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1
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Fung TS, Ryu KW, Thompson CB. Arginine: at the crossroads of nitrogen metabolism. EMBO J 2025; 44:1275-1293. [PMID: 39920310 PMCID: PMC11876448 DOI: 10.1038/s44318-025-00379-3] [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: 09/24/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 02/09/2025] Open
Abstract
L-arginine is the most nitrogen-rich amino acid, acting as a key precursor for the synthesis of nitrogen-containing metabolites and an essential intermediate in the clearance of excess nitrogen. Arginine's side chain possesses a guanidino group which has unique biochemical properties, and plays a primary role in nitrogen excretion (urea), cellular signaling (nitric oxide) and energy buffering (phosphocreatine). The post-translational modification of protein-incorporated arginine by guanidino-group methylation also contributes to epigenetic gene control. Most human cells do not synthesize sufficient arginine to meet demand and are dependent on exogenous arginine. Thus, dietary arginine plays an important role in maintaining health, particularly upon physiologic stress. How cells adapt to changes in extracellular arginine availability is unclear, mostly because nearly all tissue culture media are supplemented with supraphysiologic levels of arginine. Evidence is emerging that arginine-deficiency can influence disease progression. Here, we review new insights into the importance of arginine as a metabolite, emphasizing the central role of mitochondria in arginine synthesis/catabolism and the recent discovery that arginine can act as a signaling molecule regulating gene expression and organelle dynamics.
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Affiliation(s)
- Tak Shun Fung
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Keun Woo Ryu
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Craig B Thompson
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
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2
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Silva ÁJC, de Lavor MSL. Nitroxidative Stress, Cell-Signaling Pathways, and Manganese Porphyrins: Therapeutic Potential in Neuropathic Pain. Int J Mol Sci 2025; 26:2050. [PMID: 40076672 PMCID: PMC11900433 DOI: 10.3390/ijms26052050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/23/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Neuropathic pain, a debilitating condition arising from somatosensory system damage, significantly impacts quality of life, leading to anxiety, self-mutilation, and depression. Oxidative and nitrosative stress, an imbalance between reactive oxygen and nitrogen species (ROS/RNS) and antioxidant defenses, plays a crucial role in its pathophysiology. While reactive species are essential for physiological functions, excessive levels can cause cellular component damage, leading to neuronal dysfunction and pain. This review highlights the complex interactions between reactive species, antioxidant systems, cell signaling, and neuropathic pain. We discuss the physiological roles of ROS/RNS and the detrimental effects of oxidative and nitrosative stress. Furthermore, we explore the potential of manganese porphyrins, compounds with antioxidant properties, as promising therapeutic agents to mitigate oxidative stress and alleviate neuropathic pain by targeting key cellular pathways involved in pain. Further research is needed to fully understand their therapeutic potential in managing neuropathic pain in human and non-human animals.
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Affiliation(s)
| | - Mário Sérgio Lima de Lavor
- Department of Agricultural and Environmental Sciences, State University of Santa Cruz (UESC), Ilhéus 45662-900, BA, Brazil;
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3
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Yadav R, SanuKhan R, Kalita N, Mendiratta S, Sivaramakrishnan S, Murugan S, Samanta A. Molecular Imaging of Nitric Oxide Surrogates with Organelle-Specific Fluorescent Probes. Chem Asian J 2025; 20:e202401237. [PMID: 39629512 DOI: 10.1002/asia.202401237] [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: 09/20/2024] [Revised: 11/30/2024] [Indexed: 12/13/2024]
Abstract
Nitric oxide is an important signalling molecule responsible for maintaining body's homeostasis. Any dysregulation in NO can lead to many pathological conditions like atherosclerosis, cancers, neurodegenerative disorders, hypertension and inflammation. Several, sensing technologies are used for sensing NO. Among these, fluorescent imaging is considered to be one of the most efficient. Till date, approximately 123 fluorescent probes are reported related to nitric oxide (NO) sensing fluorescent probes for the sensitive, selective, and real-time detection of NO at both the cellular and subcellular levels. In the past five years, around 41 fluorescent probes and four review articles have been published, specifically focusing on the detection of nitric oxide. Despite considerable advancements in this area, no systematic review has summarized various organelle-targeting NO-sensing fluorescent probes. Herein, we summarized last five years from 2019 to 2024 along with the key pioneering research in this field covering divergent roles of NO across various cellular organelles. We have included 41 probes by classifying into different organelle targeting sections. We strongly believe this review will provide an advanced summary of NO specific fluorescent probes and their applications for monitoring the progression of diseases in in vitro to in vivo models such as drosophila, zebrafish, mouse models.
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Affiliation(s)
- Rashmi Yadav
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence (SNIoE), Deemed to be University, Delhi NCR, Greater Noida, Uttar Pradesh, 201314, India
| | - Rafique SanuKhan
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence (SNIoE), Deemed to be University, Delhi NCR, Greater Noida, Uttar Pradesh, 201314, India
| | - Nripankar Kalita
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence (SNIoE), Deemed to be University, Delhi NCR, Greater Noida, Uttar Pradesh, 201314, India
| | - Sana Mendiratta
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence (SNIoE), Deemed to be University, Delhi NCR, Greater Noida, Uttar Pradesh, 201314, India
| | - Shreya Sivaramakrishnan
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence (SNIoE), Deemed to be University, Delhi NCR, Greater Noida, Uttar Pradesh, 201314, India
| | - Shreekanth Murugan
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence (SNIoE), Deemed to be University, Delhi NCR, Greater Noida, Uttar Pradesh, 201314, India
| | - Animesh Samanta
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence (SNIoE), Deemed to be University, Delhi NCR, Greater Noida, Uttar Pradesh, 201314, India
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4
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Li H, Cheng Z, Wu D, Hu Q. Nitric oxide and mitochondrial function in cardiovascular diseases. Nitric Oxide 2025; 154:42-50. [PMID: 39577487 DOI: 10.1016/j.niox.2024.11.007] [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: 07/02/2024] [Revised: 09/11/2024] [Accepted: 11/19/2024] [Indexed: 11/24/2024]
Abstract
Nitric oxide (NO) has been highlighted as an important factor in cardiovascular system. As a signaling molecule in the cardiovascular system, NO can relax blood vessels, lower blood pressure, and prevent platelet aggregation. Mitochondria serve as a central hub for cellular metabolism and intracellular signaling, and their dysfunction can lead to a variety of diseases. Accumulating evidence suggests that NO can act as a regulator of mitochondria, affecting mitochondrial function and cellular activity, which in turn mediates the onset and progression of disease. However, there is a lack of comprehensive understanding of how NO regulates mitochondrial function in the cardiovascular system. This review aims to summarize the regulation of mitochondrial function by nitric oxide in cardiovascular related diseases, as well as the multifaceted and complex roles of NO in the cardiovascular system. Understanding the mechanism of NO mediated mitochondrial function can provide new insights for the prevention and treatment of cardiovascular diseases.
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Affiliation(s)
- Haoqi Li
- Department of Pharmacy, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Zijie Cheng
- Department of Pharmacy, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Dan Wu
- Department of Pharmacy, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
| | - Qingxun Hu
- Department of Pharmacy, School of Medicine, Shanghai University, Shanghai, 200444, China.
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5
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Tripodi G, Lombardo M, Kerav S, Aiello G, Baldelli S. Nitric Oxide in Parkinson's Disease: The Potential Role of Dietary Nitrate in Enhancing Cognitive and Motor Health via the Nitrate-Nitrite-Nitric Oxide Pathway. Nutrients 2025; 17:393. [PMID: 39940251 PMCID: PMC11819985 DOI: 10.3390/nu17030393] [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: 12/11/2024] [Revised: 01/14/2025] [Accepted: 01/14/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND/OBJECTIVES Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as tremor, rigidity, and bradykinesia. The pathological hallmarks of PD include Lewy bodies and mechanisms like oxidative/nitrosative stress, chronic inflammation, and mitochondrial dysfunction. Nitric oxide (NO), produced by nitric oxide synthase (NOS) isoforms, plays a dual role in neuroprotection and neurodegeneration. Excessive NO production exacerbates neuroinflammation and oxidative/nitrosative damage, contributing to dopaminergic cell death. This review explores NO's role in PD pathogenesis and investigates dietary nitrate as a therapeutic strategy to regulate NO levels. METHODS A literature review of studies addressing the role of NO in PD was conducted using major scientific databases, including PubMed, Scopus, and Web of Science, using keywords such as "nitric oxide", "NOSs", "Parkinson's disease", and "nitrate neuroprotection in PD". Studies on nitrate metabolism via the nitrate-nitrite-NO pathway and its effects on PD hallmarks were analyzed. Studies regarding the role of nitrosamine formation in PD, which are mainly formed during the nitrification process of amines (nitrogen-containing compounds), often due to chemical reactions in the presence of nitrite or nitrate, were also examined. In particular, nitrate has been shown to induce oxidative stress, affect the mitochondrial function, and contribute to inflammatory phenomena in the brain, another factor closely related to the pathogenesis of PD. RESULTS Excessive NO production, particularly from iNOS and nNOS, was strongly associated with neuroinflammation and oxidative/nitrosative stress, amplifying neuronal damage in PD. Dietary nitrate was shown to enhance NO bioavailability through the nitrate-nitrite-NO pathway, mitigating inflammation and oxidative/nitrosative damage. CONCLUSIONS Dysregulated NO production contributes significantly to PD progression via inflammatory and oxidative/nitrosative pathways. Dietary nitrate, by modulating NO levels, offers a promising therapeutic strategy to counteract these pathological mechanisms. Further clinical trials are warranted to establish its efficacy and optimize its use in PD management.
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Affiliation(s)
- Gianluca Tripodi
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166 Rome, Italy; (G.T.); (M.L.); (G.A.)
| | - Mauro Lombardo
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166 Rome, Italy; (G.T.); (M.L.); (G.A.)
| | - Sercan Kerav
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, 17100 Çanakkale, Türkiye;
| | - Gilda Aiello
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166 Rome, Italy; (G.T.); (M.L.); (G.A.)
| | - Sara Baldelli
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166 Rome, Italy; (G.T.); (M.L.); (G.A.)
- IRCCS San Raffaele Roma, 00166 Rome, Italy
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6
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Milosevic K, Milosevic A, Stevanovic I, Zivkovic A, Laketa D, Janjic MM, Bjelobaba I, Lavrnja I, Savic D. Agmatine suppresses glycolysis via the PI3K/Akt/mTOR/HIF-1α signaling pathway and improves mitochondrial function in microglia exposed to lipopolysaccharide. Biofactors 2025; 51:e2149. [PMID: 39888089 PMCID: PMC11780571 DOI: 10.1002/biof.2149] [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: 08/21/2024] [Accepted: 11/22/2024] [Indexed: 02/01/2025]
Abstract
Modulating metabolic pathways in activated microglia can alter their phenotype, which is relevant in uncontrolled neuroinflammation as a component of various neurodegenerative diseases. Here, we investigated how pretreatment with agmatine, an endogenous polyamine, affects metabolic changes in an in vitro model of neuroinflammation, a murine microglial BV-2 cell line exposed to lipopolysaccharide (LPS). Hence, we analyzed gene expression using qPCR and protein levels using Western blot and ELISA. Microglial metabolic status was assessed by measuring lactate release and cellular ATP by enzymatic and luminescence spectrophotometry. Mitochondrial functionality was analyzed by fluorescent probes detecting mitochondrial membrane potential (mtMP) and superoxide production. Our findings suggest that kinase pathways associated with hypoxia-inducible factor-1α (HIF-1α) regulate energy metabolism in pro-inflammatory activated microglia. We have shown that LPS induces HIF-1α and genes for glucose transporter and glycolytic rate, increases lactate production and causes mitochondrial dysfunction, suggesting a metabolic shift towards glycolysis. Agmatine inhibits the PI3K/Akt pathway and negatively regulates mammalian target of rapamycin (mTOR) phosphorylation and HIF-1α levels, reducing lactate and tumor necrosis factor (TNF) production, which is supported by pharmacological blockade of PI3K. Pretreatment with agmatine also rescues mitochondrial function by counteracting the LPS-induced decline in mtMP and increase in mitochondrial superoxide, resulting in an anti-apoptotic effect. Agmatine alone increases intracellular ATP levels and maintains this effect even under pro-inflammatory conditions. Our study emphasizes the ability of agmatine to engage in metabolic reprogramming of pro-inflammatory microglia through increased ATP production and modulation of signaling pathway involved in promoting glycolysis and cytokine release.
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Affiliation(s)
- Katarina Milosevic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Ana Milosevic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Ivana Stevanovic
- Medical Faculty of the Military Medical AcademyUniversity of Defense in BelgradeBelgradeSerbia
| | - Anica Zivkovic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Danijela Laketa
- Department for General Physiology and BiophysicsFaculty of Biology, University of BelgradeBelgradeSerbia
| | - Marija M. Janjic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Ivana Bjelobaba
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Irena Lavrnja
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Danijela Savic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
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7
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Danylovych HV, Danylovych YV, Pavliuk MR, Kosterin SO. Products of oxidative and non-oxidative metabolism of L-arginine as potential regulators of Ca 2+ transport in mitochondria of uterine smooth muscle. Biochim Biophys Acta Gen Subj 2024; 1868:130652. [PMID: 38857773 DOI: 10.1016/j.bbagen.2024.130652] [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: 03/14/2024] [Revised: 05/15/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
Mitochondria play a crucial role in maintaining Ca2+ homeostasis in cells. Due to the critical regulatory role of the products of oxidative and non-oxidative metabolism of L-arginine, it is essential to clarify their effect on Ca2+ transport in smooth muscle mitochondria. Experiments were performed on the uterine myocytes of rats and isolated mitochondria. The possibility of NO synthesis by mitochondria was demonstrated by confocal microscopy and spectrofluorimetry methods using the NO-sensitive fluorescent probe DAF-FM and Mitotracker Orange CM-H2TMRos. It was shown that 50 μM L-arginine stimulates the energy-dependent accumulation of Ca2+ in mitochondria using the fluorescent probe Fluo-4 AM. A similar effect occurred when using nitric oxide donors 100 μM SNP, SNAP, and sodium nitrite (SN) directly. The stimulating effect was eliminated in the presence of the NO scavenger C-PTIO. Nitric oxide reduces the electrical potential in mitochondria without causing them to swell. The stimulatory effect of spermine on the accumulation of Ca2+ by mitochondria is attributed to the enhancement of NO synthesis, which was demonstrated with the use of C-PTIO, NO-synthase inhibitors (100 μM NA and L-NAME), as well as by direct monitoring of NO synthesis fluorescent probe DAF-FM. A conclusion was drawn about the potential regulatory effect of the product of the oxidative metabolism of L-arginine - NO on the transport of Ca2+ in the mitochondria of the myometrium, as well as the corresponding effect of the product of non-oxidative metabolism -spermine by increasing the synthesis of NO in these subcellular structures.
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Affiliation(s)
- Hanna V Danylovych
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
| | - Yuriy V Danylovych
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Maksym R Pavliuk
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Sergiy O Kosterin
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
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8
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Qiu F, Liu Y, Liu Z. The Role of Protein S-Nitrosylation in Mitochondrial Quality Control in Central Nervous System Diseases. Aging Dis 2024:AD.2024.0099. [PMID: 38739938 DOI: 10.14336/ad.2024.0099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 03/25/2024] [Indexed: 05/16/2024] Open
Abstract
S-Nitrosylation is a reversible covalent post-translational modification. Under physiological conditions, S-nitrosylation plays a dynamic role in a wide range of biological processes by regulating the function of substrate proteins. Like other post-translational modifications, S-nitrosylation can affect protein conformation, activity, localization, aggregation, and protein interactions. Aberrant S-nitrosylation can lead to protein misfolding, mitochondrial fragmentation, synaptic damage, and autophagy. Mitochondria are essential organelles in energy production, metabolite biosynthesis, cell death, and immune responses, among other processes. Mitochondrial dysfunction can result in cell death and has been implicated in the development of many human diseases. Recent evidence suggests that S-nitrosylation and mitochondrial dysfunction are important modulators of the progression of several diseases. In this review, we highlight recent findings regarding the aberrant S- nitrosylation of mitochondrial proteins that regulate mitochondrial biosynthesis, fission and fusion, and autophagy. Specifically, we discuss the mechanisms by which S-nitrosylated mitochondrial proteins exercise mitochondrial quality control under pathological conditions, thereby influencing disease. A better understanding of these pathological events may provide novel therapeutic targets to mitigate the development of neurological diseases.
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Affiliation(s)
- Fang Qiu
- Department of Burn and Plastic Surgery, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong, China
| | - Yuqiang Liu
- Department of Anesthesiology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Zhiheng Liu
- Department of Anesthesiology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China
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9
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Barros CDS, Coutinho A, Tengan CH. Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms? Int J Mol Sci 2024; 25:3629. [PMID: 38612442 PMCID: PMC11011289 DOI: 10.3390/ijms25073629] [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: 02/23/2024] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.
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Affiliation(s)
| | | | - Celia H. Tengan
- Division of Neurology, Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil; (C.D.S.B.); (A.C.)
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10
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Kim SR, Park JW, Choi YJ, Sonn SK, Oh GT, Lee BH, Chang TS. Mitochondrial H 2O 2 Is a Central Mediator of Diclofenac-Induced Hepatocellular Injury. Antioxidants (Basel) 2023; 13:17. [PMID: 38275637 PMCID: PMC10812772 DOI: 10.3390/antiox13010017] [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: 12/06/2023] [Revised: 12/16/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
Nonsteroidal anti-inflammatory drug (NSAID) use is associated with adverse consequences, including hepatic injury. The detrimental hepatotoxicity of diclofenac, a widely used NSAID, is primarily connected to oxidative damage in mitochondria, which are the primary source of reactive oxygen species (ROS). The primary ROS responsible for inducing diclofenac-related hepatocellular toxicity and the principal antioxidant that mitigates these ROS remain unknown. Peroxiredoxin III (PrxIII) is the most abundant and potent H2O2-eliminating enzyme in the mitochondria of mammalian cells. Here, we investigated the role of mitochondrial H2O2 and the protective function of PrxIII in diclofenac-induced mitochondrial dysfunction and apoptosis in hepatocytes. Mitochondrial H2O2 levels were differentiated from other types of ROS using a fluorescent H2O2 indicator. Upon diclofenac treatment, PrxIII-knockdown HepG2 human hepatoma cells showed higher levels of mitochondrial H2O2 than PrxIII-expressing controls. PrxIII-depleted cells exhibited higher mitochondrial dysfunction as measured by a lower oxygen consumption rate, loss of mitochondrial membrane potential, cardiolipin oxidation, and caspase activation, and were more sensitive to apoptosis. Ectopic expression of mitochondrially targeted catalase in PrxIII-knockdown HepG2 cells or in primary hepatocytes derived from PrxIII-knockout mice suppressed the diclofenac-induced accumulation of mitochondrial H2O2 and decreased apoptosis. Thus, we demonstrated that mitochondrial H2O2 is a key mediator of diclofenac-induced hepatocellular damage driven by mitochondrial dysfunction and apoptosis. We showed that PrxIII loss results in the critical accumulation of mitochondrial H2O2 and increases the harmful effects of diclofenac. PrxIII or other antioxidants targeting mitochondrial H2O2 could be explored as potential therapeutic agents to protect against the hepatotoxicity associated with NSAID use.
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Affiliation(s)
- Sin Ri Kim
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Ji Won Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - You-Jin Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Seong Keun Sonn
- Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Goo Taeg Oh
- Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Byung-Hoon Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Tong-Shin Chang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
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11
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Haynes V, Giulivi C. Calcium-Dependent Interaction of Nitric Oxide Synthase with Cytochrome c Oxidase: Implications for Brain Bioenergetics. Brain Sci 2023; 13:1534. [PMID: 38002494 PMCID: PMC10669843 DOI: 10.3390/brainsci13111534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Targeted nitric oxide production is relevant for maintaining cellular energy production, protecting against oxidative stress, regulating cell death, and promoting neuroprotection. This study aimed to characterize the putative interaction of nitric-oxide synthase with mitochondrial proteins. The primary finding of this study is that cytochrome c oxidase (CCO) subunit IV (CCOIV) is associated directly with NOS in brain mitochondria when calcium ions are present. The matrix side of CCOIV binds to the N-terminus of NOS, supported by the abrogation of the binding by antibodies towards the N-terminus of NOS. Evidence supporting the interaction between CCOIV and NOS was provided by the coimmunoprecipitation of NOS from detergent-solubilized whole rat brain mitochondria with antibodies to CCOIV and the coimmunoprecipitation of CCOIV from crude brain NOS preparations using antibodies to NOS. The CCOIV domain that interacts with NOS was identified using a series of overlapping peptides derived from the primary sequence of CCOIV. As calcium ions not only activate NOS, but also facilitate the docking of NOS to CCOIV, this study points to a dynamic mechanism of controlling the bioenergetics by calcium changes, thereby adapting bioenergetics to cellular demands.
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Affiliation(s)
- Virginia Haynes
- School of Veterinary Medicine, Department Molecular Biosciences, University of California Davis, Davis, CA 95616, USA
| | - Cecilia Giulivi
- School of Veterinary Medicine, Department Molecular Biosciences, University of California Davis, Davis, CA 95616, USA
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDH, University of California Davis, Sacramento, CA 95817, USA
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12
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Sikora JP, Karawani J, Sobczak J. Neutrophils and the Systemic Inflammatory Response Syndrome (SIRS). Int J Mol Sci 2023; 24:13469. [PMID: 37686271 PMCID: PMC10488036 DOI: 10.3390/ijms241713469] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 08/24/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
We are not entirely able to understand, assess, and modulate the functioning of the immune system in clinical situations that lead to a systemic inflammatory response. In the search for diagnostic and treatment strategies (which are still far from perfect), it became very important to study the pathogenesis and participation of endogenous inflammation mediators. This study attempts to more precisely establish the role of neutrophils in individual phenomena occurring during an inflammatory and anti-inflammatory reaction, taking into account their cidal, immunoregulatory, and reparative abilities. Pro- and anticoagulatory properties of endothelium in systemic inflammatory response syndrome (SIRS) are emphasised, along with the resulting clinical implications (the application of immunotherapy using mesenchymal stem/stromal cells (MSCs) or IL-6 antagonists in sepsis and COVID-19 treatment, among others). Special attention is paid to reactive oxygen species (ROS), produced by neutrophils activated during "respiratory burst" in the course of SIRS; the protective and pathogenic role of these endogenous mediators is highlighted. Moreover, clinically useful biomarkers of SIRS (neutrophil extracellular traps, cell-free DNA, DAMP, TREMs, NGAL, miRNA, selected cytokines, ROS, and recognised markers of endothelial damage from the group of adhesins by means of immunohistochemical techniques) related to the neutrophils are presented, and their role in the diagnosing and forecasting of sepsis, burn disease, and COVID-19 is emphasised. Finally, examples of immunomodulation of sepsis and antioxidative thermal injury therapy are presented.
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Affiliation(s)
- Janusz P. Sikora
- Department of Paediatric Emergency Medicine, 2nd Chair of Paediatrics, Central Clinical Hospital, Medical University of Łódź, ul. Sporna 36/50, 91-738 Łódź, Poland;
| | - Jakub Karawani
- Faculty of Medicine, Lazarski University, ul. Świeradowska 43, 02-662 Warsaw, Poland;
| | - Jarosław Sobczak
- Department of Paediatric Emergency Medicine, 2nd Chair of Paediatrics, Central Clinical Hospital, Medical University of Łódź, ul. Sporna 36/50, 91-738 Łódź, Poland;
- Department of Management and Logistics in Healthcare, Medical University of Łódź, ul. Lindleya 6, 90-131 Łódź, Poland
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13
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Averbeck D. Low-Dose Non-Targeted Effects and Mitochondrial Control. Int J Mol Sci 2023; 24:11460. [PMID: 37511215 PMCID: PMC10380638 DOI: 10.3390/ijms241411460] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/26/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023] Open
Abstract
Non-targeted effects (NTE) have been generally regarded as a low-dose ionizing radiation (IR) phenomenon. Recently, regarding long distant abscopal effects have also been observed at high doses of IR) relevant to antitumor radiation therapy. IR is inducing NTE involving intracellular and extracellular signaling, which may lead to short-ranging bystander effects and distant long-ranging extracellular signaling abscopal effects. Internal and "spontaneous" cellular stress is mostly due to metabolic oxidative stress involving mitochondrial energy production (ATP) through oxidative phosphorylation and/or anaerobic pathways accompanied by the leakage of O2- and other radicals from mitochondria during normal or increased cellular energy requirements or to mitochondrial dysfunction. Among external stressors, ionizing radiation (IR) has been shown to very rapidly perturb mitochondrial functions, leading to increased energy supply demands and to ROS/NOS production. Depending on the dose, this affects all types of cell constituents, including DNA, RNA, amino acids, proteins, and membranes, perturbing normal inner cell organization and function, and forcing cells to reorganize the intracellular metabolism and the network of organelles. The reorganization implies intracellular cytoplasmic-nuclear shuttling of important proteins, activation of autophagy, and mitophagy, as well as induction of cell cycle arrest, DNA repair, apoptosis, and senescence. It also includes reprogramming of mitochondrial metabolism as well as genetic and epigenetic control of the expression of genes and proteins in order to ensure cell and tissue survival. At low doses of IR, directly irradiated cells may already exert non-targeted effects (NTE) involving the release of molecular mediators, such as radicals, cytokines, DNA fragments, small RNAs, and proteins (sometimes in the form of extracellular vehicles or exosomes), which can induce damage of unirradiated neighboring bystander or distant (abscopal) cells as well as immune responses. Such non-targeted effects (NTE) are contributing to low-dose phenomena, such as hormesis, adaptive responses, low-dose hypersensitivity, and genomic instability, and they are also promoting suppression and/or activation of immune cells. All of these are parts of the main defense systems of cells and tissues, including IR-induced innate and adaptive immune responses. The present review is focused on the prominent role of mitochondria in these processes, which are determinants of cell survival and anti-tumor RT.
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Affiliation(s)
- Dietrich Averbeck
- Laboratory of Cellular and Molecular Radiobiology, PRISME, UMR CNRS 5822/IN2P3, IP2I, Lyon-Sud Medical School, University Lyon 1, 69921 Oullins, France
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Abstract
Mitochondria are critical organelles responsible for the maintenance of cellular energy homeostasis. Thus, their dysfunction can have severe consequences in cells responsible for energy-intensive metabolic function, such as hepatocytes. Extensive research over the last decades have identified compromised mitochondrial function as a central feature in the pathophysiology of liver injury induced by an acetaminophen (APAP) overdose, the most common cause of acute liver failure in the United States. While hepatocyte mitochondrial oxidative and nitrosative stress coupled with induction of the mitochondrial permeability transition are well recognized after an APAP overdose, recent studies have revealed additional details about the organelle's role in APAP pathophysiology. This concise review highlights these new advances, which establish the central role of the mitochondria in APAP pathophysiology, and places them in the context of earlier information in the literature. Adaptive alterations in mitochondrial morphology as well as the role of cellular iron in mitochondrial dysfunction and the organelle's importance in liver recovery after APAP-induced injury will be discussed.
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15
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Chaudhary S, Ganguly S, Palanichamy JK, Singh A, Pradhan D, Bakhshi R, Chopra A, Bakhshi S. Mitochondrial gene expression signature predicts prognosis of pediatric acute myeloid leukemia patients. Front Oncol 2023; 13:1109518. [PMID: 36845715 PMCID: PMC9947241 DOI: 10.3389/fonc.2023.1109518] [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: 11/27/2022] [Accepted: 01/11/2023] [Indexed: 02/11/2023] Open
Abstract
INTRODUCTION Gene expression profile of mitochondrial-related genes is not well deciphered in pediatric acute myeloid leukaemia (AML). We aimed to identify mitochondria-related differentially expressed genes (DEGs) in pediatric AML with their prognostic significance. METHODS Children with de novo AML were included prospectively between July 2016-December 2019. Transcriptomic profiling was done for a subset of samples, stratified by mtDNA copy number. Top mitochondria-related DEGs were identified and validated by real-time PCR. A prognostic gene signature risk score was formulated using DEGs independently predictive of overall survival (OS) in multivariable analysis. Predictive ability of the risk score was estimated along with external validation in The Tumor Genome Atlas (TCGA) AML dataset. RESULTS In 143 children with AML, twenty mitochondria-related DEGs were selected for validation, of which 16 were found to be significantly dysregulated. Upregulation of SDHC (p<0.001), CLIC1 (p=0.013) and downregulation of SLC25A29 (p<0.001) were independently predictive of inferior OS, and included for developing prognostic risk score. The risk score model was independently predictive of survival over and above ELN risk categorization (Harrell's c-index: 0.675). High-risk patients (risk score above median) had significantly inferior OS (p<0.001) and event free survival (p<0.001); they were associated with poor-risk cytogenetics (p=0.021), ELN intermediate/poor risk group (p=0.016), absence of RUNX1-RUNX1T1 (p=0.027), and not attaining remission (p=0.016). On external validation, the risk score also predicted OS (p=0.019) in TCGA dataset. DISCUSSION We identified and validated mitochondria-related DEGs with prognostic impact in pediatric AML and also developed a novel 3-gene based externally validated gene signature predictive of survival.
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Affiliation(s)
- Shilpi Chaudhary
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Shuvadeep Ganguly
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Archna Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Dibyabhaba Pradhan
- Computational Genomics Centre, Indian Council of Medical Research (ICMR), New Delhi, India
| | - Radhika Bakhshi
- Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, Delhi, India
| | - Anita Chopra
- Department of Laboratory Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Sameer Bakhshi
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
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16
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Pappas G, Wilkinson ML, Gow AJ. Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy. Nitric Oxide 2023; 131:8-17. [PMID: 36470373 PMCID: PMC9839556 DOI: 10.1016/j.niox.2022.11.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/24/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Nitric oxide can interact with a wide range of proteins including many that are involved in metabolism. In this review we have summarized the effects of NO on glycolysis, fatty acid metabolism, the TCA cycle, and oxidative phosphorylation with reference to skeletal muscle. Low to moderate NO concentrations upregulate glucose and fatty acid oxidation, while higher NO concentrations shift cellular reliance toward a fully glycolytic phenotype. Moderate NO production directly inhibits pyruvate dehydrogenase activity, reducing glucose-derived carbon entry into the TCA cycle and subsequently increasing anaploretic reactions. NO directly inhibits aconitase activity, increasing reliance on glutamine for continued energy production. At higher or prolonged NO exposure, citrate accumulation can inhibit multiple ATP-producing pathways. Reduced TCA flux slows NADH/FADH entry into the ETC. NO can also inhibit the ETC directly, further limiting oxidative phosphorylation. Moderate NO production improves mitochondrial efficiency while improving O2 utilization increasing whole-body energy production. Long-term bioenergetic capacity may be increased because of NO-derived ROS, which participate in adaptive cellular redox signaling through AMPK, PCG1-α, HIF-1, and NF-κB. However, prolonged exposure or high concentrations of NO can result in membrane depolarization and opening of the MPT. In this way NO may serve as a biochemical rheostat matching energy supply with demand for optimal respiratory function.
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Affiliation(s)
- Gregory Pappas
- Department of Kinesiology & Applied Physiology, Rutgers the State University of New Jersey, NJ, 08854, USA.
| | - Melissa L Wilkinson
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers the State University of New Jersey, NJ, 08854, USA.
| | - Andrew J Gow
- Department of Kinesiology & Applied Physiology, Rutgers the State University of New Jersey, NJ, 08854, USA; Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers the State University of New Jersey, NJ, 08854, USA.
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17
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Zaric BL, Macvanin MT, Isenovic ER. Free radicals: Relationship to Human Diseases and Potential Therapeutic applications. Int J Biochem Cell Biol 2023; 154:106346. [PMID: 36538984 DOI: 10.1016/j.biocel.2022.106346] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 12/06/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022]
Abstract
Reactive species are highly-reactive enzymatically, or non-enzymatically produced compounds with important roles in physiological and pathophysiological cellular processes. Although reactive species represent an extensively researched topic in biomedical sciences, many aspects of their roles and functions remain unclear. This review aims to systematically summarize findings regarding the biochemical characteristics of various types of reactive species and specify the localization and mechanisms of their production in cells. In addition, we discuss the specific roles of free radicals in cellular physiology, focusing on the current lines of research that aim to identify the reactive oxygen species-initiated cascades of reactions resulting in adaptive or pathological cellular responses. Finally, we present recent findings regarding the therapeutic modulations of intracellular levels of reactive oxygen species, which may have substantial significance in developing novel agents for treating several diseases.
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Affiliation(s)
- Bozidarka L Zaric
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
| | - Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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18
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Steinert JR, Amal H. The contribution of an imbalanced redox signalling to neurological and neurodegenerative conditions. Free Radic Biol Med 2023; 194:71-83. [PMID: 36435368 DOI: 10.1016/j.freeradbiomed.2022.11.035] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/17/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022]
Abstract
Nitric oxide and other redox active molecules such as oxygen free radicals provide essential signalling in diverse neuronal functions, but their excess production and insufficient scavenging induces cytotoxic redox stress which is associated with numerous neurodegenerative and neurological conditions. A further component of redox signalling is mediated by a homeostatic regulation of divalent metal ions, the imbalance of which contributes to neuronal dysfunction. Additional antioxidant molecules such as glutathione and enzymes such as super oxide dismutase are involved in maintaining a physiological redox status within neurons. When cellular processes are perturbed and generation of free radicals overwhelms the antioxidants capacity of the neurons, a resulting redox damage leads to neuronal dysfunction and cell death. Cellular sources for production of redox-active molecules may include NADPH oxidases, mitochondria, cytochrome P450 and nitric oxide (NO)-generating enzymes, such as endothelial, neuronal and inducible NO synthases. Several neurodegenerative and developmental neurological conditions are associated with an imbalanced redox state as a result of neuroinflammatory processes leading to nitrosative and oxidative stress. Ongoing research aims at understanding the causes and consequences of such imbalanced redox homeostasis and its role in neuronal dysfunction.
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Affiliation(s)
- Joern R Steinert
- Division of Physiology, Pharmacology and Neuroscience, University of Nottingham, School of Life Sciences, Nottingham, NG7 2NR, UK.
| | - Haitham Amal
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
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19
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Onohuean H, Onohuean FE, Igbinoba SI, Ezeonwumelu JOC, Agu PC, Ifie JE, Deusdedit T, Aja PM. Elucidation of chemical profiles and molecular targets of Mondia whitei leave fractions bioactive as novel therapeutics: an in vitro and in silico assay. J Genet Eng Biotechnol 2022; 20:170. [PMID: 36574159 PMCID: PMC9794650 DOI: 10.1186/s43141-022-00440-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/29/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND Mondia whitei root is often used in Africa as a local therapeutic agent for libido enhancement. The fractions of the M. whitei leaves (MWL) lack chemical characterization of their bioactive components and possible molecular targets. We characterized and investigated its molecular target as therapeutic agents in an in vitro and in silico assay. Mineral compositions, antioxidant, and GC-MS characterization were studied. The cytotoxicity effect was measured on HeLa and HT-29 cells by MTT assay. In silico potential inhibitors of Cathepsin B (CathB) as a cancer biomarker were determined. RESULTS The flame photometry produced marked Na+ and K+. GC-MS revealed eighteen bioactive components. The fractions (chloroformic 47.00, ethanolic 45.52, and aqueous 40.13) of MWL caused a higher inhibition ratio compared to standards. The MWL showed a significant cytotoxic effect on the treated cell lines at concentrations of 150 and 200 μg/ml and 100, 150, and 200 μg/ml for HT-29 and HeLa cells, respectively. Ten bioactives (MWL 4, 5, 6, 8, 9, 10, 14, 15, 17, and 18) showed potential inhibition of CathB with binding affinities of -4.40 to -8.3 Kcal/Mol. However, MWL 4, 9, 14, and 17 which have higher binding affinities (-6.7, -7.1, -8.2, and -8.3, respectively) than the standard inhibitor (-6.5) were the lead molecules. CONCLUSION These chemical profiles and potential molecular targets unraveled in this study propose that MWL has a promising anticancer activity.
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Affiliation(s)
- Hope Onohuean
- grid.440478.b0000 0004 0648 1247Biomolecules, Metagenomics, Endocrine, and Tropical Disease Research Group (BMETDREG), Kampala International University Western Campus, Ishaka-Bushenyi, Uganda ,grid.440478.b0000 0004 0648 1247Biopharmaceutics Unit, Department of Pharmacology and Toxicology, Kampala International University Western Campus, Ishaka-Bushenyi, Uganda
| | - Fanny Eseohe Onohuean
- grid.440478.b0000 0004 0648 1247Biomolecules, Metagenomics, Endocrine, and Tropical Disease Research Group (BMETDREG), Kampala International University Western Campus, Ishaka-Bushenyi, Uganda
| | - Sharon Iyobor Igbinoba
- grid.440478.b0000 0004 0648 1247Biomolecules, Metagenomics, Endocrine, and Tropical Disease Research Group (BMETDREG), Kampala International University Western Campus, Ishaka-Bushenyi, Uganda ,grid.440478.b0000 0004 0648 1247Biopharmaceutics Unit, Department of Pharmacology and Toxicology, Kampala International University Western Campus, Ishaka-Bushenyi, Uganda ,grid.10824.3f0000 0001 2183 9444 Department of Clinical Pharmacy and Pharmacy Administration, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Joseph Obiezu Chukwujekwu Ezeonwumelu
- grid.440478.b0000 0004 0648 1247Biomolecules, Metagenomics, Endocrine, and Tropical Disease Research Group (BMETDREG), Kampala International University Western Campus, Ishaka-Bushenyi, Uganda ,grid.440478.b0000 0004 0648 1247Department of Clinical Pharmacy, Kampala International University Western Campus, Ishaka-Bushenyi, Uganda
| | - Peter Chinedu Agu
- grid.412141.30000 0001 2033 5930Department of Biochemistry, Faculty of Biological Sciences, Ebonyi State University, Abakaliki, Nigeria
| | - Josiah Eseoghene Ifie
- grid.440478.b0000 0004 0648 1247Department of Medical Biochemistry, Faculty of Biomedical Sciences, Kampala International University, Kampala, Uganda
| | - Tusubira Deusdedit
- grid.33440.300000 0001 0232 6272Department of Biochemistry, Faculty of Medicine, Mbarara University of Sciences and Technology, Mbarara, Uganda
| | - Patrick Maduabuchi Aja
- grid.412141.30000 0001 2033 5930Department of Biochemistry, Faculty of Biological Sciences, Ebonyi State University, Abakaliki, Nigeria ,grid.440478.b0000 0004 0648 1247Department of Medical Biochemistry, Faculty of Biomedical Sciences, Kampala International University, Kampala, Uganda ,grid.33440.300000 0001 0232 6272Department of Biochemistry, Faculty of Medicine, Mbarara University of Sciences and Technology, Mbarara, Uganda
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Vrettou S, Wirth B. S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases. Int J Mol Sci 2022; 23:15849. [PMID: 36555492 PMCID: PMC9779533 DOI: 10.3390/ijms232415849] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/24/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022] Open
Abstract
Redox post-translational modifications are derived from fluctuations in the redox potential and modulate protein function, localization, activity and structure. Amongst the oxidative reversible modifications, the S-glutathionylation of proteins was the first to be characterized as a post-translational modification, which primarily protects proteins from irreversible oxidation. However, a growing body of evidence suggests that S-glutathionylation plays a key role in core cell processes, particularly in mitochondria, which are the main source of reactive oxygen species. S-nitrosylation, another post-translational modification, was identified >150 years ago, but it was re-introduced as a prototype cell-signaling mechanism only recently, one that tightly regulates core processes within the cell’s sub-compartments, especially in mitochondria. S-glutathionylation and S-nitrosylation are modulated by fluctuations in reactive oxygen and nitrogen species and, in turn, orchestrate mitochondrial bioenergetics machinery, morphology, nutrients metabolism and apoptosis. In many neurodegenerative disorders, mitochondria dysfunction and oxidative/nitrosative stresses trigger or exacerbate their pathologies. Despite the substantial amount of research for most of these disorders, there are no successful treatments, while antioxidant supplementation failed in the majority of clinical trials. Herein, we discuss how S-glutathionylation and S-nitrosylation interfere in mitochondrial homeostasis and how the deregulation of these modifications is associated with Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and Friedreich’s ataxia.
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Affiliation(s)
- Sofia Vrettou
- Institute of Human Genetics, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
| | - Brunhilde Wirth
- Institute of Human Genetics, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
- Institute for Genetics, University of Cologne, 50674 Cologne, Germany
- Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
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Ewere EG, Okolie NP, Ndem JI, Eze GI, Oyebadejo SA. Irvingia gabonensis leaf extract scavenges nitric oxide and hydrogen peroxide in vitro and modulates arsenic-induced hepatic oxidative stress in wistar rats. CLINICAL PHYTOSCIENCE 2022. [DOI: 10.1186/s40816-022-00346-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Arsenic is a carcinogenic heavy metal that contaminates the environment, predisposing the exposed populace to its detrimental health effects. This study investigated the liver protective effect of ethanol leaf extract of Irvingia gabonensis (ELEIG) in sodium arsenite (SA)-exposed Wistar rats and its nitric oxide (NO.) and hydrogen peroxide (H2O2)-scavenging properties in vitro.
Methods
Eleven experimental groups made up of five (5) rats each (weight range 100 - 161 g) were used in this study. Group 1 (normal control) had normal rat chow and water. Group 2 received 4.1 mg/kg body weight (kgbw) of SA. Groups 3–8 received SA and graded doses of ELEIG and groups 9-11 had varied doses of ELEIG. Treatment, which spanned 14 days, was by oral gavage. Concentrations of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) as well as activities of liver enzymes (AST, ALT, ALP, and GGT) and concentrations of total bilirubin (TBIL) and direct bilirubin (DBIL) were determined using standard procedures. Standard methods were also used to determine the in vitro NO. and H2O2-scavenging properties of the extract.
Results
Exposure to SA orchestrated significant (p ˂ 0.05) increases in CAT, MDA, AST, ALT, ALP and GGT and significant (p ˂ 0.05) decreases in SOD and GPx, relative to control. There were insignificant (p ˃ 0.05) differences in TBIL and DBIL concentrations, compared with control. Simultaneous and post-treatment with ELEIG at graded doses, alleviated the noxious effects of SA. In addition, ELEIG scavenged NO. and H2O2 in concentration-dependent manner.
Conclusion
The results suggest that ELEIG possesses potent antioxidant property and combats SA-induced hepatic oxidative stress/toxicity in Wistar rats.
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22
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Morris G, Gevezova M, Sarafian V, Maes M. Redox regulation of the immune response. Cell Mol Immunol 2022; 19:1079-1101. [PMID: 36056148 PMCID: PMC9508259 DOI: 10.1038/s41423-022-00902-0] [Citation(s) in RCA: 204] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/29/2022] [Indexed: 12/20/2022] Open
Abstract
AbstractThe immune-inflammatory response is associated with increased nitro-oxidative stress. The aim of this mechanistic review is to examine: (a) the role of redox-sensitive transcription factors and enzymes, ROS/RNS production, and the activity of cellular antioxidants in the activation and performance of macrophages, dendritic cells, neutrophils, T-cells, B-cells, and natural killer cells; (b) the involvement of high-density lipoprotein (HDL), apolipoprotein A1 (ApoA1), paraoxonase-1 (PON1), and oxidized phospholipids in regulating the immune response; and (c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor-κB, HIF1α, the mechanistic target of rapamycin, the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, mitogen-activated protein kinases, 5' AMP-activated protein kinase, and peroxisome proliferator-activated receptor. The performance and survival of individual immune cells is under redox control and depends on intracellular and extracellular levels of ROS/RNS. They are heavily influenced by cellular antioxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2, and the HDL/ApoA1/PON1 complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.
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Sipping MTK, Mediesse FK, Sombes AYN, Mfopa A, Boudjeko T. Antioxidant and anti-inflammatory activities of Ganoderma resinaceum (Boud) fruiting bodies extracts. JOURNAL OF HERBMED PHARMACOLOGY 2022. [DOI: 10.34172/jhp.2022.40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Introduction: Ganoderma resinaceum is used to treat oxidative and inflammatory-related diseases such as cardiovascular and liver diseases. Thus, this study aimed to evaluate the antioxidant and anti-inflammatory activities of different extracts from G. resinaceum fruiting bodies. Methods: Aqueous crude (GRT), mycelial (MYC), exopolysaccharide (EPS I, EPS II) and water-soluble polysaccharide-rich (GRP I and GRP II) extracts of G. resinaceum were assessed for their free radical scavenging and metal chelating ions assays. The in vitro anti-inflammatory activity was evaluated by stabilization of erythrocytes’ membranes and protein denaturation assays. For the in vivo study, paw oedema was induced by administration of κ-carrageenan (0.1 mL; 1%) to male Wistar rats aged 4 to 6 weeks. Animals were pre-treated with G. resinaceum extracts (125 mg/kg) and diclofenac sodium (20 mg/kg). Inflammatory cytokine and chemokine levels were determined, and histological analysis of paw tissue was performed. Results: G. resinaceum polysaccharide-rich extracts (GRP I and GRP II) showed the best bioactivities. They scavenged DPPH (1,1-diphenyl-2-picrylhydrazyl, ABTS (2,2-azino-bis-3- ethylbenzylthiazoline-6-sulfonic acid, and NO (nitric oxide) radicals, and chelated ferrous ions, stabilized murine erythrocyte membranes, and inhibited protein denaturation. At 125 mg/kg, GRP I and GRP II restored the microarchitecture with a weak infiltration of immune cells in the subcutaneous tissues. Moreover, they decreased the overproduction of proinflammatory cytokines growth colony-stimulating factor (G-CSF), interferon gamma (IFNγ), tumour necrosis factor alpha (TNFα), chemokines (eotaxin, fractalkine) and increased the levels of anti-inflammatory cytokines (IL-10, IL-12p70). Conclusion: G. resinaceum polysaccharide extracts could be potent antioxidant and antiinflammatory agents.
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Affiliation(s)
- Marius Trésor Kemegne Sipping
- Laboratory of Phytoprotection and Valorization of Genetic Resources, Biotechnology Centre-Nkolbisson, University of Yaoundé 1, P.O. Box 17673, Etetak, Yaoundé, Cameroon
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, Yaoundé 812, Cameroon
| | - Francine Kengne Mediesse
- Laboratory of Phytoprotection and Valorization of Genetic Resources, Biotechnology Centre-Nkolbisson, University of Yaoundé 1, P.O. Box 17673, Etetak, Yaoundé, Cameroon
- Institute of Medical Research and Medicinal Plants Studies, P.O. Box. 13033, Yaoundé, Cameroon
| | - Annette Yannuvie Natia Sombes
- Laboratory of Phytoprotection and Valorization of Genetic Resources, Biotechnology Centre-Nkolbisson, University of Yaoundé 1, P.O. Box 17673, Etetak, Yaoundé, Cameroon
| | - Adamou Mfopa
- Laboratory of Phytoprotection and Valorization of Genetic Resources, Biotechnology Centre-Nkolbisson, University of Yaoundé 1, P.O. Box 17673, Etetak, Yaoundé, Cameroon
- Institute of Medical Research and Medicinal Plants Studies, P.O. Box. 13033, Yaoundé, Cameroon
| | - Thaddée Boudjeko
- Laboratory of Phytoprotection and Valorization of Genetic Resources, Biotechnology Centre-Nkolbisson, University of Yaoundé 1, P.O. Box 17673, Etetak, Yaoundé, Cameroon
- Department of Biochemistry, Faculty of Sciences, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon
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24
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Sazonova EN, Gusev IA, Malofey YB, Lanshakova AV, Vdovenko SV. Effects of Neonatal Administration of Non-Opiate Analogues of Leu-Enkephalin to Heart Tissue Homeostasis of Prepubertal Albino Rats Exposed to Hypoxia. Bull Exp Biol Med 2022; 173:188-192. [PMID: 35737163 DOI: 10.1007/s10517-022-05516-0] [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: 11/12/2021] [Indexed: 10/17/2022]
Abstract
Hypobaric hypoxia (pO2 65 mm Hg, duration 4 h) induced a significant increase in the number of cardiomyocytes expressing р53, beclin-1, endothelial NO synthase and accumulation and degranulation of mast cells in the epicardium in hearts of prepubertal female rats (age 45-47 days); the number of cardiomyocytes with nucleoli decreased, while the number of single-nucleolar cardiomyocytes increased after this exposure. Five-fold administration of non-opiate analogue of leu-enkephalin (NALE peptide: Phe-D-Ala-Gly-Phe-Leu-Arg; 100 μg/kg) during the neonatal period reduced the severity of the post-hypoxic changes in the heart. Neonatal administration of NALE (100 μg/kg) against the background of NO synthase blockade with L-NAME (50 mg/kg) did not abolish the cardioprotective effects of the peptide. A similar correction of posthypoxic changes in the heart was observed after neonatal administration of original peptide G (Phe-D-Ala-Gly-Phe-Leu-Gly; 100 μg/kg). Thus, NO synthase-NO system and C-terminal amino acid Arg in the molecule of non-opiate analogue of leu-enkephalin are not required for the cardioprotective effects of peptides. Non-opiate leu-enkephalin analogs, peptides NALE and G, can be considered as promising substances for increasing heart resistance to hypoxia during later age periods.
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Affiliation(s)
- E N Sazonova
- Far Eastern State Medical University, Ministry of Health of the Russian Federation, Khabarovsk, Russia.
- Khabarovsk Branch of the Far Eastern Research Center for Physiology and Pathology of Respiration - Research Institute for the Protection of Motherhood and Childhood, Khabarovsk, Russia.
| | - I A Gusev
- Far Eastern State Medical University, Ministry of Health of the Russian Federation, Khabarovsk, Russia
| | - Yu B Malofey
- Far Eastern State Medical University, Ministry of Health of the Russian Federation, Khabarovsk, Russia
| | - A V Lanshakova
- Far Eastern State Medical University, Ministry of Health of the Russian Federation, Khabarovsk, Russia
| | - S V Vdovenko
- Far Eastern State Medical University, Ministry of Health of the Russian Federation, Khabarovsk, Russia
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25
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Grismaldo Rodríguez A, Zamudio Rodríguez JA, Mendieta CV, Quijano Gómez S, Sanabria Barrera S, Morales Álvarez L. Effect of Platelet-Derived Growth Factor C on Mitochondrial Oxidative Stress Induced by High d-Glucose in Human Aortic Endothelial Cells. Pharmaceuticals (Basel) 2022; 15:ph15050639. [PMID: 35631465 PMCID: PMC9143891 DOI: 10.3390/ph15050639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/05/2022] [Accepted: 05/06/2022] [Indexed: 12/10/2022] Open
Abstract
Endothelial dysfunction is an early marker for cardiovascular diseases. Hyperglycemia induces endothelial dysfunction, increasing the production of reactive oxygen species. Platelet-derived growth factor C stimulates angiogenesis and revascularization in ischemic tissues of diabetic mice and promotes the migration of progenitors and mature ECs to injury sites; however, the molecular mechanisms of its actions are not described yet. Here, we evaluated the effect of PDGF-C on oxidative stress induced by HG. Human aortic endothelial cells were grown in glucose concentrations ranging from 5 mmol/L to 35 mmol/L for 1 to 24 h. Treatment with 50 ng/mL PDGF-C was done for 1 to 3 h. Cytosolic and mitochondrial ROS were measured by fluorometry, and the expression of antioxidant enzymes was evaluated by Western blot. Nrf2 and Keap1 expression was assessed by real-time PCR. High glucose induced mitochondrial ROS production. PDGF-C diminished the oxidative stress induced by high glucose, increasing SOD2 expression and SOD activity, and modulating the Keap1 expression gene. These results give new evidence about the mitochondrial antioxidant effect that PDGF-C could exert on endothelial cells exposed to high glucose and its considerable role as a therapeutic target in diabetes.
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Affiliation(s)
- Adriana Grismaldo Rodríguez
- Experimental and Computational Biochemistry Group, Faculty of Sciences, Nutrition and Biochemistry Department, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; (J.A.Z.R.); (C.V.M.)
- Correspondence: (A.G.R.); (L.M.Á.); Tel.: +57-3114566976 (A.G.R.); +57-3132107272 (L.M.Á.)
| | - Jairo A. Zamudio Rodríguez
- Experimental and Computational Biochemistry Group, Faculty of Sciences, Nutrition and Biochemistry Department, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; (J.A.Z.R.); (C.V.M.)
| | - Cindy V. Mendieta
- Experimental and Computational Biochemistry Group, Faculty of Sciences, Nutrition and Biochemistry Department, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; (J.A.Z.R.); (C.V.M.)
- Department of Clinical Epidemiology and Biostatistics, Pontificia Universidad Javeriana, Bogotá 110231, Colombia
| | - Sandra Quijano Gómez
- Immunology and Cell Biology Group, Faculty of Sciences, Microbiology Department, Pontificia Universidad Javeriana, Bogotá 110231, Colombia;
| | - Sandra Sanabria Barrera
- Traslational Biomedical Research Group, Fundación Cardiovascular de Colombia, Floridablanca 680004, Colombia;
| | - Ludis Morales Álvarez
- Experimental and Computational Biochemistry Group, Faculty of Sciences, Nutrition and Biochemistry Department, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; (J.A.Z.R.); (C.V.M.)
- Correspondence: (A.G.R.); (L.M.Á.); Tel.: +57-3114566976 (A.G.R.); +57-3132107272 (L.M.Á.)
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26
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Giordano D, Verde C, Corti P. Nitric Oxide Production and Regulation in the Teleost Cardiovascular System. Antioxidants (Basel) 2022; 11:957. [PMID: 35624821 PMCID: PMC9137985 DOI: 10.3390/antiox11050957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 01/08/2023] Open
Abstract
Nitric Oxide (NO) is a free radical with numerous critical signaling roles in vertebrate physiology. Similar to mammals, in the teleost system the generation of sufficient amounts of NO is critical for the physiological function of the cardiovascular system. At the same time, NO amounts are strictly controlled and kept within basal levels to protect cells from NO toxicity. Changes in oxygen tension highly influence NO bioavailability and can modulate the mechanisms involved in maintaining the NO balance. While NO production and signaling appears to have general similarities with mammalian systems, the wide range of environmental adaptations made by fish, particularly with regards to differing oxygen availabilities in aquatic habitats, creates a foundation for a variety of in vivo models characterized by different implications of NO production and signaling. In this review, we present the biology of NO in the teleost cardiovascular system and summarize the mechanisms of NO production and signaling with a special emphasis on the role of globin proteins in NO metabolism.
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Affiliation(s)
- Daniela Giordano
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Via Pietro Castellino 111, 80131 Napoli, Italy; (D.G.); (C.V.)
- Department of Marine Biotechnology, Stazione Zoologica Anton Dohrn (SZN), Villa Comunale, 80121 Napoli, Italy
| | - Cinzia Verde
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Via Pietro Castellino 111, 80131 Napoli, Italy; (D.G.); (C.V.)
- Department of Marine Biotechnology, Stazione Zoologica Anton Dohrn (SZN), Villa Comunale, 80121 Napoli, Italy
| | - Paola Corti
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
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27
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Zhu Z, Chambers S, Zeng Y, Bhatia M. Gases in Sepsis: Novel Mediators and Therapeutic Targets. Int J Mol Sci 2022; 23:3669. [PMID: 35409029 PMCID: PMC8998565 DOI: 10.3390/ijms23073669] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Sepsis, a potentially lethal condition resulting from failure to control the initial infection, is associated with a dysregulated host defense response to pathogens and their toxins. Sepsis remains a leading cause of morbidity, mortality and disability worldwide. The pathophysiology of sepsis is very complicated and is not yet fully understood. Worse still, the development of effective therapeutic agents is still an unmet need and a great challenge. Gases, including nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), are small-molecule biological mediators that are endogenously produced, mainly by enzyme-catalyzed reactions. Accumulating evidence suggests that these gaseous mediators are widely involved in the pathophysiology of sepsis. Many sepsis-associated alterations, such as the elimination of invasive pathogens, the resolution of disorganized inflammation and the preservation of the function of multiple organs and systems, are shaped by them. Increasing attention has been paid to developing therapeutic approaches targeting these molecules for sepsis/septic shock, taking advantage of the multiple actions played by NO, CO and H2S. Several preliminary studies have identified promising therapeutic strategies for gaseous-mediator-based treatments for sepsis. In this review article, we summarize the state-of-the-art knowledge on the pathophysiology of sepsis; the metabolism and physiological function of NO, CO and H2S; the crosstalk among these gaseous mediators; and their crucial effects on the development and progression of sepsis. In addition, we also briefly discuss the prospect of developing therapeutic interventions targeting these gaseous mediators for sepsis.
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Affiliation(s)
- Zhixing Zhu
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (Z.Z.); (S.C.)
- Department of Internal Medicine (Pulmonary and Critical Care Medicine), The Second Clinical Medical School of Fujian Medical University, Quanzhou 362002, China;
| | - Stephen Chambers
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (Z.Z.); (S.C.)
| | - Yiming Zeng
- Department of Internal Medicine (Pulmonary and Critical Care Medicine), The Second Clinical Medical School of Fujian Medical University, Quanzhou 362002, China;
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (Z.Z.); (S.C.)
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28
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Boumezber S, Yelekçi K. Screening of novel and selective inhibitors for neuronal nitric oxide synthase (nNOS) via structure-based drug design techniques. J Biomol Struct Dyn 2022; 41:3607-3629. [PMID: 35322764 DOI: 10.1080/07391102.2022.2054471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
NO, or nitric oxide, is produced by a family of enzymes called nitric oxide synthase (NOS) from L-arginine. NO regulates many physiological functions such as smooth muscle relaxation, immune defense, and memory function. The overproduction of NO by the neuronal isoform of nitric oxide synthase (nNOS) is implicated in neurodegeneration and neuropathic pain, making nNOS inhibition a promising therapeutic approach. Many developed nNOS inhibitors, generally L-arginine mimetics, have some issues in selectivity and bioavailability. According to earlier studies, targeting nNOS has the advantage of decreasing excess NO in the brain while avoiding the negative consequences of inhibiting the two isozymes: endothelial NOS (eNOS) and inducible NOS (iNOS). This study applied structure-based virtual screening, molecular docking, and molecular dynamics simulations to design potent and selective inhibitors against nNOS over related isoforms (eNOS and iNOS) using human X-ray crystal structures of the NOS isoforms. It was discovered that some compounds displayed a very good inhibitory potency for hnNOS and moderate selectivity for the other isozymes, eNOS and iNOS, in addition to good solubility and desirable physiochemical properties. The compounds which showed good stability and selectivity with nNOS, such as ZINC000013485422, can be interesting and informative guidance for designing more potent human nNOS inhibitors.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Sarah Boumezber
- Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, Istanbul, Turkey
| | - Kemal Yelekçi
- Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, Istanbul, Turkey
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29
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Chen MM, Li Y, Deng SL, Zhao Y, Lian ZX, Yu K. Mitochondrial Function and Reactive Oxygen/Nitrogen Species in Skeletal Muscle. Front Cell Dev Biol 2022; 10:826981. [PMID: 35265618 PMCID: PMC8898899 DOI: 10.3389/fcell.2022.826981] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/26/2022] [Indexed: 12/06/2022] Open
Abstract
Skeletal muscle fibers contain a large number of mitochondria, which produce ATP through oxidative phosphorylation (OXPHOS) and provide energy for muscle contraction. In this process, mitochondria also produce several types of "reactive species" as side product, such as reactive oxygen species and reactive nitrogen species which have attracted interest. Mitochondria have been proven to have an essential role in the production of skeletal muscle reactive oxygen/nitrogen species (RONS). Traditionally, the elevation in RONS production is related to oxidative stress, leading to impaired skeletal muscle contractility and muscle atrophy. However, recent studies have shown that the optimal RONS level under the action of antioxidants is a critical physiological signal in skeletal muscle. Here, we will review the origin and physiological functions of RONS, mitochondrial structure and function, mitochondrial dynamics, and the coupling between RONS and mitochondrial oxidative stress. The crosstalk mechanism between mitochondrial function and RONS in skeletal muscle and its regulation of muscle stem cell fate and myogenesis will also be discussed. In all, this review aims to describe a comprehensive and systematic network for the interaction between skeletal muscle mitochondrial function and RONS.
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Affiliation(s)
- Ming-Ming Chen
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yan Li
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shou-Long Deng
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Yue Zhao
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Zheng-Xing Lian
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Kun Yu
- College of Animal Science and Technology, China Agricultural University, Beijing, China
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30
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Lavin KM, Coen PM, Baptista LC, Bell MB, Drummer D, Harper SA, Lixandrão ME, McAdam JS, O’Bryan SM, Ramos S, Roberts LM, Vega RB, Goodpaster BH, Bamman MM, Buford TW. State of Knowledge on Molecular Adaptations to Exercise in Humans: Historical Perspectives and Future Directions. Compr Physiol 2022; 12:3193-3279. [PMID: 35578962 PMCID: PMC9186317 DOI: 10.1002/cphy.c200033] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well-positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise-induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193-3279, 2022.
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Affiliation(s)
- Kaleen M. Lavin
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Center for Human Health, Resilience, and Performance, Institute for Human and Machine Cognition, Pensacola, Florida, USA
| | - Paul M. Coen
- Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Liliana C. Baptista
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Margaret B. Bell
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Devin Drummer
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sara A. Harper
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Manoel E. Lixandrão
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jeremy S. McAdam
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Samia M. O’Bryan
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sofhia Ramos
- Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Lisa M. Roberts
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rick B. Vega
- Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Bret H. Goodpaster
- Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Marcas M. Bamman
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Center for Human Health, Resilience, and Performance, Institute for Human and Machine Cognition, Pensacola, Florida, USA
| | - Thomas W. Buford
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
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Naryzhnaya NV, Maslov LN, Derkachev IA, Ma H, Zhang Y, Prasad NR, Singh N, Fu F, Pei JM, Sarybaev A, Sydykov A. The effect of adaptation to hypoxia on cardiac tolerance to ischemia/reperfusion. J Biomed Res 2022:1-25. [PMID: 37183617 PMCID: PMC10387748 DOI: 10.7555/jbr.36.20220125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
The acute myocardial infarction (AMI) and sudden cardiac death (SCD), both associated with acute cardiac ischemia, are one of the leading causes of adult death in economically developed countries. The development of new approaches for the treatment and prevention of AMI and SCD remains the highest priority for medicine. A study on the cardiovascular effects of chronic hypoxia (CH) may contribute to the development of these methods. Chronic hypoxia exerts both positive and adverse effects. The positive effects are the infarct-reducing, vasoprotective, and antiarrhythmic effects, which can lead to the improvement of cardiac contractility in reperfusion. The adverse effects are pulmonary hypertension and right ventricular hypertrophy. This review presents a comprehensive overview of how CH enhances cardiac tolerance to ischemia/reperfusion. It is an in-depth analysis of the published data on the underlying mechanisms, which can lead to future development of the cardioprotective effect of CH. A better understanding of the CH-activated protective signaling pathways may contribute to new therapeutic approaches in an increase of cardiac tolerance to ischemia/reperfusion.
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32
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Huang H, Qiu R, Yang H, Ren F, Wu F, Zhang Y, Zhang H, Li C. Advanced NIR ratiometric probes for intravital biomedical imaging. Biomed Mater 2021; 17. [PMID: 34879355 DOI: 10.1088/1748-605x/ac4147] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 12/08/2021] [Indexed: 02/08/2023]
Abstract
Near-infrared (NIR) fluorescence imaging technology (NIR-I region, 650-950 nm and NIR-II region, 1000-1700 nm), with deeper tissue penetration and less disturbance from auto-fluorescence than that in visible region (400-650 nm), is playing a more and more extensive role in the field of biomedical imaging. With the development of precise medicine, intelligent NIR fluorescent probes have been meticulously designed to provide more sensitive, specific and accurate feedback on detection. Especially, recently developed ratiometric fluorescent probes have been devoted to quantify physiological and pathological parameters with a combination of responsive fluorescence changes and self-calibration. Herein, we systemically introduced the construction strategies of NIR ratiometric fluorescent probes and their applications in biological imagingin vivo, such as molecular detection, pH and temperature measurement, drug delivery monitoring and treatment evaluation. We further summarized possible optimization on the design of ratiometric probes for quantitative analysis with NIR fluorescence, and prospected the broader optical applications of ratiometric probes in life science and clinical translation.
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Affiliation(s)
- Haoying Huang
- Department of Nuclear Medicine and PET Center, The Second Hospital of Zhejiang University, School of Medicine, Hangzhou, People's Republic of China.,CAS Key Laboratory of Nano-Bio Interface, Suzhou Key Laboratory of Functional Molecular, Imaging Technology Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, People's Republic of China
| | - Ruijuan Qiu
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Key Laboratory of Functional Molecular, Imaging Technology Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, People's Republic of China
| | - Hongchao Yang
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Key Laboratory of Functional Molecular, Imaging Technology Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, People's Republic of China
| | - Feng Ren
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Key Laboratory of Functional Molecular, Imaging Technology Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, People's Republic of China
| | - Feng Wu
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Key Laboratory of Functional Molecular, Imaging Technology Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, People's Republic of China
| | - Yejun Zhang
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Key Laboratory of Functional Molecular, Imaging Technology Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, People's Republic of China
| | - Hong Zhang
- Department of Nuclear Medicine and PET Center, The Second Hospital of Zhejiang University, School of Medicine, Hangzhou, People's Republic of China
| | - Chunyan Li
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Key Laboratory of Functional Molecular, Imaging Technology Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, People's Republic of China
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Singh S, Singh T, Kunja C, Dhoat NS, Dhania NK. Gene-editing, immunological and iPSCs based therapeutics for muscular dystrophy. Eur J Pharmacol 2021; 912:174568. [PMID: 34656607 DOI: 10.1016/j.ejphar.2021.174568] [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: 06/24/2021] [Revised: 09/25/2021] [Accepted: 10/11/2021] [Indexed: 10/20/2022]
Abstract
Muscular dystrophy is a well-known genetically heterogeneous group of rare muscle disorders. This progressive disease causes the breakdown of skeletal muscles over time and leads to grave weakness. This breakdown is caused by a diverse pattern of mutations in dystrophin and dystrophin associated protein complex. These mutations lead to the production of altered proteins in response to which, the body stimulates production of various cytokines and immune cells, particularly reactive oxygen species and NFκB. Immune cells display/exhibit a dual role by inducing muscle damage and muscle repair. Various anti-oxidants, anti-inflammatory and glucocorticoid drugs serve as potent therapeutics for muscular dystrophy. Along with the above mentioned therapeutics, induced pluripotent stem cells also serve as a novel approach paving a way for personalized treatment. These pluripotent stem cells allow regeneration of large numbers of regenerative myogenic progenitors that can be administered in muscular dystrophy patients which assist in the recovery of lost muscle fibers. In this review, we have summarized gene-editing, immunological and induced pluripotent stem cell based therapeutics for muscular dystrophy treatment.
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Affiliation(s)
- Shagun Singh
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda-151001, Punjab, India
| | - Tejpal Singh
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda-151001, Punjab, India
| | - Chaitanya Kunja
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda-151001, Punjab, India
| | - Navdeep S Dhoat
- Department of Pediatrics Surgery, All India Institute of Medical Sciences, Bathinda, 151001, Punjab, India
| | - Narender K Dhania
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda-151001, Punjab, India.
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Geldon S, Fernández-Vizarra E, Tokatlidis K. Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells. Front Cell Dev Biol 2021; 9:720656. [PMID: 34557489 PMCID: PMC8452992 DOI: 10.3389/fcell.2021.720656] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/04/2021] [Indexed: 12/24/2022] Open
Abstract
Mitochondria are double-membrane organelles that contain their own genome, the mitochondrial DNA (mtDNA), and reminiscent of its endosymbiotic origin. Mitochondria are responsible for cellular respiration via the function of the electron oxidative phosphorylation system (OXPHOS), located in the mitochondrial inner membrane and composed of the four electron transport chain (ETC) enzymes (complexes I-IV), and the ATP synthase (complex V). Even though the mtDNA encodes essential OXPHOS components, the large majority of the structural subunits and additional biogenetical factors (more than seventy proteins) are encoded in the nucleus and translated in the cytoplasm. To incorporate these proteins and the rest of the mitochondrial proteome, mitochondria have evolved varied, and sophisticated import machineries that specifically target proteins to the different compartments defined by the two membranes. The intermembrane space (IMS) contains a high number of cysteine-rich proteins, which are mostly imported via the MIA40 oxidative folding system, dependent on the reduction, and oxidation of key Cys residues. Several of these proteins are structural components or assembly factors necessary for the correct maturation and function of the ETC complexes. Interestingly, many of these proteins are involved in the metalation of the active redox centers of complex IV, the terminal oxidase of the mitochondrial ETC. Due to their function in oxygen reduction, mitochondria are the main generators of reactive oxygen species (ROS), on both sides of the inner membrane, i.e., in the matrix and the IMS. ROS generation is important due to their role as signaling molecules, but an excessive production is detrimental due to unwanted oxidation reactions that impact on the function of different types of biomolecules contained in mitochondria. Therefore, the maintenance of the redox balance in the IMS is essential for mitochondrial function. In this review, we will discuss the role that redox regulation plays in the maintenance of IMS homeostasis as well as how mitochondrial ROS generation may be a key regulatory factor for ETC biogenesis, especially for complex IV.
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Affiliation(s)
| | - Erika Fernández-Vizarra
- Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Kostas Tokatlidis
- Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration. Biomolecules 2021; 11:biom11071012. [PMID: 34356637 PMCID: PMC8301949 DOI: 10.3390/biom11071012] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/18/2022] Open
Abstract
Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca2+ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca2+ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca2+ overload results in an increase in mitochondrial Ca2+, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases.
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Ushio-Fukai M, Ash D, Nagarkoti S, Belin de Chantemèle EJ, Fulton DJR, Fukai T. Interplay Between Reactive Oxygen/Reactive Nitrogen Species and Metabolism in Vascular Biology and Disease. Antioxid Redox Signal 2021; 34:1319-1354. [PMID: 33899493 PMCID: PMC8418449 DOI: 10.1089/ars.2020.8161] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Reactive oxygen species (ROS; e.g., superoxide [O2•-] and hydrogen peroxide [H2O2]) and reactive nitrogen species (RNS; e.g., nitric oxide [NO•]) at the physiological level function as signaling molecules that mediate many biological responses, including cell proliferation, migration, differentiation, and gene expression. By contrast, excess ROS/RNS, a consequence of dysregulated redox homeostasis, is a hallmark of cardiovascular disease. Accumulating evidence suggests that both ROS and RNS regulate various metabolic pathways and enzymes. Recent studies indicate that cells have mechanisms that fine-tune ROS/RNS levels by tight regulation of metabolic pathways, such as glycolysis and oxidative phosphorylation. The ROS/RNS-mediated inhibition of glycolytic pathways promotes metabolic reprogramming away from glycolytic flux toward the oxidative pentose phosphate pathway to generate nicotinamide adenine dinucleotide phosphate (NADPH) for antioxidant defense. This review summarizes our current knowledge of the mechanisms by which ROS/RNS regulate metabolic enzymes and cellular metabolism and how cellular metabolism influences redox homeostasis and the pathogenesis of disease. A full understanding of these mechanisms will be important for the development of new therapeutic strategies to treat diseases associated with dysregulated redox homeostasis and metabolism. Antioxid. Redox Signal. 34, 1319-1354.
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Affiliation(s)
- Masuko Ushio-Fukai
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Medicine (Cardiology) and Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Dipankar Ash
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Medicine (Cardiology) and Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Sheela Nagarkoti
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Medicine (Cardiology) and Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Eric J Belin de Chantemèle
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Medicine (Cardiology) and Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - David J R Fulton
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Tohru Fukai
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
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Sharma V, Fernando V, Letson J, Walia Y, Zheng X, Fackelman D, Furuta S. S-Nitrosylation in Tumor Microenvironment. Int J Mol Sci 2021; 22:ijms22094600. [PMID: 33925645 PMCID: PMC8124305 DOI: 10.3390/ijms22094600] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/19/2021] [Accepted: 04/22/2021] [Indexed: 02/07/2023] Open
Abstract
S-nitrosylation is a selective and reversible post-translational modification of protein thiols by nitric oxide (NO), which is a bioactive signaling molecule, to exert a variety of effects. These effects include the modulation of protein conformation, activity, stability, and protein-protein interactions. S-nitrosylation plays a central role in propagating NO signals within a cell, tissue, and tissue microenvironment, as the nitrosyl moiety can rapidly be transferred from one protein to another upon contact. This modification has also been reported to confer either tumor-suppressing or tumor-promoting effects and is portrayed as a process involved in every stage of cancer progression. In particular, S-nitrosylation has recently been found as an essential regulator of the tumor microenvironment (TME), the environment around a tumor governing the disease pathogenesis. This review aims to outline the effects of S-nitrosylation on different resident cells in the TME and the diverse outcomes in a context-dependent manner. Furthermore, we will discuss the therapeutic potentials of modulating S-nitrosylation levels in tumors.
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New insights on nitric oxide: Focus on animal models of schizophrenia. Behav Brain Res 2021; 409:113304. [PMID: 33865887 DOI: 10.1016/j.bbr.2021.113304] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/30/2021] [Accepted: 04/12/2021] [Indexed: 12/11/2022]
Abstract
Schizophrenia is a devastating complex disorder characterised by a constellation of behavioral deficits with the underlying mechanisms not fully known. Nitric oxide (NO) has emerged as a key signaling molecule implicated in schizophrenia. Three nitric oxide sinthases (NOS), endothelial, neuronal, and inducible, release NO within the cell. Animal models of schizophrenia are grouped in four groups, neurovedelopmental, glutamatergic, dopaminergic and genetic. In this review, we aim to evaluate changes in NO levels in animal models of schizophrenia and the resulting long-lasting behavioral and neural consequences. In particular, NO levels are substantially modified, region-specific, in various neurodevelopmental models, e.g. bilateral excitotoxic lesion of the ventral hippocampus (nVHL), maternal immune activation and direct NO manipulations early in development, among others. In regards to glutamatergic models of schizophrenia, phencyclidine (PCP) administration increases NO levels in the prefrontal cortex (PFC) and ventral hippocampus. As far as genetic models are concerned, neuronal NOS knock-out mice display schizophrenia-related behaviors. Administration of NO donors can reverse schizophrenia-related behavioral deficits. While most modifications in NO are derived from neuronal NOS, recent evidence indicates that PCP treatment increases NO from the inducible NOS isoform. From a pharmacological perspective, treatment with various antipsychotics including clozapine, haloperidol and risperidone normalize NO levels in the PFC as well as improve behavioral deficits in nVHL rats. NO induced from the neuronal and inducible NOS is relevant to schizophrenia and warrants further research.
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Andries A, Rozenski J, Vermeersch P, Mekahli D, Van Schepdael A. Recent progress in the LC-MS/MS analysis of oxidative stress biomarkers. Electrophoresis 2020; 42:402-428. [PMID: 33280143 DOI: 10.1002/elps.202000208] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/17/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022]
Abstract
The presence of a dynamic and balanced equilibrium between the production of reactive oxygen (ROS) and nitrogen (RNS) species and the in-house antioxidant defense mechanisms is characteristic for a healthy body. During oxidative stress (OS), this balance is switched to increased production of ROS and RNS, exceeding the capacity of physiological antioxidant systems. This can cause damage to biological molecules, leading to loss of function and even cell death. Nowadays, there is increasing scientific and clinical interest in OS and the associated parameters to measure the degree of OS in biofluids. An increasing number of reports using LC-MS/MS methods for the analysis of OS biomarkers can be found. Since bioanalysis is usually complicated by matrix effects, various types of cleanup procedures are used to effectively separate the biomarkers from the matrix. This is an essential part of the analysis to prepare a reproducible and homogenous solution suitable for injection onto the column. The present review gives a summary of the chromatographic methods used for the determination of OS biomarkers in both urine and plasma, serum, and whole blood samples. The first part mainly describes the biological background of the different OS biomarkers, while the second part reports examples of chromatographic methods for the analysis of different metabolites connected with OS in biofluids, covering a period from 2015 till early 2020. The selected examples mainly include LC-MS/MS methods for isoprostanes, oxidized proteins, oxidized lipoproteins, and DNA/RNA biomarkers. The last part explains the clinical relevance of this review.
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Affiliation(s)
- Asmin Andries
- Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, KU Leuven - University of Leuven, Leuven, Belgium
| | - Jef Rozenski
- KU Leuven - Rega Institute for Medical Research, Medicinal Chemistry, Leuven, Belgium
| | - Pieter Vermeersch
- Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.,Center for Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Djalila Mekahli
- Department of Development and Regeneration, Laboratory of Pediatrics, PKD group, KU Leuven - University of Leuven, Leuven, Belgium.,Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Ann Van Schepdael
- Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, KU Leuven - University of Leuven, Leuven, Belgium
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Parodi-Rullán R, Sone JY, Fossati S. Endothelial Mitochondrial Dysfunction in Cerebral Amyloid Angiopathy and Alzheimer's Disease. J Alzheimers Dis 2020; 72:1019-1039. [PMID: 31306129 DOI: 10.3233/jad-190357] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is the most prevalent form of dementia. Cerebrovascular dysfunction is one of the earliest events in the pathogenesis of AD, as well as in vascular and mixed dementias. Cerebral amyloid angiopathy (CAA), the deposition of amyloid around cerebral vessels, is observed in up to 90% of AD patients and in approximately 50% of elderly individuals over 80 years of age. CAA is a strong contributor to vascular dysfunction in AD. CAA-laden brain vessels are characterized by dysfunctional hemodynamics and leaky blood-brain barrier (BBB), contributing to clearance failure and further accumulation of amyloid-β (Aβ) in the cerebrovasculature and brain parenchyma. Mitochondrial dysfunction is increasingly recognized as an important early initiator of the pathogenesis of AD and CAA. The objective of this review is to discuss the effects of Aβ on cerebral microvascular cell function, focusing on its impact on endothelial mitochondria. After introducing CAA and its etiology and genetic risk factors, we describe the pathological relationship between cerebrovascular amyloidosis and brain microvascular endothelial cell dysfunction, critically analyzing its roles in disease progression, hypoperfusion, and BBB integrity. Then, we focus on discussing the effect of Aβ challenge on endothelial mitochondrial dysfunction pathways, and their contribution to the progression of neurovascular dysfunction in AD and dementia. Finally, we report potential pharmacological and non-pharmacological mitochondria-targeted therapeutic strategies which may help prevent or delay cerebrovascular failure.
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Affiliation(s)
- Rebecca Parodi-Rullán
- Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Je Yeong Sone
- Department of Psychiatry, Center for Brain Health, NYU School of Medicine, New York, NY, USA
| | - Silvia Fossati
- Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
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41
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Effectuality of chitosan biopolymer and its derivatives during antioxidant applications. Int J Biol Macromol 2020; 164:1342-1369. [DOI: 10.1016/j.ijbiomac.2020.07.197] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 02/07/2023]
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42
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Bottani E, Lamperti C, Prigione A, Tiranti V, Persico N, Brunetti D. Therapeutic Approaches to Treat Mitochondrial Diseases: "One-Size-Fits-All" and "Precision Medicine" Strategies. Pharmaceutics 2020; 12:E1083. [PMID: 33187380 PMCID: PMC7696526 DOI: 10.3390/pharmaceutics12111083] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/08/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022] Open
Abstract
Primary mitochondrial diseases (PMD) refer to a group of severe, often inherited genetic conditions due to mutations in the mitochondrial genome or in the nuclear genes encoding for proteins involved in oxidative phosphorylation (OXPHOS). The mutations hamper the last step of aerobic metabolism, affecting the primary source of cellular ATP synthesis. Mitochondrial diseases are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. The limited information of the natural history, the limitations of currently available preclinical models, coupled with the large variability of phenotypical presentations of PMD patients, have strongly penalized the development of effective therapies. However, new therapeutic strategies have been emerging, often with promising preclinical and clinical results. Here we review the state of the art on experimental treatments for mitochondrial diseases, presenting "one-size-fits-all" approaches and precision medicine strategies. Finally, we propose novel perspective therapeutic plans, either based on preclinical studies or currently used for other genetic or metabolic diseases that could be transferred to PMD.
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Affiliation(s)
- Emanuela Bottani
- Department of Diagnostics and Public Health, Section of Pharmacology, University of Verona, 37134 Verona, Italy
| | - Costanza Lamperti
- Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, 20126 Milan, Italy; (C.L.); (V.T.)
| | - Alessandro Prigione
- Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Clinic Düsseldorf (UKD), Heinrich Heine University (HHU), 40225 Dusseldorf, Germany;
| | - Valeria Tiranti
- Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, 20126 Milan, Italy; (C.L.); (V.T.)
| | - Nicola Persico
- Department of Clinical Science and Community Health, University of Milan, 20122 Milan, Italy;
- Fetal Medicine and Surgery Service, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Dario Brunetti
- Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, 20126 Milan, Italy; (C.L.); (V.T.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy
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Sygitowicz G, Sitkiewicz D. Molecular mechanisms of organ damage in sepsis: an overview. Braz J Infect Dis 2020; 24:552-560. [PMID: 33169675 PMCID: PMC9392098 DOI: 10.1016/j.bjid.2020.09.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/11/2020] [Accepted: 09/30/2020] [Indexed: 02/08/2023] Open
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Li A, Yi J, Li X, Zhou J. Physiological Ca 2+ Transients Versus Pathological Steady-State Ca 2+ Elevation, Who Flips the ROS Coin in Skeletal Muscle Mitochondria. Front Physiol 2020; 11:595800. [PMID: 33192612 PMCID: PMC7642813 DOI: 10.3389/fphys.2020.595800] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/05/2020] [Indexed: 12/20/2022] Open
Abstract
Mitochondria are both the primary provider of ATP and the pivotal regulator of cell death, which are essential for physiological muscle activities. Ca2+ plays a multifaceted role in mitochondrial function. During muscle contraction, Ca2+ influx into mitochondria activates multiple enzymes related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation, resulting in increased ATP synthesis to meet the energy demand. Pathophysiological conditions such as skeletal muscle denervation or unloading also lead to elevated Ca2+ levels inside mitochondria. However, the outcomes of this steady-state elevation of mitochondrial Ca2+ level include exacerbated reactive oxygen species (ROS) generation, sensitized opening of mitochondrial permeability transition pore (mPTP), induction of programmed cell death, and ultimately muscle atrophy. Previously, both acute and long-term endurance exercises have been reported to activate certain signaling pathways to counteract ROS production. Meanwhile, electrical stimulation is known to help prevent apoptosis and alleviate muscle atrophy in denervated animal models and patients with motor impairment. There are various mechanistic studies that focus on the excitation-transcription coupling framework to understand the beneficial role of exercise and electrical stimulation. Interestingly, a recent study has revealed an unexpected role of rapid mitochondrial Ca2+ transients in keeping mPTP at a closed state with reduced mitochondrial ROS production. This discovery motivated us to contribute this review article to inspire further discussion about the potential mechanisms underlying differential outcomes of physiological mitochondrial Ca2+ transients and pathological mitochondrial Ca2+ elevation in skeletal muscle ROS production.
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Affiliation(s)
- Ang Li
- Department of Kinesiology, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
| | - Jianxun Yi
- Department of Kinesiology, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
| | - Xuejun Li
- Department of Kinesiology, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
| | - Jingsong Zhou
- Department of Kinesiology, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
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Gerdes HJ, Yang M, Heisner JS, Camara AKS, Stowe DF. Modulation of peroxynitrite produced via mitochondrial nitric oxide synthesis during Ca 2+ and succinate-induced oxidative stress in cardiac isolated mitochondria. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2020; 1861:148290. [PMID: 32828729 DOI: 10.1016/j.bbabio.2020.148290] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/23/2020] [Accepted: 07/29/2020] [Indexed: 01/09/2023]
Abstract
We hypothesized that NO• is generated in isolated cardiac mitochondria as the source for ONOO- production during oxidative stress. We monitored generation of ONOO- from guinea pig isolated cardiac mitochondria subjected to excess Ca2+ uptake before adding succinate and determined if ONOO- production was dependent on a nitric oxide synthase (NOS) located in cardiac mitochondria (mtNOS). Mitochondria were suspended in experimental buffer at pH 7.15, and treated with CaCl2 and then the complex II substrate Na-succinate, followed by menadione, a quinone redox cycler, to generate O2•-. L-tyrosine was added to the mitochondrial suspension where it is oxidized by ONOO- to form dityrosine (diTyr) in proportion to the ONOO- present. We found that exposing mitochondria to excess CaCl2 before succinate resulted in an increase in diTyr and amplex red fluorescence (H2O2) signals, indicating that mitochondrial oxidant stress, induced by elevated mtCa2+ and succinate, increased mitochondrial ONOO- production via NO• and O2•-. Changes in mitochondrial ONOO- production dependent on NOS were evidenced by using NOS inhibitors L-NAME/L-NNA, TEMPOL, a superoxide dismutase (SOD) mimetic, and PTIO, a potent global NO• scavenger. L-NAME and L-NNA decreased succinate and menadione-mediated ONOO- production, PTIO decreased production of ONOO-, and TEMPOL decreased ONOO- levels by converting more O2•- to H2O2. Electron microscopy showed immuno-gold labeled iNOS and nNOS in mitochondria isolated from cardiomyocytes and heart tissue. Western blots demonstrated iNOS and nNOS bands in total heart tissue, bands for both iNOS and nNOS in β-tubulin-free non-purified (crude) mitochondrial preparations, and a prominent iNOS band, but no nNOS band, in purified (Golgi and ER-free) mitochondria. Prior treatment of guinea pigs with lipopolysacharride (LPS) enhanced expression of iNOS in liver mitochondria but not in heart mitochondria. Our results indicate that release of ONOO- into the buffer is dependent both on O2•- released from mitochondria and NO• derived from a mtCa2+-inducible nNOS isoform, possibly attached to mitochondria, and a mtNOS isoform like iNOS that is non-inducible.
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Affiliation(s)
- Harrison J Gerdes
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Meiying Yang
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - James S Heisner
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Amadou K S Camara
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - David F Stowe
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Biomedical Engineering, Medical College of Wisconsin and Marquette University, Milwaukee, WI, USA; Research Service, Zablocki Veterans Affairs Medical Center, Milwaukee, WI, USA.
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Vadlakonda L, Indracanti M, Kalangi SK, Gayatri BM, Naidu NG, Reddy ABM. The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer. J Diabetes Metab Disord 2020; 19:1731-1775. [PMID: 33520860 DOI: 10.1007/s40200-020-00566-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
Purpose Re-examine the current metabolic models. Methods Review of literature and gene networks. Results Insulin activates Pi uptake, glutamine metabolism to stabilise lipid membranes. Tissue turnover maintains the metabolic health. Current model of intermediary metabolism (IM) suggests glucose is the source of energy, and anaplerotic entry of fatty acids and amino acids into mitochondria increases the oxidative capacity of the TCA cycle to produce the energy (ATP). The reduced cofactors, NADH and FADH2, have different roles in regulating the oxidation of nutrients, membrane potentials and biosynthesis. Trans-hydrogenation of NADH to NADPH activates the biosynthesis. FADH2 sustains the membrane potential during the cell transformations. Glycolytic enzymes assume the non-canonical moonlighting functions, enter the nucleus to remodel the genetic programmes to affect the tissue turnover for efficient use of nutrients. Glycosylation of the CD98 (4F2HC) stabilises the nutrient transporters and regulates the entry of cysteine, glutamine and BCAA into the cells. A reciprocal relationship between the leucine and glutamine entry into cells regulates the cholesterol and fatty acid synthesis and homeostasis in cells. Insulin promotes the Pi transport from the blood to tissues, activates the mitochondrial respiratory activity, and glutamine metabolism, which activates the synthesis of cholesterol and the de novo fatty acids for reorganising and stabilising the lipid membranes for nutrient transport and signal transduction in response to fluctuations in the microenvironmental cues. Fatty acids provide the lipid metabolites, activate the second messengers and protein kinases. Insulin resistance suppresses the lipid raft formation and the mitotic slippage activates the fibrosis and slow death pathways.
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Affiliation(s)
| | - Meera Indracanti
- Institute of Biotechnology, University of Gondar, Gondar, Ethiopia
| | - Suresh K Kalangi
- Amity Stem Cell Institute, Amity University Haryana, Amity Education Valley Pachgaon, Manesar, Gurugram, HR 122413 India
| | - B Meher Gayatri
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
| | - Navya G Naidu
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
| | - Aramati B M Reddy
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
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Measurement of Oxidative Stress Markers In Vitro Using Commercially Available Kits. ACTA ACUST UNITED AC 2020. [DOI: 10.1007/978-3-030-47318-1_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
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48
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Cunningham RP, Sheldon RD, Rector RS. The Emerging Role of Hepatocellular eNOS in Non-alcoholic Fatty Liver Disease Development. Front Physiol 2020; 11:767. [PMID: 32719616 PMCID: PMC7350778 DOI: 10.3389/fphys.2020.00767] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/11/2020] [Indexed: 12/29/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is comprised of a spectrum of liver injury ranging from excess fat accumulation in the liver (steatosis), to steatohepatitis (NASH), to its end stage of cirrhosis. A hallmark of NAFLD progression is the decline in function of hepatic mitochondria, although the mechanisms remain unresolved. Given the important role endothelial nitric oxide synthase (eNOS) plays in mitochondrial dynamics in other tissues, it has emerged as a potential mediator of maintaining mitochondrial function in the liver. In this mini review, we summarize the most relevant findings that extends current understanding of eNOS as a regulator of mitochondrial biogenesis, and identifies a potential additional role in mitochondrial turnover and attenuating inflammation during NAFLD development and progression.
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Affiliation(s)
- Rory P Cunningham
- Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States.,Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Ryan D Sheldon
- Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, United States
| | - R Scott Rector
- Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States.,Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States.,Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO, United States
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Jesus AA, Passaglia P, Santos BM, Rodrigues-Santos I, Flores RA, Batalhão ME, Stabile AM, Cárnio EC. Chronic molecular hydrogen inhalation mitigates short and long-term memory loss in polymicrobial sepsis. Brain Res 2020; 1739:146857. [PMID: 32348775 DOI: 10.1016/j.brainres.2020.146857] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 04/04/2020] [Accepted: 04/24/2020] [Indexed: 01/13/2023]
Abstract
The central nervous system (CNS) is one of the first physiological systems to be affected in sepsis. During the exacerbated systemic inflammatory response at the early stage of sepsis, circulatory inflammatory mediators are able to reach the CNS leading to neuroinflammation and, consequently, long-term impairment in learning and memory formation is observed. The acute treatment with molecular hydrogen (H2) exerts important antioxidative, antiapoptotic, and anti-inflammatory effects in sepsis, but little is known about the mechanism itself and the efficacy of chronic H2 inhalation in sepsis treatment. Thus, we tested two hypotheses. We first hypothesized that chronic H2 inhalation is also an effective therapy to treat memory impairment induced by sepsis. The second hypothesis is that H2 treatment decreases sepsis-induced neuroinflammation in the hippocampus and prefrontal cortex, important areas related to short and long-term memory processing. Our results indicate that (1) chronic exposure of hydrogen gas is a simple, safe and promising therapeutic strategy to prevent memory loss in patients with sepsis and (2) acute H2 inhalation decreases neuroinflammation in memory-related areas and increases total nuclear factor E2-related factor 2 (Nrf2), a transcription factorthat regulates a vast group of antioxidant and inflammatory agents expression in these areas of septic animals.
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Affiliation(s)
- Aline A Jesus
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Patrícia Passaglia
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Bruna M Santos
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Isabelle Rodrigues-Santos
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Rafael A Flores
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Marcelo E Batalhão
- Department of General and Specialized Nursing, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900 Brazil
| | - Angelita M Stabile
- Department of General and Specialized Nursing, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900 Brazil
| | - Evelin C Cárnio
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil; Department of General and Specialized Nursing, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900 Brazil.
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The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it? Mol Biol Rep 2020; 47:5587-5620. [PMID: 32564227 DOI: 10.1007/s11033-020-05590-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 06/12/2020] [Indexed: 12/12/2022]
Abstract
Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.
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