO levels, predominantly from inducible NOS (iNOS), tipically triggered by inflammation, inhibit both processes through pro-apoptotic mechanisms. Nevertheless, these phenomena are not merely simplistic; they can be influenced by a variety of other factors. We explore the intricate interplay of NO/NOS with key signaling pathways crucial in neurogenesis and osteogenesis, including mechanical stimuli, Wnt, interleukins, BMPs, NF-κB, etc., revealing their influence on neuroinflammation, neurogenesis, and osteoblast differentiation. The temporal and spatial dynamics of NO/NOS activity and the implications for therapeutic intervention have been discussed. Precise modulation of NO levels and NOS isoforms, potentially through targeted therapies manipulating these interacting signaling pathways, emerges as a promising strategy for promoting bone and neural regeneration. This review highlights the critical need for a balanced approach in therapeutic strategies to harness the beneficial effects of NO/NOS while mitigating its detrimental consequences.
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Affiliation(s)
- Niloofar Alahdad
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Shayesteh Kokabi Hamidpour
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Mohammad Ali Yazdanpanah
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Mobina Amiri
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Rafieh Alizadeh
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Mahdi Rezayat
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shima Tavakol
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Research and Development, Tavakol BioMimetic Technologies Company, Tehran, Iran.
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Aryal B, Kwakye J, Ariyo OW, Ghareeb AFA, Milfort MC, Fuller AL, Khatiwada S, Rekaya R, Aggrey SE. Major Oxidative and Antioxidant Mechanisms During Heat Stress-Induced Oxidative Stress in Chickens. Antioxidants (Basel) 2025; 14:471. [PMID: 40298812 PMCID: PMC12023971 DOI: 10.3390/antiox14040471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 04/30/2025] Open
Abstract
Heat stress (HS) is one of the most important stressors in chickens, and its adverse effects are primarily caused by disturbing the redox homeostasis. An increase in electron leakage from the mitochondrial electron transport chain is the major source of free radical production under HS, which triggers other enzymatic systems to generate more radicals. As a defense mechanism, cells have enzymatic and non-enzymatic antioxidant systems that work cooperatively against free radicals. The generation of free radicals, particularly the reactive oxygen species (ROS) and reactive nitrogen species (RNS), under HS condition outweighs the cellular antioxidant capacity, resulting in oxidative damage to macromolecules, including lipids, carbohydrates, proteins, and DNA. Understanding these detrimental oxidative processes and protective defense mechanisms is important in developing mitigation strategies against HS. This review summarizes the current understanding of major oxidative and antioxidant systems and their molecular mechanisms in generating or neutralizing the ROS/RNS. Importantly, this review explores the potential mechanisms that lead to the development of oxidative stress in heat-stressed chickens, highlighting their unique behavioral and physiological responses against thermal stress. Further, we summarize the major findings associated with these oxidative and antioxidant mechanisms in chickens.
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Affiliation(s)
- Bikash Aryal
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691, USA;
| | - Josephine Kwakye
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
| | - Oluwatomide W. Ariyo
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
| | - Ahmed F. A. Ghareeb
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
- Boehringer Ingelheim Animal Health (BIAH), Gainesville, GA 30501, USA
| | - Marie C. Milfort
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
| | - Alberta L. Fuller
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
| | - Saroj Khatiwada
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691, USA;
| | - Romdhane Rekaya
- Department of Animal and Dairy Science, The University of Georgia, Athens, GA 30602, USA;
| | - Samuel E. Aggrey
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
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Filho CC, Melfior L, Ramos SL, Pizi MSO, Taruhn LF, Muller ME, Nunes TK, Schmitt LDO, Gaspar JM, de Oliveira MDA, Tassinari G, Cruz L, Latini A. Tetrahydrobiopterin and Autism Spectrum Disorder: A Systematic Review of a Promising Therapeutic Pathway. Brain Sci 2025; 15:151. [PMID: 40002484 PMCID: PMC11853471 DOI: 10.3390/brainsci15020151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/25/2025] [Accepted: 01/30/2025] [Indexed: 02/27/2025] Open
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, along with restricted and repetitive patterns of behavior, interests, or activities. ASD encompasses a wide spectrum of clinical presentations and functional impairments, ranging from mild to severe. Despite its prevalence, the underlying physiopathological mechanisms of ASD remain largely unknown, resulting in a lack of effective targeted therapeutic interventions, contributing to significant financial and emotional burdens on affected families and the healthcare system. Emerging evidence suggests that dysfunction in the tetrahydrobiopterin (BH4) pathway may impair the activity of monoaminergic and nitric oxide (NO)-dependent neurons in individuals with ASD. To explore this potential mechanism, we conducted a systematic review to analyze such impairments to gather information on whether the off-label use of BH4 could represent a novel pharmacological approach for managing ASD. Following the PRISMA 2020 guidelines, we systematically reviewed the literature from four databases: PubMed, Virtual Health Library, Cochrane Library, and SciELO, from January 1967 to December 2021. The quality of the included studies was assessed using the Newcastle-Ottawa scale. The inclusion criteria for this systematic review focused on identifying articles published in English that contained the following keywords, used in various combinations: autism, ASD, autism spectrum disorder, BH4, tetrahydrobiopterin, neopterin, NO, nitric oxide. The analysis was performed between December 2020 and December 2021. The collected data demonstrated that BH4 metabolism was altered in individuals with ASD. Lower levels of BH4 were reported in biological samples from ASD-affected individuals compared to age- and sex-matched controls. Additionally, neopterin levels were elevated in plasma and urine, but decreased in cerebrospinal fluid, while nitric oxide levels were consistently reported to be higher across studies. Treatment with BH4 has shown potential in improving ASD-related symptoms. The reported increase in neopterin in biological fluids indicates inflammation, while the reduction in BH4 levels suggests a potential shift in its metabolic role. Specifically, BH4 may be diverted from its primary role in neurotransmitter synthesis to function as an antioxidant or to perpetuate inflammation through NO production. Given that BH4 is a critical cofactor in monoaminergic neurotransmission, its dysfunction highlights the molecule's therapeutic potential. BH4, already FDA-approved for other conditions, emerges as a promising off-label candidate to alleviate ASD symptomatology.
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Affiliation(s)
- Clóvis Colpani Filho
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
- Medicine School, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Lucas Melfior
- Medicine School, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Sthephanie Luiz Ramos
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
- Medicine School, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | | | - Lilian Freitas Taruhn
- Medicine School, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Margrit Ellis Muller
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
- Medicine School, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Thiago Kucera Nunes
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Luísa de Oliveira Schmitt
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
- Pharmacy School, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Joana Margarida Gaspar
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Miguel de Abreu de Oliveira
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Giovanna Tassinari
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Luisa Cruz
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Alexandra Latini
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
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Gonzalez M, Clayton S, Wauson E, Christian D, Tran QK. Promotion of nitric oxide production: mechanisms, strategies, and possibilities. Front Physiol 2025; 16:1545044. [PMID: 39917079 PMCID: PMC11799299 DOI: 10.3389/fphys.2025.1545044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 01/07/2025] [Indexed: 02/09/2025] Open
Abstract
The discovery of nitric oxide (NO) and the role of endothelial cells (ECs) in its production has revolutionized medicine. NO can be produced by isoforms of NO synthases (NOS), including the neuronal (nNOS), inducible (iNOS), and endothelial isoforms (eNOS), and via the non-classical nitrate-nitrite-NO pathway. In particular, endothelium-derived NO, produced by eNOS, is essential for cardiovascular health. Endothelium-derived NO activates soluble guanylate cyclase (sGC) in vascular smooth muscle cells (VSMCs), elevating cyclic GMP (cGMP), causing vasodilation. Over the past four decades, the importance of this pathway in cardiovascular health has fueled the search for strategies to enhance NO bioavailability and/or preserve the outcomes of NO's actions. Currently approved approaches operate in three directions: 1) providing exogenous NO, 2) promoting sGC activity, and 3) preventing degradation of cGMP by inhibiting phosphodiesterase 5 activity. Despite clear benefits, these approaches face challenges such as the development of nitrate tolerance and endothelial dysfunction. This highlights the need for sustainable options that promote endogenous NO production. This review will focus on strategies to promote endogenous NO production. A detailed review of the mechanisms regulating eNOS activity will be first provided, followed by a review of strategies to promote endogenous NO production based on the levels of available preclinical and clinical evidence, and perspectives on future possibilities.
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Affiliation(s)
| | | | | | | | - Quang-Kim Tran
- Department of Physiology and Pharmacology, Des Moines University Medicine and Health Sciences, West Des Moines, IA, United States
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Stuivenberg GA, Poon A, Burton JP, Spence JD. Potential effects of probiotics on atherosclerosis. MICROBIOME RESEARCH REPORTS 2024; 4:11. [PMID: 40207282 PMCID: PMC11977382 DOI: 10.20517/mrr.2024.22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 11/29/2024] [Accepted: 12/11/2024] [Indexed: 04/11/2025]
Abstract
The rising global incidence of atherosclerosis highlights the inadequacies in our understanding of the pathophysiology and treatment of the disease. Increasing evidence outlines the importance of the intestinal microbiome in atherosclerosis, wherein gut-derived uremic toxins (GDUTs) may be of concern. Plasma levels of the GDUTs trimethylamine n-oxide (TMAO), p-cresyl sulfate, and indoxyl sulfate are associated with accelerated renal function decline and increased cardiovascular risk. Thus, reducing the amount of GDUTs in circulation is expected to benefit patients with atherosclerosis. Because some beneficial bacteria can clear GDUTs in vitro and in vivo, orally administered probiotics targeting the intestinal tract represent a promising way to bring about these changes. Atherosclerosis such, this perspective reviews the potential use of probiotics to treat atherosclerosis, particularly in patients with non-traditional risk factors and/or impaired renal function.
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Affiliation(s)
- Gerrit A. Stuivenberg
- Microbiology and Immunology, Western University, London N6A 3K7, Canada
- The Canadian Centre for Human Microbiome and Probiotic Research, Lawson Health Research Institute, London N6A 4V2, Canada
| | - Annabel Poon
- Microbiology and Immunology, Western University, London N6A 3K7, Canada
- The Canadian Centre for Human Microbiome and Probiotic Research, Lawson Health Research Institute, London N6A 4V2, Canada
| | - Jeremy P. Burton
- Microbiology and Immunology, Western University, London N6A 3K7, Canada
- The Canadian Centre for Human Microbiome and Probiotic Research, Lawson Health Research Institute, London N6A 4V2, Canada
| | - J. David Spence
- Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London N6G 2V4, Canada
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Kannenkeril D, Bosch A, Kolwelter J, Striepe K, Berner L, Pietschner R, Ott C, Schiffer M, Achenbach S, Schmieder RE. PCSK-9-inhibitor therapy improves endothelial function in high-risk patients with cardiovascular disease. Clin Res Cardiol 2024:10.1007/s00392-024-02556-6. [PMID: 39565386 DOI: 10.1007/s00392-024-02556-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/04/2024] [Indexed: 11/21/2024]
Abstract
BACKGROUND Impaired endothelial function predicts cardiovascular events. The aim of this study was to analyze the effect of evolocumab on endothelial function in patients with cardiovascular disease. METHODS This was a prospective, double-blinded, randomized, controlled, single center study including patients with cardiovascular disease and treated with statins. Patients were consecutively randomized (1:1) to either evolocumab treatment or placebo. All patients underwent examination of endothelial function at baseline, and after 1, 4 and 8 weeks of treatment by a semi-automatic high-resolution ultrasound system (UNEX EF 18G). Parameters of endothelial function were flow-mediated vasodilation (FMD), low flow-mediated vasoconstriction (L-FMC) and vasoactive range (VAR). RESULTS Hundred three patients with a mean age of 66.2 ± 7.7 years and a mean LDL-cholesterol of 98 ± 19.1 mg/dl completed the study. The change in VAR from baseline to week 8 was significantly different with evolocumab compared to placebo (p = 0.045). Moreover, VAR increased after 8 weeks of treatment with evolocumab compared to baseline (p = 0.034). No change has been noticed in FMD and L-FMC after 8 weeks of treatment with evolocumab. In subgroup analyses, VAR improved in patients with age ≤ 67 years, lower systolic blood pressure (≤ 125 mmHg) and higher baseline LDL-cholesterol (> 95 mg/dl), (p = 0.006, p = 0.049 and p = 0.042, respectively) after 8 weeks of evolocumab treatment. No serious adverse event related to study medication occurred during the study. CONCLUSION Our data indicate that endothelial function improved with evolocumab treatment in high-risk patients on statin therapy with preexisting cardiovascular disease. Our results contribute to the mechanistic explanation why lower incidence of the cardiovascular composite endpoint has been demonstrated in the FOURIER study.
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Affiliation(s)
- Dennis Kannenkeril
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
| | - Agnes Bosch
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
| | - Julie Kolwelter
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
- Department of Cardiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Kristina Striepe
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
| | - Laura Berner
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
| | - Robert Pietschner
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
| | - Christian Ott
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
| | - Mario Schiffer
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
| | - Stephan Achenbach
- Department of Cardiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Roland E Schmieder
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany.
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Chakraborty S, Choudhuri A, Mishra A, Sengupta R. The hunt for transnitrosylase. Nitric Oxide 2024; 152:31-47. [PMID: 39299646 DOI: 10.1016/j.niox.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/04/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024]
Abstract
The biochemical interplay between antioxidants and pro-oxidants maintains the redox homeostatic balance of the cell, which, when perturbed to moderate or high extents, has been implicated in the onset and/or progression of chronic diseases such as diabetes mellitus, cancer, and neurodegenerative diseases. Thioredoxin, glutaredoxin, and lipoic acid-like thiol oxidoreductase systems constitute a unique ensemble of robust cellular antioxidant defenses, owing to their indispensable roles as S-denitrosylases, S-deglutathionylases, and disulfide reductants in maintaining a reduced free thiol state with biological relevance. Thus, in cells subjected to nitrosative stress, cellular antioxidants will S-denitrosylate their cognate S-nitrosoprotein substrates, rather than participate in trans-S-nitrosylation via protein-protein interactions. Researchers have been at the forefront of vaguely establishing the concept of 'transnitrosylation' and its influence on pathophysiology with experimental evidence from in vitro studies that lack proper biochemical logic. The suggestive and reiterative use of antioxidants as transnitrosylases in the scientific literature leaves us on a cliffhanger with several open-ended questions that prompted us to 'hunt' for scientific logic behind the trans-S-nitrosylation chemistry. Given the gravity of the situation and to look at the bigger picture of 'trans-S-nitrosylation', we aim to present a novel attempt at justifying the hesitance in accepting antioxidants as capable of transnitrosylating their cognate protein partners and reflecting on the need to resolve the controversy that would be crucial from the perspective of understanding therapeutic outcomes involving such cellular antioxidants in disease pathogenesis. Further characterization is required to identify the regulatory mechanisms or conditions where an antioxidant like Trx, Grx, or DJ-1 can act as a cellular transnitrosylase.
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Affiliation(s)
- Surupa Chakraborty
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Ankita Choudhuri
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Akansha Mishra
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Rajib Sengupta
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India.
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Fidanboylu M, Thomas SA. L-Arginine and asymmetric dimethylarginine (ADMA) transport across the mouse blood-brain and blood-CSF barriers: Evidence of saturable transport at both interfaces and CNS to blood efflux. PLoS One 2024; 19:e0305318. [PMID: 39446890 PMCID: PMC11501026 DOI: 10.1371/journal.pone.0305318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/09/2024] [Indexed: 10/26/2024] Open
Abstract
L-Arginine is the physiological substrate for the nitric oxide synthase (NOS) family, which synthesises nitric oxide (NO) in endothelial and neuronal cells. NO synthesis can be inhibited by endogenous asymmetric dimethylarginine (ADMA). NO has explicit roles in cellular signalling and vasodilation. Impaired NO bioavailability represents the central feature of endothelial dysfunction associated with vascular diseases. Interestingly, dietary supplementation with L-arginine has been shown to alleviate endothelial dysfunctions caused by impaired NO synthesis. In this study the transport kinetics of [3H]-arginine and [3H]-ADMA into the central nervous system (CNS) were investigated using physicochemical assessment and the in situ brain/choroid plexus perfusion technique in anesthetized mice. Results indicated that L-arginine and ADMA are tripolar cationic amino acids and have a gross charge at pH 7.4 of 0.981. L-Arginine (0.00149±0.00016) has a lower lipophilicity than ADMA (0.00226±0.00006) as measured using octanol-saline partition coefficients. The in situ perfusion studies revealed that [3H]-arginine and [3H]-ADMA can cross the blood-brain barrier (BBB) and the blood-CSF barrier. [3H]-Arginine (11.6nM) and [3H]-ADMA (62.5nM) having unidirectional transfer constants (Kin) into the frontal cortex of 5.84±0.86 and 2.49±0.35 μl.min-1.g-1, respectively, and into the CSF of 1.08±0.24 and 2.70±0.90 μl.min-1.g-1, respectively. In addition, multiple-time uptake studies revealed the presence of CNS-to-blood efflux of ADMA. Self- and cross-inhibition studies indicated the presence of transporters at the BBB and the blood-CSF barriers for both amino acids, which were shared to some degree. Importantly, these results are the first to demonstrate: (i) saturable transport of [3H]-ADMA at the blood-CSF barrier (choroid plexus) and (ii) a significant CNS to blood efflux of [3H]-ADMA. Our results suggest that the arginine paradox, in other words the clinical observation that NO-deficient patients respond well to oral supplementation with L-arginine even though the plasma concentration is sufficient to saturate endothelial NOS, could be related to altered ADMA transport (efflux).
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Affiliation(s)
- Mehmet Fidanboylu
- Pharmaceutical Sciences Research Division, King’s College London, London, United Kingdom
- Institute of Pharmaceutical Science, King’s College London, London, United Kingdom
| | - Sarah Ann Thomas
- Pharmaceutical Sciences Research Division, King’s College London, London, United Kingdom
- Institute of Pharmaceutical Science, King’s College London, London, United Kingdom
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10
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Wang X, Yang X, Qi X, Fan G, Zhou L, Peng Z, Yang J. Anti-atherosclerotic effect of incretin receptor agonists. Front Endocrinol (Lausanne) 2024; 15:1463547. [PMID: 39493783 PMCID: PMC11527663 DOI: 10.3389/fendo.2024.1463547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 09/30/2024] [Indexed: 11/05/2024] Open
Abstract
Incretin receptor agonists (IRAs), primarily composed of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs), work by mimicking the actions of the endogenous incretin hormones in the body. GLP-1RAs have been approved for use as monotherapy and in combination with GIPRAs for the management of type 2 diabetes mellitus (T2DM). In addition to their role in glucose regulation, IRAs have demonstrated various benefits such as cardiovascular protection, obesity management, and regulation of bone turnover. Some studies have suggested that IRAs not only aid in glycemic control but also exhibit anti-atherosclerotic effects. These agents have been shown to modulate lipid abnormalities, reduce blood pressure, and preserve the structural and functional integrity of the endothelium. Furthermore, IRAs have the ability to mitigate inflammation by inhibiting macrophage activation and promoting M2 polarization. Research has also indicated that IRAs can decrease macrophage foam cell formation and prevent vascular smooth muscle cell (VSMC) phenotype switching, which are pivotal in atheromatous plaque formation and stability. This review offers a comprehensive overview of the protective effects of IRAs in atherosclerotic disease, with a focus on their impact on atherogenesis.
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Affiliation(s)
- Xin Wang
- Department of Metabolism and Endocrinology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xin Yang
- Department of Metabolism and Endocrinology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xiaoyan Qi
- Department of Metabolism and Endocrinology, Shenzhen Nanshan People's Hospital; The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China
| | - Gang Fan
- Department of Urology, Shenzhen Nanshan People's Hospital; The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China
| | - Lingzhi Zhou
- Department of pediatrics, Shenzhen Nanshan People's Hospital; The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China
| | - Zhengliang Peng
- Department of Emergency, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jing Yang
- Department of Metabolism and Endocrinology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Department of Metabolism and Endocrinology, Shenzhen Nanshan People's Hospital; The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China
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11
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Lin HY, Lu JH, Lin RJ, Chueh KS, Juan TJ, Mao JW, Lee YC, Chuang SM, Shen MC, Sun TW, Juan YS. Effects of Nitric Oxide on Bladder Detrusor Overactivity through the NRF2 and HIF-1α Pathways: A Rat Model Induced by Metabolic Syndrome and Ovarian Hormone Deficiency. Int J Mol Sci 2024; 25:11103. [PMID: 39456884 PMCID: PMC11507610 DOI: 10.3390/ijms252011103] [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: 08/22/2024] [Revised: 10/01/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
Metabolic syndrome (MetS) includes cardiovascular risk factors like obesity, dyslipidemia, hypertension, and glucose intolerance, which increase the risk of overactive bladder (OAB), characterized by urgency, frequency, urge incontinence, and nocturia. Both MetS and ovarian hormone deficiency (OHD) are linked to bladder overactivity. Nitric oxide (NO) is known to reduce inflammation and promote healing but its effect on bladder overactivity in MetS and OHD is unclear. This study aimed to investigate NO's impact on detrusor muscle hyperactivity in rats with MetS and OHD. Female Sprague-Dawley rats were divided into seven groups based on diet and treatments involving L-arginine (NO precursor) and L-NAME (NOS inhibitor). After 12 months on a high-fat, high-sugar diet with or without OVX, a cystometrogram and tracing analysis of voiding behavior were used to identify the symptoms of detrusor hyperactivity. The MetS with or without OHD group had a worse bladder contractile response while L-arginine ameliorated bladder contractile function. In summary, MetS with or without OHD decreased NO production, reduced angiogenesis, and enhanced oxidative stress to cause bladder overactivity, mediated through the NF-kB signaling pathway, whereas L-arginine ameliorated the symptoms of detrusor overactivity and lessened oxidative damage via the NRF2/HIF-1α signaling pathway in MetS with or without OHD-induced OAB.
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Affiliation(s)
- Hung-Yu Lin
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung 84001, Taiwan;
- Division of Urology, Department of Surgery, E-Da Cancer Hospital, I-Shou University, Kaohsiung 824005, Taiwan
- Division of Urology, Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan
| | - Jian-He Lu
- Center for Agricultural, Forestry, Fishery, Livestock and Aquaculture Carbon Emission Inventory and Emerging Compounds, General Research Service Center, National Pingtung University of Science and Technology, Pingtung County 912301, Taiwan;
| | - Rong-Jyh Lin
- Department of Parasitology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
| | - Kuang-Shun Chueh
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80661, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (J.-W.M.); (S.-M.C.); (M.-C.S.); (T.-W.S.)
| | - Tai-Jui Juan
- Kaohsiung Armed Forces General Hospital, Kaohsiung 802301, Taiwan
- Department of Thoracic Surgery Division, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Jing-Wen Mao
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (J.-W.M.); (S.-M.C.); (M.-C.S.); (T.-W.S.)
| | - Yi-Chen Lee
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
| | - Shu-Mien Chuang
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (J.-W.M.); (S.-M.C.); (M.-C.S.); (T.-W.S.)
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Mei-Chen Shen
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (J.-W.M.); (S.-M.C.); (M.-C.S.); (T.-W.S.)
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Ting-Wei Sun
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (J.-W.M.); (S.-M.C.); (M.-C.S.); (T.-W.S.)
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Yung-Shun Juan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (J.-W.M.); (S.-M.C.); (M.-C.S.); (T.-W.S.)
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
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12
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Buck HV, Torre OM, Leser JM, Gould NR, Ward CW, Stains JP. Nitric oxide contributes to rapid sclerostin protein loss following mechanical load. Biochem Biophys Res Commun 2024; 727:150315. [PMID: 38950493 DOI: 10.1016/j.bbrc.2024.150315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 06/24/2024] [Indexed: 07/03/2024]
Abstract
In response to mechanical loading of bone, osteocytes produce nitric oxide (NO•) and decrease sclerostin protein expression, leading to an increase in bone mass. However, it is unclear whether NO• production and sclerostin protein loss are mechanistically linked, and, if so, the nature of their hierarchical relationship within an established mechano-transduction pathway. Prior work showed that following fluid-shear stress (FSS), osteocytes produce NOX2-derived reactive oxygen species, inducing calcium (Ca2+) influx. Increased intracellular Ca2+ results in calcium-calmodulin dependent protein kinase II (CaMKII) activation, which regulates the lysosomal degradation of sclerostin protein. Here, we extend our discoveries, identifying NO• as a regulator of sclerostin degradation downstream of mechano-activated CaMKII. Pharmacological inhibition of nitric oxide synthase (NOS) activity in Ocy454 osteocyte-like cells prevented FSS-induced sclerostin protein loss. Conversely, short-term treatment with a NO• donor in Ocy454 cells or isolated murine long bones was sufficient to induce the rapid decrease in sclerostin protein abundance, independent of changes in Sost gene expression. Ocy454 cells express all three NOS genes, and transfection with siRNAs targeting eNOS/Nos3 was sufficient to prevent FSS-induced loss of sclerostin protein, while siRNAs targeting iNOS/Nos2 mildly blunted the loss of sclerostin but did not reach statistical significance. Similarly, siRNAs targeting both eNOS/Nos3 and iNOS/Nos2 prevented FSS-induced NO• production. Together, these data show iNOS/Nos2 and eNOS/Nos3 are the primary producers of FSS-dependent NO•, and that NO• is necessary and sufficient for sclerostin protein control. Further, selective inhibition of elements within this sclerostin-controlling mechano-transduction pathway indicated that NO• production occurs downstream of CaMKII activation. Targeting Camk2d and Camk2g with siRNA in Ocy454 cells prevented NO• production following FSS, indicating that CaMKII is needed for NO• production. However, NO• donation (1min) resulted in a significant increase in CaMKII activation, suggesting that NO• may have the ability to tune CaMKII response. Together, these data support that CaMKII is necessary for, and may be modulated by NO•, and that the interaction of these two signals is involved in the control of sclerostin protein abundance, consistent with a role in bone anabolic responses.
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Affiliation(s)
- Heather V Buck
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Olivia M Torre
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Jenna M Leser
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Nicole R Gould
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Christopher W Ward
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Joseph P Stains
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
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13
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Wan W, Wang N. Polarized benzene rings can promote the interaction between CaM and the CaMBD region of nNOS. Front Mol Neurosci 2024; 17:1461272. [PMID: 39290828 PMCID: PMC11405375 DOI: 10.3389/fnmol.2024.1461272] [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: 07/08/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024] Open
Abstract
Introduction The neuronal nitric oxide synthase (nNOS) subtype of nitric oxide synthase (NOS) is an enzyme required for learning and memory. Overactivation of nNOS can lead to oxidative/nitrite stress, which is complicit in the pathophysiology of various neurological and psychiatric disorders. Previous studies have shown that calmodulin (CaM) forms complexes with Ca2+ and binds to the calmodulin-binding domain (CaMBD) of nNOS, thereby upregulating its catalytic activity in hippocampal neurons. To date, there has been no explanation for the non-covalent interactions in the CaMBD-CaM binding structure model of nNOS. Methods In this study, we aimed to investigate the intrinsic factors involved in the binding of CaM to NOS-CaMBD and designed interfering peptides based on the N0 peptide structure of the original nNOS-CaMBD sequence: N1 (obtained from the L734F mutation), N2 (obtained from the F731Y and F740Y mutations), and N3 (obtained from the F731L, V738L, and F740L mutations). We employed homology modeling to construct six CaM-peptide complex models, aiming to elucidate the roles of key amino acid residues within the N0 peptide in its interaction with CaM by means of molecular dynamics simulations. The effect of the peptides on the activation and release of NO by nNOS in neurons was assessed using murine primary neuronal cells. Results When measuring neuronal NO content, it was found that adding N2 and N3 to cultivated neurons significantly increased nNOS activity, leading to the increased NO production. We found that interfering peptides could stably bind to CaM. Among them, N2 and CaM exhibited the strongest binding ability, indicating that the polarized benzene ring significantly enhanced the binding between nNOS-CaMBD and CaM. Conversely, the binding ability between N0 and CaM was the weakest, as they exhibited the worst polar contact, weakest hydrogen bonding, and the lowest binding free energy. The simulation results also highlighted several important amino acid residues: The K76 of CaM plays an important role in polar contact and hydrogen bonding formation, the L734 residue suppressed model flexibility to a certain extent and had an adverse effect on the overall binding free energy of the model. These results, compared with the results of cellular NO content, a preliminary verification of the antagonistic competitive mechanism between CaM allosteric activation of nNOS and SUMOylation hyperactivation was performed. Discussion In summary, this study explored the ability and mode of action of key residues in nNOS-CaMBD on the binding of interfering peptides to CaM, thereby providing new structural perspectives for the activation of nNOS by CaM and recommendations for drug design targeting the specific inhibition of nNOS.
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Affiliation(s)
- Wei Wan
- Research Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center of Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Nan Wang
- Research Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center of Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
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Milusheva M, Stoyanova M, Gledacheva V, Stefanova I, Todorova M, Pencheva M, Stojnova K, Tsoneva S, Nedialkov P, Nikolova S. 2-Amino- N-Phenethylbenzamides for Irritable Bowel Syndrome Treatment. Molecules 2024; 29:3375. [PMID: 39064953 PMCID: PMC11280360 DOI: 10.3390/molecules29143375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain or discomfort. Mebeverine is an antispasmodic that has been widely used in clinical practice to relieve the symptoms of IBS. However, its systemic use usually leads to side effects. Therefore, the current paper aimed to synthesize more effective medicines for IBS treatment. We used ring opening of isatoic anhydride for the synthesis in reaction with 2-phenylethylamine. In silico simulation predicted spasmolytic activity for 2-amino-N-phenethylbenzamides. The newly synthesized compounds demonstrated a relaxation effect similar to mebeverine but did not affect the serotonin or Ca2+-dependent signaling pathway of contractile activity (CA) in contrast. Having in mind the anti-inflammatory potential of antispasmodics, the synthesized molecules were tested in vitro and ex vivo for their anti-inflammatory effects. Four of the newly synthesized compounds demonstrated very good activity by preventing albumin denaturation compared to anti-inflammatory drugs/agents well-established in medicinal practice. The newly synthesized compounds also inhibited the expression of interleukin-1β and stimulated the expression of neuronal nitric oxide synthase (nNOS), and, consequently, nitric oxide (NO) synthesis by neurons of the myenteric plexus. This characterizes the newly synthesized compounds as biologically active relaxants, offering a cleaner and more precise application in pharmacological practice, thereby enhancing their potential therapeutic value.
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Affiliation(s)
- Miglena Milusheva
- Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 4000 Plovdiv, Bulgaria or (M.M.); (M.S.); (M.T.)
- Department of Bioorganic Chemistry, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
| | - Mihaela Stoyanova
- Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 4000 Plovdiv, Bulgaria or (M.M.); (M.S.); (M.T.)
| | - Vera Gledacheva
- Department of Medical Physics and Biophysics, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (V.G.); (I.S.); (M.P.)
| | - Iliyana Stefanova
- Department of Medical Physics and Biophysics, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (V.G.); (I.S.); (M.P.)
| | - Mina Todorova
- Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 4000 Plovdiv, Bulgaria or (M.M.); (M.S.); (M.T.)
| | - Mina Pencheva
- Department of Medical Physics and Biophysics, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (V.G.); (I.S.); (M.P.)
| | - Kirila Stojnova
- Department of General and Inorganic Chemistry with Methodology of Chemistry Education, Faculty of Chemistry, University of Plovdiv, 4000 Plovdiv, Bulgaria;
| | - Slava Tsoneva
- Department of Analytical Chemistry and Computer Chemistry, University of Plovdiv, 4000 Plovdiv, Bulgaria;
| | - Paraskev Nedialkov
- Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria;
| | - Stoyanka Nikolova
- Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 4000 Plovdiv, Bulgaria or (M.M.); (M.S.); (M.T.)
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Graton ME, Spaans F, He R, Chatterjee P, Kirschenman R, Quon A, Phillips TJ, Case CP, Davidge ST. Sex-specific differences in the mechanisms for enhanced thromboxane A 2-mediated vasoconstriction in adult offspring exposed to prenatal hypoxia. Biol Sex Differ 2024; 15:52. [PMID: 38898532 PMCID: PMC11188502 DOI: 10.1186/s13293-024-00627-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 06/14/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment. METHODS Pregnant Sprague-Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence. RESULTS Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels. CONCLUSIONS Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring.
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Affiliation(s)
- Murilo E Graton
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, T6G 2R3, Canada
- Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada
| | - Floor Spaans
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, T6G 2R3, Canada
- Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada
| | - Rose He
- Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada
- Department of Physiology, University of Alberta, Edmonton, AB, T6G 2R3, Canada
| | - Paulami Chatterjee
- Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada
- Department of Physiology, University of Alberta, Edmonton, AB, T6G 2R3, Canada
| | - Raven Kirschenman
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, T6G 2R3, Canada
- Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada
| | - Anita Quon
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, T6G 2R3, Canada
- Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada
| | - Tom J Phillips
- UK Dementia Research Institute, Cardiff University, Cardiff, W1T 7NF, UK
| | - C Patrick Case
- Musculoskeletal Research Unit, University of Bristol, Bristol, BS8 1QU, UK
| | - Sandra T Davidge
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, T6G 2R3, Canada.
- Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada.
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16
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Chirivi M, Contreras GA. Endotoxin-induced alterations of adipose tissue function: a pathway to bovine metabolic stress. J Anim Sci Biotechnol 2024; 15:53. [PMID: 38581064 PMCID: PMC10998405 DOI: 10.1186/s40104-024-01013-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/14/2024] [Indexed: 04/07/2024] Open
Abstract
During the periparturient period, dairy cows exhibit negative energy balance due to limited appetite and increased energy requirements for lactogenesis. The delicate equilibrium between energy availability and expenditure puts cows in a state of metabolic stress characterized by excessive lipolysis in white adipose tissues (AT), increased production of reactive oxygen species, and immune cell dysfunction. Metabolic stress, especially in AT, increases the risk for metabolic and inflammatory diseases. Around parturition, cows are also susceptible to endotoxemia. Bacterial-derived toxins cause endotoxemia by promoting inflammatory processes and immune cell infiltration in different organs and systems while impacting metabolic function by altering lipolysis, mitochondrial activity, and insulin sensitivity. In dairy cows, endotoxins enter the bloodstream after overcoming the defense mechanisms of the epithelial barriers, particularly during common periparturient conditions such as mastitis, metritis, and pneumonia, or after abrupt changes in the gut microbiome. In the bovine AT, endotoxins induce a pro-inflammatory response and stimulate lipolysis in AT, leading to the release of free fatty acids into the bloodstream. When excessive and protracted, endotoxin-induced lipolysis can impair adipocyte's insulin signaling pathways and lipid synthesis. Endotoxin exposure can also induce oxidative stress in AT through the production of reactive oxygen species by inflammatory cells and other cellular components. This review provides insights into endotoxins' impact on AT function, highlighting the gaps in our knowledge of the mechanisms underlying AT dysfunction, its connection with periparturient cows' disease risk, and the need to develop effective interventions to prevent and treat endotoxemia-related inflammatory conditions in dairy cattle.
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Affiliation(s)
- Miguel Chirivi
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA
| | - G Andres Contreras
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA.
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Knuchel R, Erlic Z, Gruber S, Amar L, Larsen CK, Gimenez-Roqueplo AP, Mulatero P, Tetti M, Pecori A, Pamporaki C, Langton K, Peitzsch M, Ceccato F, Prejbisz A, Januszewicz A, Adolf C, Remde H, Lenzini L, Dennedy M, Deinum J, Jefferson E, Blanchard A, Zennaro MC, Eisenhofer G, Beuschlein F. Association of adrenal steroids with metabolomic profiles in patients with primary and endocrine hypertension. Front Endocrinol (Lausanne) 2024; 15:1370525. [PMID: 38596218 PMCID: PMC11002274 DOI: 10.3389/fendo.2024.1370525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 03/05/2024] [Indexed: 04/11/2024] Open
Abstract
Introduction Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing's syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT. Methods Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus. Results After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites - 18 in PPGL, 15 in CS, and 23 in PA - were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites. Discussions Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL's metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.
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Affiliation(s)
- Robin Knuchel
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich (USZ) und Universität Zürich (UZH), Zurich, Switzerland
| | - Zoran Erlic
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich (USZ) und Universität Zürich (UZH), Zurich, Switzerland
| | - Sven Gruber
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich (USZ) und Universität Zürich (UZH), Zurich, Switzerland
| | - Laurence Amar
- Université Paris Cité, Paris Cardiovascular Research Center (PARCC), L'Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
- Département de Médecine Génomique des Tumeurs et des Cancers, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
- Centre de référence en maladies rares de la surrénale, Hôpital Européen Georges Pompidou, Paris, France
| | - Casper K. Larsen
- Université Paris Cité, Paris Cardiovascular Research Center (PARCC), L'Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Anne-Paule Gimenez-Roqueplo
- Université Paris Cité, Paris Cardiovascular Research Center (PARCC), L'Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
- Département de Médecine Génomique des Tumeurs et des Cancers, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
| | - Paolo Mulatero
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Martina Tetti
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Alessio Pecori
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Christina Pamporaki
- Medical Clinic III, University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Dresden, Germany
| | - Katharina Langton
- Medical Clinic III, University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Dresden, Germany
| | - Mirko Peitzsch
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Filippo Ceccato
- Unita' Operativa Complessa (UOC) Endocrinologia, Dipartimento di Medicina DIMED, Azienda Ospedaliera-Università di Padova, Padua, Italy
| | - Aleksander Prejbisz
- Department of Hypertension, National Institute of Cardiology, Warsaw, Poland
| | - Andrzej Januszewicz
- Department of Hypertension, National Institute of Cardiology, Warsaw, Poland
| | - Christian Adolf
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München, Munich, Germany
| | - Hanna Remde
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
| | - Livia Lenzini
- Internal & Emergency Medicine Unit, Department of Medicine - DIMED, University of Padua, Padua, Italy
| | - Michael Dennedy
- The Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland
| | - Jaap Deinum
- Department of Medicine, Section of Vascular Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Emily Jefferson
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, United Kingdom
| | - Anne Blanchard
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre d’Investigations Cliniques, Paris, France
| | - Maria-Christina Zennaro
- Université Paris Cité, Paris Cardiovascular Research Center (PARCC), L'Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité Hypertension artérielle, Paris, France
| | - Graeme Eisenhofer
- Medical Clinic III, University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Dresden, Germany
| | - Felix Beuschlein
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich (USZ) und Universität Zürich (UZH), Zurich, Switzerland
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München, Munich, Germany
- The LOOP Zurich - Medical Research Center, Zurich, Switzerland
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Pereira DA, Luizon MR, Palei AC, Tanus-Santos JE, Cavalli RC, Sandrim VC. Functional polymorphisms of NOS3 and GUCY1A3 affect both nitric oxide formation and association with hypertensive disorders of pregnancy. Front Genet 2024; 15:1293082. [PMID: 38469120 PMCID: PMC10925623 DOI: 10.3389/fgene.2024.1293082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 02/12/2024] [Indexed: 03/13/2024] Open
Abstract
Impaired nitric oxide (NO) formation may be associated with endothelial dysfunction and increased cardiovascular disease risk in preeclampsia (PE). Functional single-nucleotide polymorphisms (SNPs) of nitric oxide synthase 3 (NOS3) (rs3918226) and guanylate cyclase 1, soluble, alpha 3 (GUCY1A3) (rs7692387) increase susceptibility to the adverse consequences due to inadequate generation of NO by the endothelium. However, no previous study has examined whether these SNPs affect NO formation in healthy pregnancy and in gestational hypertension (GH) and PE. Here, we compared the alleles and genotypes of NOS3 (rs3918226) and GUCY1A3 (rs7692387) SNPs in normotensive pregnant women (NP, n = 153), in GH (n = 96) and PE (n = 163), and examined whether these SNPs affect plasma nitrite concentrations (a marker of NO formation) in these groups. We further examined whether the interaction among SNP genotypes is associated with GH and PE. Genotypes were determined using TaqMan allele discrimination assays, and plasma nitrite concentrations were determined by an ozone-based chemiluminescence assay. Multifactor dimensionality reduction was used to examine the interactions among SNP genotypes. Regarding NOS3 rs3918226, the CT genotype (p = 0.046) and T allele (p = 0.020) were more frequent in NP than in GH, and GH patients carrying the CT+TT genotypes showed lower nitrite concentrations than NP carrying the CT+TT genotypes (p < 0.05). Regarding GUCY1A3 rs7692387, the GA genotype (p = 0.013) and A allele (p = 0.016) were more frequent in PE than in NP, and NP women carrying the GG genotype showed higher nitrite concentrations than GH or PE patients carrying the GG genotype (p < 0.05). However, we found no significant interactions among genotypes for these functional SNPs to be associated with GH or PE. Our novel findings suggest that NOS3 rs3918226 and GUCY1A3 rs7692387 may affect NO formation and association with hypertensive disorders of pregnancy.
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Affiliation(s)
- Daniela A. Pereira
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Marcelo R. Luizon
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Department of Biophysics and Pharmacology, Institute of Biosciences, Universidade Estadual Paulista (UNESP), Botucatu, Brazil
| | - Ana C. Palei
- Department of Surgery, University of Mississippi Medical Center, Jackson, MS, United States
| | - José E. Tanus-Santos
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil
| | - Ricardo C. Cavalli
- Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil
| | - Valeria C. Sandrim
- Department of Biophysics and Pharmacology, Institute of Biosciences, Universidade Estadual Paulista (UNESP), Botucatu, Brazil
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Coavoy-Sanchez SA, da Costa Marques LA, Costa SKP, Muscara MN. Role of Gasotransmitters in Inflammatory Edema. Antioxid Redox Signal 2024; 40:272-291. [PMID: 36974358 DOI: 10.1089/ars.2022.0089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Significance: Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are, to date, the identified members of the gasotransmitter family, which consists of gaseous signaling molecules that play central roles in the regulation of a wide variety of physiological and pathophysiological processes, including inflammatory edema. Recent Advances: Recent studies show the potential anti-inflammatory and antiedematogenic effects of NO-, CO-, and H2S-donors in vivo. In general, it has been observed that the therapeutical effects of NO-donors are more relevant when administered at low doses at the onset of the inflammatory process. Regarding CO-donors, their antiedematogenic effects are mainly associated with inhibition of proinflammatory mediators (such as inducible NO synthase [iNOS]-derived NO), and the observed protective effects of H2S-donors seem to be mediated by reducing some proinflammatory enzyme activities. Critical Issues: The most recent investigations focus on the interactions among the gasotransmitters under different pathophysiological conditions. However, the biochemical/pharmacological nature of these interactions is neither general nor fully understood, although specifically dependent on the site where the inflammatory edema occurs. Future Directions: Considering the nature of the involved mechanisms, a deeper knowledge of the interactions among the gasotransmitters is mandatory. In addition, the development of new pharmacological tools, either donors or synthesis inhibitors of the three gasotransmitters, will certainly aid the basic investigations and open new strategies for the therapeutic treatment of inflammatory edema. Antioxid. Redox Signal. 40, 272-291.
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Affiliation(s)
| | | | - Soraia Katia Pereira Costa
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| | - Marcelo Nicolas Muscara
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
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20
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Mirzababaei A, Mahmoodi M, Keshtkar A, Ashraf H, Abaj F, Khosravinia D, Radmehr M, Rasaei N, Mirzaei K. Association between dietary intakes of Nitrate and Nitrite with Angina and atherogenic index in adults: A cross-sectional study from Tehran University of Medical Sciences employees` cohort (TEC) study. Curr Probl Cardiol 2024; 49:102206. [PMID: 37967801 DOI: 10.1016/j.cpcardiol.2023.102206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 11/11/2023] [Indexed: 11/17/2023]
Abstract
BACKGROUND Previous studies have shown that the intake of nitrate and nitrite may be associated with cardiovascular disease. Therefore, this study sought to investigate the association between dietary intakes of nitrate and nitrite with the odds of angina and atherogenic index in adults. METHODS The study analyzed 1182 adults aged 20+ in the Tehran University of Medical Sciences (TUMS) Employee's Cohort study (TEC), focusing on dietary intakes, angina, and atherogenic indexes, using a validated food frequency questionnaire (FFQ) and the Rose Angina Questionnaire (RAQ). RESULT The study found a significant inverse relationship between nitrate intake and odds of grade 2 angina. The highest dietary nitrate was associated with 29 % lower odds of grade 1 angina and also, 46 % lower odds of angina possible (P<0.05). Adults with the highest nitrate intake had 29 % lower odds of grade 1 angina and 46 % lower odds of angina possible. Adherence to nitrate reduced CRI, Atherogenic index of plasma, and TyG in participants, but no significant association was found with other factors. CONCLUSION The study suggests that high nitrate and nitrite intake can alter angina risk, and a reverse association was found between dietary nitrate intake and various atherogenic indices.
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Affiliation(s)
- Atieh Mirzababaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mahmoodi
- Department of Cellular and Molecular Nutrition, School of Nutritional Science and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbasali Keshtkar
- Department of Disaster and Emergency Health, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Haleh Ashraf
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Faezeh Abaj
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Darya Khosravinia
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mina Radmehr
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Niloufar Rasaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
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21
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Prado Y, Aravena D, Gatica S, Llancalahuen FM, Aravena C, Gutiérrez-Vera C, Carreño LJ, Cabello-Verrugio C, Simon F. From genes to systems: The role of food supplementation in the regulation of sepsis-induced inflammation. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166909. [PMID: 37805092 DOI: 10.1016/j.bbadis.2023.166909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 09/29/2023] [Accepted: 09/29/2023] [Indexed: 10/09/2023]
Abstract
Systemic inflammation includes a widespread immune response to a harmful stimulus that results in extensive systemic damage. One common example of systemic inflammation is sepsis, which is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Under the pro-inflammatory environment of sepsis, oxidative stress contributes to tissue damage due to dysfunctional microcirculation that progressively causes the failure of multiple organs that ultimately triggers death. To address the underlying inflammatory condition in critically ill patients, progress has been made to assess the beneficial effects of dietary supplements, which include polyphenols, amino acids, fatty acids, vitamins, and minerals that are recognized for their immuno-modulating, anticoagulating, and analgesic properties. Therefore, we aimed to review and discuss the contribution of food-derived supplementation in the regulation of inflammation from gene expression to physiological responses and summarize the precedented potential of current therapeutic approaches during systemic inflammation.
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Affiliation(s)
- Yolanda Prado
- Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Diego Aravena
- Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Sebastian Gatica
- Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Felipe M Llancalahuen
- Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Cristobal Aravena
- Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Cristián Gutiérrez-Vera
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile; Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Chile
| | - Leandro J Carreño
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile; Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Chile
| | - Claudio Cabello-Verrugio
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile; Laboratory of Muscle Pathology, Fragility and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago, Chile
| | - Felipe Simon
- Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile; Millennium Nucleus of Ion Channel-Associated Diseases, Santiago, Chile.
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Edem EE, Oguntala OA, Ikuelogbon DA, Nebo KE, Fafure AA, Akinluyi ET, Isaac GT, Kunlere OE. Prolonged ketamine therapy differentially rescues psychobehavioural deficits via modulation of nitro-oxidative stress and oxytocin receptors in the gut-brain-axis of chronically-stressed mice. Psychoneuroendocrinology 2023; 158:106370. [PMID: 37678086 DOI: 10.1016/j.psyneuen.2023.106370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 07/30/2023] [Accepted: 08/18/2023] [Indexed: 09/09/2023]
Abstract
Ketamine is an anaesthetic known to have short but rapid-acting anti-depressant effects; however, the neurobehavioural effects of its prolonged use and its role on the oxytocin system in the gut-brain axis are largely undetermined. Female BALB/c mice were either exposed to the chronic unpredictable mild stress (CUMS) paradigm for 21 days and then treated with ketamine in four doses for 14 days or exposed to CUMS and treated simultaneously in four doses of ketamine during the last two weeks of CUMS exposure. After each dose, the forced swim test was conducted to assess depressive-like behaviour. Before sacrifice, all the mice were subjected to behavioural tests to assess anxiety, memory, and social interaction. Prolonged treatment of depression with ketamine did not rescue depressive-like behaviour. It did, however, improve depression-associated anxiety-like behaviours, short-term memory and social interaction deficits when compared to the stressed untreated mice. Furthermore, ketamine treatment enhanced plasma oxytocin levels, expression of oxytocin receptors; as well as abrogated nitro-oxidative stress biomarkers in the intestinal and hippocampal tissues. Taken together, our findings indicate that while short-term use of ketamine has anti-depressant benefits, its prolonged therapeutic use does not seem to adequately resolve depressive-like behaviour in mice.
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Affiliation(s)
- Edem Ekpenyong Edem
- Neuroscience Unit, Department of Human Anatomy, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria; Department of Anatomy, College of Medicine, University of Lagos, Idi-Araba, Lagos State, Nigeria.
| | - Oluwatomisn Adeyosola Oguntala
- Neuroscience Unit, Department of Human Anatomy, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | | | - Kate Eberechukwu Nebo
- Neuroscience Unit, Department of Human Anatomy, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | - Adedamola Adediran Fafure
- Neuroscience Unit, Department of Human Anatomy, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | - Elizabeth Toyin Akinluyi
- Neuropharmacology Unit, Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | - Godspower Tochukwu Isaac
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, Nigeria
| | - Oladunni Eunice Kunlere
- Neuroscience Unit, Department of Human Anatomy, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
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Elkrief D, Matusovsky O, Cheng YS, Rassier DE. From amino-acid to disease: the effects of oxidation on actin-myosin interactions in muscle. J Muscle Res Cell Motil 2023; 44:225-254. [PMID: 37805961 DOI: 10.1007/s10974-023-09658-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/15/2023] [Indexed: 10/10/2023]
Abstract
Actin-myosin interactions form the basis of the force-producing contraction cycle within the sarcomere, serving as the primary mechanism for muscle contraction. Post-translational modifications, such as oxidation, have a considerable impact on the mechanics of these interactions. Considering their widespread occurrence, the explicit contributions of these modifications to muscle function remain an active field of research. In this review, we aim to provide a comprehensive overview of the basic mechanics of the actin-myosin complex and elucidate the extent to which oxidation influences the contractile cycle and various mechanical characteristics of this complex at the single-molecule, myofibrillar and whole-muscle levels. We place particular focus on amino acids shown to be vulnerable to oxidation in actin, myosin, and some of their binding partners. Additionally, we highlight the differences between in vitro environments, where oxidation is controlled and limited to actin and myosin and myofibrillar or whole muscle environments, to foster a better understanding of oxidative modification in muscle. Thus, this review seeks to encompass a broad range of studies, aiming to lay out the multi layered effects of oxidation in in vitro and in vivo environments, with brief mention of clinical muscular disorders associated with oxidative stress.
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Affiliation(s)
- Daren Elkrief
- Department of Physiology, McGill University, Montreal, QC, Canada
| | - Oleg Matusovsky
- Department of Kinesiology and Physical Education, McGill University, Montreal, QC, Canada
| | - Yu-Shu Cheng
- Department of Kinesiology and Physical Education, McGill University, Montreal, QC, Canada
| | - Dilson E Rassier
- Department of Physiology, McGill University, Montreal, QC, Canada.
- Department of Kinesiology and Physical Education, McGill University, Montreal, QC, Canada.
- Simon Fraser University, Burnaby, BC, Canada.
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Choi S, Haam CE, Byeon S, Oh EY, Choi SK, Lee YH. Investigating the Cardiovascular Benefits of Dapagliflozin: Vasodilatory Effect on Isolated Rat Coronary Arteries. Int J Mol Sci 2023; 24:16873. [PMID: 38069193 PMCID: PMC10706647 DOI: 10.3390/ijms242316873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 11/23/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is an antidiabetic medication that reduces blood glucose. Although it is well known that dapagliflozin has additional benefits beyond glycemic control, such as reducing blood pressure and lowering the risk of cardiovascular events, no sufficient research data are available on the direct effect of dapagliflozin on cardiovascular function. Thus, in this study, we investigated the direct vascular effect of dapagliflozin on isolated rat coronary arteries. The left descending coronary arteries of 13-week-old male Sprague Dawley rats were cut into segments 2-3 mm long and mounted in a multi-wire myography system to measure isometric tension. Dapagliflozin effectively reduced blood vessel constriction induced by U-46619 (500 nM) in coronary arteries regardless of the endothelium. Treatment with an eNOS inhibitor (L-NNA, 100 μM), sGC inhibitor (ODQ, 5 μM), or COX inhibitor (indomethacin, 3 μM) did not affect the vasodilation induced by dapagliflozin. The application of a Ca2+-activated K+ channel (KCa) blocker (TEA, 2 mM), voltage-dependent K+ channel (KV) blocker (4-AP, 2 mM), ATP-sensitive K+ channel blocker (KATP) glibenclamide (3 μM), and inward-rectifier K+ channel (KIR) blocker (BaCl2, 30 μM) did not affect the dapagliflozin-induced vasodilation either. The treatment with dapagliflozin decreased contractile responses induced by the addition of Ca2+, which suggested that the extracellular Ca2+ influx was inhibited by dapagliflozin. Treatment with dapagliflozin decreased the phosphorylation level of the 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that dapagliflozin has a significant vasodilatory effect on rat coronary arteries. Our findings suggest a novel pharmacologic approach for the treatment of cardiovascular diseases in diabetic patients through the modulation of Ca2+ homeostasis via dapagliflozin administration.
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Affiliation(s)
| | | | | | | | - Soo-Kyoung Choi
- Department of Physiology, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun-gu, Seoul 03722, Republic of Korea; (S.C.); (C.E.H.)
| | - Young-Ho Lee
- Department of Physiology, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun-gu, Seoul 03722, Republic of Korea; (S.C.); (C.E.H.)
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25
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Silva M, Faustino P. From Stress to Sick(le) and Back Again-Oxidative/Antioxidant Mechanisms, Genetic Modulation, and Cerebrovascular Disease in Children with Sickle Cell Anemia. Antioxidants (Basel) 2023; 12:1977. [PMID: 38001830 PMCID: PMC10669666 DOI: 10.3390/antiox12111977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/30/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023] Open
Abstract
Sickle cell anemia (SCA) is a genetic disease caused by the homozygosity of the HBB:c.20A>T mutation, which results in the production of hemoglobin S (HbS). In hypoxic conditions, HbS suffers autoxidation and polymerizes inside red blood cells, altering their morphology into a sickle shape, with increased rigidity and fragility. This triggers complex pathophysiological mechanisms, including inflammation, cell adhesion, oxidative stress, and vaso-occlusion, along with metabolic alterations and endocrine complications. SCA is phenotypically heterogeneous due to the modulation of both environmental and genetic factors. Pediatric cerebrovascular disease (CVD), namely ischemic stroke and silent cerebral infarctions, is one of the most impactful manifestations. In this review, we highlight the role of oxidative stress in the pathophysiology of pediatric CVD. Since oxidative stress is an interdependent mechanism in vasculopathy, occurring alongside (or as result of) endothelial dysfunction, cell adhesion, inflammation, chronic hemolysis, ischemia-reperfusion injury, and vaso-occlusion, a brief overview of the main mechanisms involved is included. Moreover, the genetic modulation of CVD in SCA is discussed. The knowledge of the intricate network of altered mechanisms in SCA, and how it is affected by different genetic factors, is fundamental for the identification of potential therapeutic targets, drug development, and patient-specific treatment alternatives.
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Affiliation(s)
- Marisa Silva
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Av. Padre Cruz, 1649-016 Lisboa, Portugal;
| | - Paula Faustino
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Av. Padre Cruz, 1649-016 Lisboa, Portugal;
- Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental (ISAMB), Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
- Laboratório Associado TERRA, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
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Dugbartey GJ. Nitric oxide in kidney transplantation. Biomed Pharmacother 2023; 167:115530. [PMID: 37722191 DOI: 10.1016/j.biopha.2023.115530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/05/2023] [Accepted: 09/15/2023] [Indexed: 09/20/2023] Open
Abstract
Kidney transplantation is the treatment of choice for patients with kidney failure. Compared to dialysis therapy, it provides better quality of life and confers significant survival advantage at a relatively lower cost. However, the long-term success of this life-saving intervention is severely hampered by an inexorable clinical problem referred to as ischemia-reperfusion injury (IRI), and increases the incidence of post-transplant complications including loss of renal graft function and death of transplant recipients. Burgeoning evidence shows that nitric oxide (NO), a poisonous gas at high concentrations, and with a historic negative public image as an environmental pollutant, has emerged as a potential candidate that holds clinical promise in mitigating IRI and preventing acute and chronic graft rejection when it is added to kidney preservation solutions at low concentrations or when administered to the kidney donor prior to kidney procurement and to the recipient or to the reperfusion circuit at the start and during reperfusion after renal graft preservation. Interestingly, dysregulated or abnormal endogenous production and metabolism of NO is associated with IRI in kidney transplantation. From experimental and clinical perspectives, this review presents endogenous enzymatic production of NO as well as its exogenous sources, and then discusses protective effects of constitutive nitric oxide synthase (NOS)-derived NO against IRI in kidney transplantation via several signaling pathways. The review also highlights a few isolated studies of renal graft protection by NO produced by inducible NOS.
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Affiliation(s)
- George J Dugbartey
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana; Accra College of Medicine, Magnolia St, JVX5+FX9, East Legon, Accra, Ghana.
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Błaszkiewicz M, Walulik A, Florek K, Górecki I, Sławatyniec O, Gomułka K. Advances and Perspectives in Relation to the Molecular Basis of Diabetic Retinopathy-A Review. Biomedicines 2023; 11:2951. [PMID: 38001952 PMCID: PMC10669459 DOI: 10.3390/biomedicines11112951] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/26/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Diabetes mellitus (DM) is a growing problem nowadays, and diabetic retinopathy (DR) is its predominant complication. Currently, DR diagnosis primarily relies on fundoscopic examination; however, novel biomarkers may facilitate that process and make it widely available. In this current review, we delve into the intricate roles of various factors and mechanisms in DR development, progression, prediction, and their association with therapeutic approaches linked to the underlying pathogenic pathways. Specifically, we focus on advanced glycation end products, vascular endothelial growth factor (VEGF), asymmetric dimethylarginine, endothelin-1, and the epigenetic regulation mediated by microRNAs (miRNAs) in the context of DR.
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Affiliation(s)
- Michał Błaszkiewicz
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Agata Walulik
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Kamila Florek
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Ignacy Górecki
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Olga Sławatyniec
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Krzysztof Gomułka
- Clinical Department of Internal Medicine, Pneumology and Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
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Roy R, Wilcox J, Webb AJ, O’Gallagher K. Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential. Int J Mol Sci 2023; 24:15200. [PMID: 37894881 PMCID: PMC10607291 DOI: 10.3390/ijms242015200] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics.
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Affiliation(s)
- Roman Roy
- Cardiovascular Department, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
| | - Joshua Wilcox
- Cardiovascular Department, Guy’s and St. Thomas’ NHS Foundation Trust, London SE1 7EH, UK;
| | - Andrew J. Webb
- Department of Clinical Pharmacology, British Heart Foundation Centre, School of Cardiovascular and Metabolic Medicine and Sciences, King’s College London, London SE1 7EH, UK;
| | - Kevin O’Gallagher
- Cardiovascular Department, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK
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Cai M, Zhao D, Han X, Han S, Zhang W, Zang Z, Gai C, Rong R, Gao T. The role of perivascular adipose tissue-secreted adipocytokines in cardiovascular disease. Front Immunol 2023; 14:1271051. [PMID: 37822930 PMCID: PMC10562567 DOI: 10.3389/fimmu.2023.1271051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 08/28/2023] [Indexed: 10/13/2023] Open
Abstract
Perivascular adipose tissue and the vessel wall are connected through intricate bidirectional paracrine and vascular secretory signaling pathways. The secretion of inflammatory factors and oxidative products by the vessel wall in the diseased segment has the ability to influence the phenotype of perivascular adipocytes. Additionally, the secretion of adipokines by perivascular adipose tissue exacerbates the inflammatory response in the diseased vessel wall. Therefore, quantitative and qualitative studies of perivascular adipose tissue are of great value in the context of vascular inflammation and may provide a reference for the assessment of cardiovascular ischemic disease.
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Affiliation(s)
- Meichao Cai
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Dongsheng Zhao
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao Han
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shuang Han
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenxin Zhang
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhennan Zang
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chenchen Gai
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Rong Rong
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tian Gao
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
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Santoro L, Zaccone V, Falsetti L, Ruggieri V, Danese M, Miro C, Di Giorgio A, Nesci A, D’Alessandro A, Moroncini G, Santoliquido A. Role of Endothelium in Cardiovascular Sequelae of Long COVID. Biomedicines 2023; 11:2239. [PMID: 37626735 PMCID: PMC10452509 DOI: 10.3390/biomedicines11082239] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/26/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
The global action against coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection, shed light on endothelial dysfunction. Although SARS-CoV-2 primarily affects the pulmonary system, multiple studies have documented pan-vascular involvement in COVID-19. The virus is able to penetrate the endothelial barrier, damaging it directly or indirectly and causing endotheliitis and multi-organ injury. Several mechanisms cooperate to development of endothelial dysfunction, including endothelial cell injury and pyroptosis, hyperinflammation and cytokine storm syndrome, oxidative stress and reduced nitric oxide bioavailability, glycocalyx disruption, hypercoagulability, and thrombosis. After acute-phase infection, some patients reported signs and symptoms of a systemic disorder known as long COVID, in which a broad range of cardiovascular (CV) disorders emerged. To date, the exact pathophysiology of long COVID remains unclear: in addition to the persistence of acute-phase infection mechanisms, specific pathways of CV damage have been postulated, such as persistent viral reservoirs in the heart or an autoimmune response to cardiac antigens through molecular mimicry. The aim of this review is to provide an overview of the main molecular patterns of enduring endothelial activation following SARS-CoV-2 infection and to offer the latest summary of CV complications in long COVID.
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Affiliation(s)
- Luca Santoro
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (L.S.); (A.D.G.); (A.N.); (A.D.); (A.S.)
| | - Vincenzo Zaccone
- Department of Emergency Medicine, Internal and Sub-Intensive Medicine, Azienda Ospedaliero-Universitaria delle Marche, 60126 Ancona, Italy
| | - Lorenzo Falsetti
- Clinica Medica, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, 60126 Ancona, Italy; (L.F.); (G.M.)
| | - Vittorio Ruggieri
- Department of Internal Medicine, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (V.R.); (M.D.); (C.M.)
| | - Martina Danese
- Department of Internal Medicine, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (V.R.); (M.D.); (C.M.)
| | - Chiara Miro
- Department of Internal Medicine, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (V.R.); (M.D.); (C.M.)
| | - Angela Di Giorgio
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (L.S.); (A.D.G.); (A.N.); (A.D.); (A.S.)
| | - Antonio Nesci
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (L.S.); (A.D.G.); (A.N.); (A.D.); (A.S.)
| | - Alessia D’Alessandro
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (L.S.); (A.D.G.); (A.N.); (A.D.); (A.S.)
| | - Gianluca Moroncini
- Clinica Medica, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, 60126 Ancona, Italy; (L.F.); (G.M.)
| | - Angelo Santoliquido
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (L.S.); (A.D.G.); (A.N.); (A.D.); (A.S.)
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Teng Z, Wang H, Guo F, Han Z, Wang Y. eNOS polymorphisms on male infertility: An updated systematic review and meta-analysis. Medicine (Baltimore) 2023; 102:e33993. [PMID: 37327284 PMCID: PMC10270503 DOI: 10.1097/md.0000000000033993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/25/2023] [Indexed: 06/18/2023] Open
Abstract
BACKGROUND This meta-analysis was performed to examine the association of 3 endothelial nitric oxide synthase (eNOS) gene polymorphisms with male infertility. METHODS The literature on the relation between the mutant of eNOS and male infertility before July 1, 2022, was conducted in Pubmed, Medline, and Web of Science. The search strategy is as follows: (eNOS OR ECNOS OR nitric oxide synthase 3 OR NOS3) AND (polymorphism OR mutation OR variation OR SNP OR genotype) AND (male infertility). Statistical analysis was performed with the web of MetaGenyo, Stata 12, trial sequential analysis 0.9Beta, and the web of GTEx. RESULTS Overall, 13 studies (26 case-controls) were included involving 6518 cases and 5461 controls for 3 polymorphisms (rs2070744, rs1799983, rs61722009) of eNOS. We found that eNOS rs2070744 was correlated with an increased risk of male infertility (C vs. T: odds ratio [OR], 1.48; 95% confidence interval [CI], [1.19-1.85]; CC vs. TT: OR, 2.59; 95% CI, [1.40-4.80]; CT vs. TT: OR, 1.17; 95% CI, [1.00-1.38]; CC vs. CT + TT: OR, 2.50; 95% CI, [1.35-4.62]; CC + CT vs. TT: OR, 1.41; 95% CI, [1.21-1.64]). And eNOS rs1799983 was correlated with an increased risk of male infertility (allele contrast T vs. G: OR, 1.41; 95% CI, [1.01-1.96]; P = .043; recessive model TT vs. TG + GG: OR, 2.00; 95% CI, [1.03-3.90]; P = .042). In the stratified analysis of rs61722009, we found Asians might be correlated with an increased risk of male infertility (4a vs. 4b: OR, 1.50; 95% CI, [0.94-2.38]; 4a4a vs. 4b4b: OR, 2.56; 95% CI, [0.70-9.38]; 4a4b vs. 4b4b: OR, 1.36; 95% CI, [0.87-2.13]; 4a4a vs. 4a4b + 4b4b: OR, 2.57; 95% CI, [0.91-7.30]; 4a4a + 4a4b vs. 4b4b: OR, 1.44; 95% CI, [0.87-2.40]). CONCLUSION The eNOS rs2070744 polymorphism and rs1799983 are associated with the risk of male infertility, and rs61722009 might be a risk factor for Asians.
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Affiliation(s)
- Zhihai Teng
- Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hu Wang
- Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Fengran Guo
- Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhenwei Han
- Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yaxuan Wang
- Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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Marini E, Sodano F, Rolando B, Chegaev K, Maresca DC, Ianaro A, Ercolano G, Lazzarato L. New lipophilic organic nitrates: candidates for chronic skin disease therapy. Biol Chem 2023; 404:601-606. [PMID: 36867068 DOI: 10.1515/hsz-2022-0324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 02/17/2023] [Indexed: 03/04/2023]
Abstract
Organic nitrates are widely used, but their chronic efficacy is blunted due to the development of tolerance. The properties of new tolerance free organic nitrates were studied. Their lipophilicity profile and passive diffusion across polydimethylsiloxane membrane and pig ear-skin, and their efficacy in tissue regeneration using HaCaT keratinocytes were evaluated. The permeation results show that these nitrates have a suitable profile for NO topical administration on the skin. Furthermore, the derivatives with higher NO release exerted a pro-healing effect on HaCaT cells. This new class of organic nitrates might be a promising strategy for the chronic treatment of skin pathologies.
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Affiliation(s)
- Elisabetta Marini
- Department of Drug Science and Technology, University of Turin, I-10125 Turin, Italy
| | - Federica Sodano
- Department of Pharmacy, University of Naples «Federico II», I-80131 Naples, Italy
| | - Barbara Rolando
- Department of Drug Science and Technology, University of Turin, I-10125 Turin, Italy
| | - Konstantin Chegaev
- Department of Drug Science and Technology, University of Turin, I-10125 Turin, Italy
| | | | - Angela Ianaro
- Department of Pharmacy, University of Naples «Federico II», I-80131 Naples, Italy
| | - Giuseppe Ercolano
- Department of Pharmacy, University of Naples «Federico II», I-80131 Naples, Italy
| | - Loretta Lazzarato
- Department of Drug Science and Technology, University of Turin, I-10125 Turin, Italy
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Eichwald T, da Silva LDB, Staats Pires AC, Niero L, Schnorrenberger E, Filho CC, Espíndola G, Huang WL, Guillemin GJ, Abdenur JE, Latini A. Tetrahydrobiopterin: Beyond Its Traditional Role as a Cofactor. Antioxidants (Basel) 2023; 12:1037. [PMID: 37237903 PMCID: PMC10215290 DOI: 10.3390/antiox12051037] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/19/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
Tetrahydrobiopterin (BH4) is an endogenous cofactor for some enzymatic conversions of essential biomolecules, including nitric oxide, and monoamine neurotransmitters, and for the metabolism of phenylalanine and lipid esters. Over the last decade, BH4 metabolism has emerged as a promising metabolic target for negatively modulating toxic pathways that may result in cell death. Strong preclinical evidence has shown that BH4 metabolism has multiple biological roles beyond its traditional cofactor activity. We have shown that BH4 supports essential pathways, e.g., to generate energy, to enhance the antioxidant resistance of cells against stressful conditions, and to protect from sustained inflammation, among others. Therefore, BH4 should not be understood solely as an enzyme cofactor, but should instead be depicted as a cytoprotective pathway that is finely regulated by the interaction of three different metabolic pathways, thus assuring specific intracellular concentrations. Here, we bring state-of-the-art information about the dependency of mitochondrial activity upon the availability of BH4, as well as the cytoprotective pathways that are enhanced after BH4 exposure. We also bring evidence about the potential use of BH4 as a new pharmacological option for diseases in which mitochondrial disfunction has been implicated, including chronic metabolic disorders, neurodegenerative diseases, and primary mitochondriopathies.
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Affiliation(s)
- Tuany Eichwald
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88037-100, SC, Brazil; (T.E.); (L.N.); (C.C.F.); (G.E.)
- Laboratory for Energy Metabolism, Division of Metabolic Disorders, CHOC Children’s Hospital, Orange, CA 92868, USA; (W.-L.H.); (J.E.A.)
| | - Lucila de Bortoli da Silva
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88037-100, SC, Brazil; (T.E.); (L.N.); (C.C.F.); (G.E.)
| | - Ananda Christina Staats Pires
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88037-100, SC, Brazil; (T.E.); (L.N.); (C.C.F.); (G.E.)
- Neuroinflammation Group, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
| | - Laís Niero
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88037-100, SC, Brazil; (T.E.); (L.N.); (C.C.F.); (G.E.)
| | - Erick Schnorrenberger
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88037-100, SC, Brazil; (T.E.); (L.N.); (C.C.F.); (G.E.)
| | - Clovis Colpani Filho
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88037-100, SC, Brazil; (T.E.); (L.N.); (C.C.F.); (G.E.)
| | - Gisele Espíndola
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88037-100, SC, Brazil; (T.E.); (L.N.); (C.C.F.); (G.E.)
- Neuroinflammation Group, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
| | - Wei-Lin Huang
- Laboratory for Energy Metabolism, Division of Metabolic Disorders, CHOC Children’s Hospital, Orange, CA 92868, USA; (W.-L.H.); (J.E.A.)
| | - Gilles J. Guillemin
- Neuroinflammation Group, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia
| | - José E. Abdenur
- Laboratory for Energy Metabolism, Division of Metabolic Disorders, CHOC Children’s Hospital, Orange, CA 92868, USA; (W.-L.H.); (J.E.A.)
| | - Alexandra Latini
- Laboratório de Bioenergética e Estresse Oxidativo—LABOX, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88037-100, SC, Brazil; (T.E.); (L.N.); (C.C.F.); (G.E.)
- Laboratory for Energy Metabolism, Division of Metabolic Disorders, CHOC Children’s Hospital, Orange, CA 92868, USA; (W.-L.H.); (J.E.A.)
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Asgari A, Jurasz P. Role of Nitric Oxide in Megakaryocyte Function. Int J Mol Sci 2023; 24:ijms24098145. [PMID: 37175857 PMCID: PMC10179655 DOI: 10.3390/ijms24098145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/22/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Megakaryocytes are the main members of the hematopoietic system responsible for regulating vascular homeostasis through their progeny platelets, which are generally known for maintaining hemostasis. Megakaryocytes are characterized as large polyploid cells that reside in the bone marrow but may also circulate in the vasculature. They are generated directly or through a multi-lineage commitment step from the most primitive progenitor or Hematopoietic Stem Cells (HSCs) in a process called "megakaryopoiesis". Immature megakaryocytes enter a complicated development process defined as "thrombopoiesis" that ultimately results in the release of extended protrusions called proplatelets into bone marrow sinusoidal or lung microvessels. One of the main mediators that play an important modulatory role in hematopoiesis and hemostasis is nitric oxide (NO), a free radical gas produced by three isoforms of nitric oxide synthase within the mammalian cells. In this review, we summarize the effect of NO and its signaling on megakaryopoiesis and thrombopoiesis under both physiological and pathophysiological conditions.
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Affiliation(s)
- Amir Asgari
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G-2E1, Canada
| | - Paul Jurasz
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G-2E1, Canada
- Department of Pharmacology, University of Alberta, Edmonton, AB T6G-2H7, Canada
- Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G-2S2, Canada
- Mazankowski Alberta Heart Institute, Edmonton, AB T6G-2R7, Canada
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Bondonno CP, Zhong L, Bondonno NP, Sim M, Blekkenhorst LC, Liu A, Rajendra A, Pokharel P, Erichsen DW, Neubauer O, Croft KD, Hodgson JM. Nitrate: The Dr. Jekyll and Mr. Hyde of human health? Trends Food Sci Technol 2023. [DOI: 10.1016/j.tifs.2023.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
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Hsu CY, Huang CY, Shih CM, Lin YW, Huang PH, Lin SJ, Liu CW, Lin CY, Lin FY. Tumor Necrosis Factor Superfamily 14 (LIGHT) Restricts Neovascularization by Decreasing Circulating Endothelial Progenitor Cells and Function. Int J Mol Sci 2023; 24:ijms24086997. [PMID: 37108160 PMCID: PMC10138919 DOI: 10.3390/ijms24086997] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/29/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Tumor necrosis factor superfamily 14 (TNFSF14) is also known as the LT-related inducible ligand (LIGHT). It can bind to the herpesvirus invasion mediator and lymphotoxin-β receptor to perform its biological activity. LIGHT has multiple physiological functions, including strengthening the synthesis of nitric oxide, reactive oxygen species, and cytokines. LIGHT also stimulates angiogenesis in tumors and induces the synthesis of high endothelial venules; degrades the extracellular matrix in thoracic aortic dissection, and induces the expression of interleukin-8, cyclooxygenase-2, and cell adhesion molecules in endothelial cells. While LIGHT induces tissue inflammation, its effects on angiogenesis after tissue ischemia are unclear. Thus, we analyzed these effects in the current study. In this study, the animal model of hind limb ischemia surgery in C57BL/6 mice was performed. Doppler ultrasound, immunohistochemical staining, and Western blotting were employed to analyze the situation of angiogenesis. In addition, human endothelial progenitor cells (EPCs) were used for in vitro studies to analyze the possible mechanisms. The results in the animal study showed that LIGHT injection inhibited angiogenesis in ischemic limbs. For the in vitro studies, LIGHT inhibited the expression of integrins and E-selectin; decreased migration and tube formation capabilities, mitochondrial respiration, and succinate dehydrogenase activity; and promoted senescence in EPCs. Western blotting revealed that the impairment of EPC function by LIGHT may be due to its effects on the proper functioning of the intracellular Akt signaling pathway, endothelial nitrite oxide synthase (eNOS), and mitochondrial respiration. In conclusion, LIGHT inhibits angiogenesis after tissue ischemia. This may be related to the clamped EPC function.
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Affiliation(s)
- Chien-Yi Hsu
- Taipei Heart Institute and Division of Cardiology, Department of Internal Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
| | - Chun-Yao Huang
- Taipei Heart Institute and Division of Cardiology, Department of Internal Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan City 320, Taiwan
| | - Chun-Ming Shih
- Taipei Heart Institute and Division of Cardiology, Department of Internal Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
| | - Yi-Wen Lin
- Institute of Oral Biology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Po-Hsun Huang
- Division of Cardiology, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Shing-Jong Lin
- Taipei Heart Institute and Division of Cardiology, Department of Internal Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
| | - Chen-Wei Liu
- Department of Basic Medical Science, College of Medicine, University of Arizona, Phoenix, AZ 85721, USA
| | - Cheng-Yen Lin
- Healthcare Information and Management Department, Ming Chuan University, Taoyuan 333, Taiwan
| | - Feng-Yen Lin
- Taipei Heart Institute and Division of Cardiology, Department of Internal Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
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Lv R, Huang J, Li M, Chen X, Gu B, Cao N. The potential involvement of MRP5 pump in urethral dysfunction in streptozotocin-induced diabetic rats. Int Urol Nephrol 2023; 55:285-293. [PMID: 36327005 DOI: 10.1007/s11255-022-03405-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
PURPOSE To examine the effects of i.v. administration of MK-571, a MRP4/5 pump inhibitor, on urethral function in the urethane-anesthetized rat, and the changes of urethral multidrug resistance protein 5 (MRP5) pump in streptozotocin (STZ)-induced diabetes mellitus (DM) rats. METHODS Isovolumetric cystometry and urethral perfusion pressure (UPP) measurements were carried out in normal control (NC) group and 8week DM groups under urethane anesthesia. When stable rhythmic bladder contractions were showed, UPP parameters were recorded after successive administration of various dose of MK-571. Additionally, urethral cyclic guanosine monophosphate (cGMP) protein level was evaluated by ELISA, and changes of MRP5 pump and neurogenic nitric oxide synthase (nNOs) in the urethra were examined with immunohistochemical staining and Western blot analysis. RESULTS In NC group, UPPnadir was significantly decreased but UPP change increased after administration of MK-571, while no significant differences in UPP parameters were observed in 8-week DM group. Furthermore, urethral MRP5 protein level was up-regulated, whereas urethral cGMP and nNOS protein levels were down-regulated in 8-week DM group. CONCLUSIONS MK-571 could not restore NO-mediated urethral relaxation dysfunction in DM rats, which may be attributed to the up-regulation of urethral MRP5 pump, and thus decrease of intracellular cGMP concentration in the urethra. These novel results would be useful for a better understanding of DM-related lower urinary tract dysfunction LUT (LUTD). Also, they could be helpful to study the importance of MRP pumps in the control of urethral relaxation mechanisms under physiological and pathological states.
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Affiliation(s)
- Rong Lv
- Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.,Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai, China
| | - Jianwen Huang
- Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.,Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai, China
| | - Mingzhuo Li
- Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.,Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai, China
| | - Xun Chen
- Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.,Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai, China
| | - Baojun Gu
- Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.,Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai, China
| | - Nailong Cao
- Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China. .,Shanghai Eastern Institute of Urologic Reconstruction, Shanghai Jiao Tong University, Shanghai, China.
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Mobility Coupled with Motivation Promotes Survival: The Evolution of Cognition as an Adaptive Strategy. BIOLOGY 2023; 12:biology12010080. [PMID: 36671772 PMCID: PMC9855669 DOI: 10.3390/biology12010080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023]
Abstract
Morphine plays a critical regulatory role in both simple and complex plant species. Dopamine is a critical chemical intermediate in the morphine biosynthetic pathway and may have served as a primordial agonist in developing catecholamine signaling pathways. While dopamine remains the preeminent catecholamine in invertebrate neural systems, epinephrine is the major product of catecholamine synthetic pathways in vertebrate species. Given that the enzymatic steps leading to the generation of morphine are similar to those constraining the evolutionary adaptation of the biosynthesis of catecholamines, we hypothesize that the emergence of these more advanced signaling pathways was based on conservation and selective "retrofitting" of pre-existing enzyme activities. This is consistent with observations that support the recruitment of enzymatically synthesized tetrahydrobiopterin (BH4), which is a cofactor for tyrosine hydroxylase, the enzyme responsible for dopamine production. BH4 is also an electron donor involved in the production of nitric oxide (NO). The links that coordinate BH4-mediated NO and catecholaminergic-mediated processes provide these systems with the capacity to regulate numerous downstream signaling pathways. We hypothesize that the evolution of catecholamine signaling pathways in animal species depends on the acquisition of a mobile lifestyle and motivationally driven feeding, sexual, and self-protective responses.
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Rajendra A, Bondonno NP, Rainey-Smith SR, Gardener SL, Hodgson JM, Bondonno CP. Potential role of dietary nitrate in relation to cardiovascular and cerebrovascular health, cognition, cognitive decline and dementia: a review. Food Funct 2022; 13:12572-12589. [PMID: 36377891 DOI: 10.1039/d2fo02427f] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
There is currently no effective treatment for dementia, of which Alzheimer's disease (AD) is the most common form. It is, therefore, imperative to focus on evidence-based preventive strategies to combat this extremely debilitating chronic disease. Nitric oxide (NO) is a key signalling molecule in the cardiovascular, cerebrovascular, and central nervous systems. Vegetables rich in nitrate, such as spinach and beetroot, are an important source of NO, with beneficial effects on validated markers of cardiovascular health and an association with a lower risk of cardiovascular disease. Given the link between cardiovascular disease risk factors and dementia, together with the important role of NO in vascular health and cognition, it is important to determine whether dietary nitrate could also improve cognitive function, markers of brain health, and lower risk of dementia. This review presents an overview of NO's role in the cardiovascular, cerebrovascular, and central nervous systems; an overview of the available evidence that nitrate, through effects on NO, improves cardiovascular health; and evaluates the current evidence regarding dietary nitrate's potential role in cerebrovascular health, cognitive function, and brain health assessed via biomarkers.
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Affiliation(s)
- Anjana Rajendra
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.
| | - Nicola P Bondonno
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia. .,Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Stephanie R Rainey-Smith
- Centre for Healthy Ageing, Health Futures Institute, Murdoch University, Murdoch, Western Australia, Australia.,Australian Alzheimer's Research Foundation, Perth, Western Australia, Australia.,Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.,Lifestyle Approaches Towards Cognitive Health Research Group, Murdoch University, Murdoch, Western Australia, Australia.,School of Psychological Science, University of Western Australia, Perth, Western Australia, Australia
| | - Samantha L Gardener
- Australian Alzheimer's Research Foundation, Perth, Western Australia, Australia.,Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.,Lifestyle Approaches Towards Cognitive Health Research Group, Murdoch University, Murdoch, Western Australia, Australia
| | - Jonathan M Hodgson
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia. .,Medical School, The University of Western Australia, Royal Perth Hospital Research Foundation, Perth, Western Australia, Australia
| | - Catherine P Bondonno
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia. .,Medical School, The University of Western Australia, Royal Perth Hospital Research Foundation, Perth, Western Australia, Australia
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Omar M, Abdelal HO. Nitric oxide in parasitic infections: a friend or foe? J Parasit Dis 2022; 46:1147-1163. [PMID: 36457767 PMCID: PMC9606182 DOI: 10.1007/s12639-022-01518-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/20/2022] [Indexed: 11/28/2022] Open
Abstract
The complex interaction between the host and the parasite remains a puzzling question. Control of parasitic infections requires an efficient immune response that must be balanced against destructive pathological consequences. Nitric oxide is a nitrogenous free radical which has many molecular targets and serves diverse functions. Apart from being a signaling messenger, nitric oxide is critical for controlling numerous infections. There is still controversy surrounding the exact role of nitric oxide in the immune response against different parasitic species. It proved protective against intracellular protozoa, as well as extracellular helminths. At the same time, it plays a pivotal role in stimulating detrimental pathological changes in the infected hosts. Several reports have discussed the anti-parasitic and immunoregulatory functions of nitric oxide, which could directly influence the control of the infection. Nevertheless, there is scarce literature addressing the harmful cytotoxic impacts of this mediator. Thus, this review provides insights into the most updated concepts and controversies regarding the dual nature and opposing sides of nitric oxide during the course of different parasitic infections.
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Affiliation(s)
- Marwa Omar
- Department of Medical Parasitology, Faculty of Medicine, Zagazig University, Gameyet Almohafza St. 1, Menya Al-Kamh, City of Zagazig, 44511 Sharkia Governorate Egypt
| | - Heba O. Abdelal
- LIS: Cross-National Data Center, Maison des Sciences Humaines - 5e étage, 11- porte des Sciences, L-4366 Esch-Belval, Luxembourg
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Effects of Intravesical Electrical Stimulation on Urinary Adenosine Triphosphate and Nitric Oxide in Rats With Detrusor Underactivity Induced By Bilateral Pelvic Nerve Crush Injury: The Possible Underlying Mechanism. Int Neurourol J 2022; 26:288-298. [PMID: 36599337 PMCID: PMC9816450 DOI: 10.5213/inj.2244162.081] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/07/2022] [Indexed: 12/30/2022] Open
Abstract
PURPOSE To explore the effect of intravesical electrical stimulation (IVES) on urinary adenosine triphosphate (ATP) and nitric oxide (NO) in rats with detrusor underactivity (DU) induced by bilateral pelvic nerve crush (bPNC), and to determine the underlying peripheral mechanism. METHODS Twenty-four female Sprague-Dawley rats were equally divided into 3 groups: sham; bPNC; and IVES. Rats in the IVES group began to receive IVES treatment 10 days after bPNC (20 minutes per day for 14 consecutive days). After the 14th IVES, rat urine was collected and cystometry was performed. The serum creatinine, blood urea nitrogen, and urinary ATP and NO levels were measured, and a routine urinalysis was performed. RESULTS The maximum cystometric capacity (MCC), maximum changes in bladder pressure during filling (∆FP), and postvoid residual urine (PVR) in the IVES group were significantly lower than the bPNC group, and the maximum changes in bladder pressure during voiding (∆VP) was significantly higher than the bPNC group. Compared with the sham group, the MCC, ∆FP and PVR were significantly increased, and the maximum voiding pressure (MVP) and ∆VP were significantly decreased in the bPNC group. After bPNC, urinary ATP was significantly decreased, and urinary NO was significantly increased. In IVES-treated rats, urinary ATP was significantly higher than the bPNC group, and NO was significantly lower than the bPNC group. In addition, the ATP-to-NO ratio of the rats in the bPNC group was significantly lower than the sham and IVES groups. Correlation analysis showed that the ATP and NO were not correlated with the MCC, ∆FP, MVP, ∆VP, and PVR. CONCLUSION Promoting the release of urothelial ATP and inhibiting the release of urothelial NO may be one of the peripheral mechanisms underlying IVES in the treatment of DU. Specifically, IVES may shift the balance between excitation and inhibition toward excitation.
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Erkoc P, von Reumont BM, Lüddecke T, Henke M, Ulshöfer T, Vilcinskas A, Fürst R, Schiffmann S. The Pharmacological Potential of Novel Melittin Variants from the Honeybee and Solitary Bees against Inflammation and Cancer. Toxins (Basel) 2022; 14:toxins14120818. [PMID: 36548715 PMCID: PMC9786170 DOI: 10.3390/toxins14120818] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 11/24/2022] Open
Abstract
The venom of honeybees is composed of numerous peptides and proteins and has been used for decades as an anti-inflammatory and anti-cancer agent in traditional medicine. However, the bioactivity of specific biomolecular components has been evaluated for the predominant constituent, melittin. So far, only a few melittin-like peptides from solitary bee species have been investigated, and the molecular mechanisms of bee venoms as therapeutic agents remain largely unknown. Here, the preclinical pharmacological activities of known and proteo-transcriptomically discovered new melittin variants from the honeybee and more ancestral variants from phylogenetically older solitary bees were explored in the context of cancer and inflammation. We studied the effects of melittin peptides on cytotoxicity, second messenger release, and inflammatory markers using primary human cells, non-cancer, and cancerous cell lines. Melittin and some of its variants showed cytotoxic effects, induced Ca2+ signaling and inhibited cAMP production, and prevented LPS-induced NO synthesis but did not affect the IP3 signaling and pro-inflammatory activation of endothelial cells. Compared to the originally-described melittin, some phylogenetically more ancestral variants from solitary bees offer potential therapeutic modalities in modulating the in vitro inflammatory processes, and hindering cancer cell viability/proliferation, including aggressive breast cancers, and are worth further investigation.
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Affiliation(s)
- Pelin Erkoc
- Institute of Pharmaceutical Biology, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University Frankfurt, 60438 Frankfurt, Germany
- LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt, Germany
- Correspondence: (P.E.); (B.M.v.R.)
| | - Björn Marcus von Reumont
- LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt, Germany
- Applied Bioinformatics Group, Faculty of Biological Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 13, 60438 Frankfurt, Germany
- Correspondence: (P.E.); (B.M.v.R.)
| | - Tim Lüddecke
- LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt, Germany
- Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology (IME-BR), 235394 Giessen, Germany
| | - Marina Henke
- LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), 60596 Frankfurt, Germany
| | - Thomas Ulshöfer
- LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), 60596 Frankfurt, Germany
| | - Andreas Vilcinskas
- LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt, Germany
- Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology (IME-BR), 235394 Giessen, Germany
| | - Robert Fürst
- Institute of Pharmaceutical Biology, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University Frankfurt, 60438 Frankfurt, Germany
- LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt, Germany
| | - Susanne Schiffmann
- LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325 Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), 60596 Frankfurt, Germany
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Probiotics Bring New Hope for Atherosclerosis Prevention and Treatment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3900835. [PMID: 36193065 PMCID: PMC9526629 DOI: 10.1155/2022/3900835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 09/12/2022] [Accepted: 09/17/2022] [Indexed: 11/26/2022]
Abstract
Cardiovascular disease is the leading cause of human mortality and morbidity worldwide. Atherosclerosis (AS) is the underlying pathological responsible in most acute and severe cardiovascular diseases including myocardial infarction and stroke. However, current drugs applied to the treatment of AS are not clinically effective, and there is a large residual risk of cardiovascular disease and multiple side effects. Increasing evidence supports a close relationship between microorganisms and the incidence of AS. Recent data have shown that probiotics can improve multiple key factors involved in the development and progression of AS, including cholesterol metabolism imbalance, endothelial dysfunction, proinflammatory factor production, macrophage polarization, intestinal flora disturbance, and infection with pathogenic microorganisms, and therefore probiotics have attracted great interest as a novel potential “medicine”. This review is aimed at summarizing the effects of probiotics on various influencing factors, and providing valuable insights in the search for early prevention and potential therapeutic strategies for AS.
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Enhancement of Nitric Oxide Bioavailability by Modulation of Cutaneous Nitric Oxide Stores. Biomedicines 2022; 10:biomedicines10092124. [PMID: 36140225 PMCID: PMC9496039 DOI: 10.3390/biomedicines10092124] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/22/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022] Open
Abstract
The generation of nitric oxide (NO) in the skin plays a critical role in wound healing and the response to several stimuli, such as UV exposure, heat, infection, and inflammation. Furthermore, in the human body, NO is involved in vascular homeostasis and the regulation of blood pressure. Physiologically, a family of enzymes termed nitric oxide synthases (NOS) generates NO. In addition, there are many methods of non-enzymatic/NOS-independent NO generation, e.g., the reduction of NO derivates (NODs) such as nitrite, nitrate, and nitrosylated proteins under certain conditions. The skin is the largest and heaviest human organ and contains a comparatively high concentration of these NODs; therefore, it represents a promising target for many therapeutic strategies for NO-dependent pathological conditions. In this review, we give an overview of how the cutaneous NOD stores can be targeted and modulated, leading to a further accumulation of NO-related compounds and/or the local and systemic release of bioactive NO, and eventually, NO-related physiological effects with a potential therapeutical use for diseases such as hypertension, disturbed microcirculation, impaired wound healing, and skin infections.
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L-Arginine increases AMPK phosphorylation and the oxidation of energy substrates in hepatocytes, skeletal muscle cells, and adipocytes. Amino Acids 2022; 54:1553-1568. [PMID: 35972552 DOI: 10.1007/s00726-022-03195-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 08/01/2022] [Indexed: 12/16/2022]
Abstract
Previous work has shown that dietary L-arginine (Arg) supplementation reduced white fat mass in obese rats. The present study was conducted with cell models to define direct effects of Arg on energy-substrate oxidation in hepatocytes, skeletal muscle cells, and adipocytes. BNL CL.2 mouse hepatocytes, C2C12 mouse myotubes, and 3T3-L1 mouse adipocytes were treated with different extracellular concentrations of Arg (0, 15, 50, 100 and 400 µM) or 400 µM Arg + 0.5 mM NG-nitro-L-arginine methyl ester (L-NAME; an NOS inhibitor) for 48 h. Increasing Arg concentrations in culture medium dose-dependently enhanced (P < 0.05) the oxidation of glucose and oleic acid to CO2 in all three cell types, lactate release from C2C12 cells, and the incorporation of oleic acid into esterified lipids in BNL CL.2 and 3T3-L1 cells. Arg at 400 µM also stimulated (P < 0.05) the phosphorylation of AMP-activated protein kinase (AMPK) in all three cell types and increased (P < 0.05) NO production in C2C12 and BNL CL.2 cells. The inhibition of NOS by L-NAME moderately reduced (P < 0.05) glucose and oleic acid oxidation, lactate release, and the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in BNL CL.2 cells, but had no effect (P > 0.05) on these variables in C2C12 or 3T3-L1 cells. Collectively, these results indicate that Arg increased AMPK activity and energy-substrate oxidation in BNL CL.2, C2C12, and 3T3-L1 cells through both NO-dependent and NO-independent mechanisms.
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Geiger M, Hayter E, Martin R, Spence D. Red blood cells in type 1 diabetes and multiple sclerosis and technologies to measure their emerging roles. J Transl Autoimmun 2022; 5:100161. [PMID: 36039310 PMCID: PMC9418496 DOI: 10.1016/j.jtauto.2022.100161] [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] [Received: 04/20/2022] [Revised: 07/14/2022] [Accepted: 07/21/2022] [Indexed: 11/15/2022] Open
Abstract
Autoimmune diseases affect over 40 million people in the United States. The cause of most autoimmune diseases is unknown; therefore, most therapies focus on treating the symptoms. This review will focus on the autoimmune diseases type 1 diabetes (T1D) and multiple sclerosis (MS) and the emerging roles of red blood cells (RBCs) in the mechanisms and treatment of T1D and MS. An understanding of the role of the RBC in human health is increasing, especially with respect to its role in the regulation of vascular caliber and vessel dilation. The RBC is known to participate in the regulation of blood flow through the release of key signaling molecules, such as adenosine triphosphate (ATP) and the potent vasodilator nitric oxide (NO). However, while these RBC-derived molecules are known to be determinants of blood flow in vivo, disruptions in their concentrations in the circulation are often measured in common autoimmune diseases. Chemical and physical properties of the RBC may play a role in autoimmune disease onset, especially T1D and MS, and complications associated with downstream extracellular levels of ATP and NO. Finally, both ATP and NO are highly reactive molecules in the circulation. Coupled with the challenging matrix posed by the bloodstream, the measurement of these two species is difficult, thus prompting an appraisal of recent and novel methods to quantitatively determining these potential early indicators of immune response.
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Affiliation(s)
- M. Geiger
- Institute of Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI 48824, USA
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - E. Hayter
- Department of Chemistry, Saint Louis University, St. Louis, MO 63103, USA
| | - R.S. Martin
- Department of Chemistry, Saint Louis University, St. Louis, MO 63103, USA
| | - D. Spence
- Institute of Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI 48824, USA
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
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Endothelial Nitric Oxide Synthase in the Perivascular Adipose Tissue. Biomedicines 2022; 10:biomedicines10071754. [PMID: 35885059 PMCID: PMC9313312 DOI: 10.3390/biomedicines10071754] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/18/2022] [Accepted: 07/18/2022] [Indexed: 01/08/2023] Open
Abstract
Perivascular adipose tissue (PVAT) is a special type of ectopic fat depot that adheres to most vasculatures. PVAT has been shown to exert anticontractile effects on the blood vessels and confers protective effects against metabolic and cardiovascular diseases. PVAT plays a critical role in vascular homeostasis via secreting adipokine, hormones, and growth factors. Endothelial nitric oxide synthase (eNOS; also known as NOS3 or NOSIII) is well-known for its role in the generation of vasoprotective nitric oxide (NO). eNOS is primarily expressed, but not exclusively, in endothelial cells, while recent studies have identified its expression in both adipocytes and endothelial cells of PVAT. PVAT eNOS is an important player in the protective role of PVAT. Different studies have demonstrated that, under obesity-linked metabolic diseases, PVAT eNOS may be even more important than endothelium eNOS in obesity-induced vascular dysfunction, which may be attributed to certain PVAT eNOS-specific functions. In this review, we summarized the current understanding of eNOS expression in PVAT, its function under both physiological and pathological conditions and listed out a few pharmacological interventions of interest that target eNOS in PVAT.
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Solanki K, Rajpoot S, Bezsonov EE, Orekhov AN, Saluja R, Wary A, Axen C, Wary K, Baig MS. The expanding roles of neuronal nitric oxide synthase (NOS1). PeerJ 2022; 10:e13651. [PMID: 35821897 PMCID: PMC9271274 DOI: 10.7717/peerj.13651] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/07/2022] [Indexed: 01/17/2023] Open
Abstract
The nitric oxide synthases (NOS; EC 1.14.13.39) use L-arginine as a substrate to produce nitric oxide (NO) as a by-product in the tissue microenvironment. NOS1 represents the predominant NO-producing enzyme highly enriched in the brain and known to mediate multiple functions, ranging from learning and memory development to maintaining synaptic plasticity and neuronal development, Alzheimer's disease (AD), psychiatric disorders and behavioral deficits. However, accumulating evidence indicate both canonical and non-canonical roles of NOS1-derived NO in several other tissues and chronic diseases. A better understanding of NOS1-derived NO signaling, and identification and characterization of NO-metabolites in non-neuronal tissues could become useful in diagnosis and prognosis of diseases associated with NOS1 expression. Continued investigation on the roles of NOS1, therefore, will synthesize new knowledge and aid in the discovery of small molecules which could be used to titrate the activities of NOS1-derived NO signaling and NO-metabolites. Here, we address the significance of NOS1 and its byproduct NO in modifying pathophysiological events, which could be beneficial in understanding both the disease mechanisms and therapeutics.
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Affiliation(s)
- Kundan Solanki
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, India
| | - Sajjan Rajpoot
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, India
| | - Evgeny E. Bezsonov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, Moscow, Russia
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia
- Department of Biology and General Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Alexander N. Orekhov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, Moscow, Russia
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Rohit Saluja
- Department of Biochemistry, All India Institute of Medical Sciences, Bibinagar, Hyderabad, India
| | - Anita Wary
- Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Cassondra Axen
- Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Kishore Wary
- Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Mirza S. Baig
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, India
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Tangeten C, Zouaoui Boudjeltia K, Delporte C, Van Antwerpen P, Korpak K. Unexpected Role of MPO-Oxidized LDLs in Atherosclerosis: In between Inflammation and Its Resolution. Antioxidants (Basel) 2022; 11:antiox11050874. [PMID: 35624738 PMCID: PMC9137493 DOI: 10.3390/antiox11050874] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 01/02/2023] Open
Abstract
Inflammation and its resolution are the result of the balance between pro-inflammatory and pro-resolving factors, such as specialized pro-resolving mediators (SPMs). This balance is crucial for plaque evolution in atherosclerosis, a chronic inflammatory disease. Myeloperoxidase (MPO) has been related to oxidative stress and atherosclerosis, and MPO-oxidized low-density lipoproteins (Mox-LDLs) have specific characteristics and effects. They participate in foam cell formation and cause specific reactions when interacting with macrophages and endothelial cells. They also increase the production of intracellular reactive oxygen species (ROS) in macrophages and the resulting antioxidant response. Mox-LDLs also drive macrophage polarization. Mox-LDLs are known to be pro-inflammatory particles. However, in the presence of Mox-LDLs, endothelial cells produce resolvin D1 (RvD1), a SPM. SPMs are involved in the resolution of inflammation by stimulating efferocytosis and by reducing the adhesion and recruitment of neutrophils and monocytes. RvD1 also induces the synthesis of other SPMs. In vitro, Mox-LDLs have a dual effect by promoting RvD1 release and inducing a more anti-inflammatory phenotype macrophage, thereby having a mixed effect on inflammation. In this review, we discuss the interrelationship between MPO, Mox-LDLs, and resolvins, highlighting a new perception of the role of Mox-LDLs in atherosclerosis.
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Affiliation(s)
- Cecilia Tangeten
- RD3-Pharmacognosy, Bioanalysis and Drug Discovery, Faculty of Pharmacy, Université Libre de Bruxelles, 1050 Brussels, Belgium; (C.D.); (P.V.A.)
- Correspondence: ; Tel.: +32-2-650-5331
| | - Karim Zouaoui Boudjeltia
- Laboratory of Experimental Medicine, ULB 222 Unit, CHU-Charleroi, A. Vésale Hospital, Université Libre de Bruxelles, 6110 Montigny-le-Tilleul, Belgium; (K.Z.B.); (K.K.)
| | - Cedric Delporte
- RD3-Pharmacognosy, Bioanalysis and Drug Discovery, Faculty of Pharmacy, Université Libre de Bruxelles, 1050 Brussels, Belgium; (C.D.); (P.V.A.)
| | - Pierre Van Antwerpen
- RD3-Pharmacognosy, Bioanalysis and Drug Discovery, Faculty of Pharmacy, Université Libre de Bruxelles, 1050 Brussels, Belgium; (C.D.); (P.V.A.)
| | - Keziah Korpak
- Laboratory of Experimental Medicine, ULB 222 Unit, CHU-Charleroi, A. Vésale Hospital, Université Libre de Bruxelles, 6110 Montigny-le-Tilleul, Belgium; (K.Z.B.); (K.K.)
- Department of Geriatric Medicine, CHU-Charleroi, Université Libre de Bruxelles, 6042 Charleroi, Belgium
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Gather F, Ihrig-Biedert I, Kohlhas P, Krutenko T, Peitz M, Brüstle O, Pautz A, Kleinert H. A specific, non-immune system-related isoform of the human inducible nitric oxide synthase is expressed during differentiation of human stem cells into various cell types. Cell Commun Signal 2022; 20:47. [PMID: 35392923 PMCID: PMC8991583 DOI: 10.1186/s12964-022-00855-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 03/03/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND NOS2 expression is mostly found in bacteria-exposed or cytokine-treated tissues and is mostly connected to innate immune reactions. There are three isoforms of NOS2 (NOS2-1 to -3). In RNA-seq data sets, analyzing inflammatory gene expression, only expression of the NOS2-1 mRNA isoform is detected. However, the expression of NOS2 in differentiating human pluripotent stems (hPSCs) has not been analyzed yet. METHODS Public available RNA-seq databases were screened for data of hPSCs during differentiation to different target cells. An isoform specific algorithm was used to analyze NOS2 mRNA isoform expression. In addition, we differentiated four different human iPSC cell lines toward cortical neurons and analyzed NOS2 mRNA expression by qRT-PCR and 5'-RACE. The functionality of the NOS2-2 protein was analyzed by transient transfection of expression clones in human DLD1 cells and nitrate measurement in the supernatant of these cells. RESULTS In RNA-seq databases we detected a transient expression of the NOS2 mRNA during the differentiation of hPSCs to cardiomyocytes, chondrocytes, mesenchymal stromal cells, neurons, syncytiotrophoblast cells, and trophoblasts. NOS2 mRNA isoform specific analyses showed, that the transiently expressed NOS2 mRNA in differentiating hPSC (NOS2-2; "diff-iNOS") differ remarkably from the already described NOS2 transcript found in colon or induced islets (NOS2-1; "immuno-iNOS"). Also, analysis of the NOS2 mRNA- and protein expression during the differentiation of four different hiPSC lines towards cortical neurons showed a transient expression of the NOS2 mRNA and NOS2 protein on day 18 of the differentiation course. 5'-RACE experiments and isoform specific qRT-PCR analyses revealed that only the NOS2-2 mRNA isoform was expressed in these experiments. To analyze the functionality of the NOS2-2 protein, we transfected human DLD-1 cells with tetracycline inducible expression clones encoding the NOS2-1- or -2 coding sequence. After induction of the NOS2-1 or -2 mRNA expression by tetracycline a similar nitrate production was measured proofing the functionality of the NOS2-2 protein isoform. CONCLUSIONS Our data show that a differentiation specific NOS2 isoform (NOS2-2) is transiently expressed during differentiation of hPSC. Video Abstract.
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Affiliation(s)
- Fabian Gather
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,Department of Molecular Embryology, Institute for Anatomy and Cell Biology, Freiburg, Germany
| | - Irmgard Ihrig-Biedert
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Paul Kohlhas
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Tamara Krutenko
- Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty & University Hospital Bonn, Bonn, Germany
| | - Michael Peitz
- Cell Programming Core Facility, Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty & University Hospital Bonn, Bonn, Germany.,Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty & University Hospital Bonn, Bonn, Germany
| | - Oliver Brüstle
- Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty & University Hospital Bonn, Bonn, Germany
| | - Andrea Pautz
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
| | - Hartmut Kleinert
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
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