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Basak D, Mostofa A, Madala HR, Srivenugopal KS. Novel Pathways of Oxidative and Nitrosative Inactivation of the Human MGMT Protein in Colon Cancer and Glioblastoma Cells: Increased Efficacy of Alkylating Agents In Vitro and In Vivo. Diseases 2025; 13:32. [PMID: 39997039 PMCID: PMC11854478 DOI: 10.3390/diseases13020032] [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: 08/11/2024] [Revised: 12/31/2024] [Accepted: 01/20/2025] [Indexed: 02/26/2025] Open
Abstract
Background: O6-Methylguanine-DNA methyltransferase (MGMT) is a unique antimutagenic DNA repair protein that plays a crucial role in conferring resistance to various alkylating agents in brain tumor therapy. In this study, we exploited the susceptibility of the active site Cys145 of MGMT for thiolation and nitrosylation, both of which inactivate the enzyme. Methods: We designed a redox perturbing glutathione mimetic, a platinated homoglutathione disulfide (hGTX) by adding small amounts of cisplatin (1000:10) and used a nitric oxide-donor spermine NONOate. N6022, a potent inhibitor of S-nitrosoglutathione reductase was used to extend the retention of nitrosylated MGMT in tumor cell culture and subcutaneous xenografts. Results: Both hGTX and spermine NONOate inhibited MGMT activity in HT29, SF188, T98G, and other brain tumor cells. There was a robust increase in the alkylation-induced DNA interstrand cross-linking, G2/M cell cycle arrest, cytotoxicity, and the levels of apoptotic markers when either of the agents was used with alkylating agents. In the nude mice bearing T98G and HT29-luc2 xenografts, combinations of hGTX and spermine NONOate with alkylating agents produced a marked reduction in MGMT protein and tumor growth delay and regressions. N6022 treatment increased the presence of nitrosylated MGMT for a longer time, thereby extending the DNA-repair deficient state both in cell culture and preclinical settings. Conclusions: Our findings highlight the options for redox-driven therapeutic strategies for MGMT and suggest that oxidative and/or nitrosative inactivation of DNA repair in combination with alkylating agents could be exploited.
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Affiliation(s)
- Debasish Basak
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA
| | - Agm Mostofa
- Office of Bioequivalence/Generic Drug, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA;
| | | | - Kalkunte S. Srivenugopal
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA;
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Nagasaki T, Wenzel SE. Asthma exacerbations and airway redox imbalance under type 2 inflammatory conditions. Respir Investig 2024; 62:923-928. [PMID: 39182396 DOI: 10.1016/j.resinv.2024.08.003] [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: 03/19/2024] [Revised: 07/13/2024] [Accepted: 08/07/2024] [Indexed: 08/27/2024]
Abstract
Asthma is a chronic inflammatory airway disease characterized by bronchial hyperresponsiveness and reversibility. Despite considerable advances in asthma treatment based on our understanding of its pathophysiology, asthma exacerbations remain challenging. To reduce asthma exacerbations, it is essential to identify triggers, patients' risk factors, and underlying mechanisms. While exposure to viruses and environmental stimuli are known common triggers for asthma exacerbations, the key factors involved in asthma exacerbations have been identified as type 2 inflammation. Type 2 inflammatory biomarkers have been demonstrated to be useful in predicting individuals at risk of exacerbations. Furthermore, recent clinical trials of targeted biological therapy, which blocks the type 2 pathway, have supported the critical role of type 2 inflammation in asthma exacerbations. Although the specific mechanisms linking type 2 inflammation to asthma exacerbations have not yet been fully elucidated, increasing evidence shows that reduction/oxidation (redox) imbalance likely plays an important role in this association. Under type 2 inflammatory conditions, human airway epithelial cells activate 15-lipoxygenase-1 in complex with phosphatidylethanolamine binding protein-1, leading to the generation of electrophilic hydroperoxyl-phospholipids. When the accumulation of reactive lipid peroxidation surpasses a specific glutathione-dependent activity, these electrophilic compounds are not neutralized, leading to programmed cell death, ferroptosis. Reduced glutathione levels, caused by type 2 inflammation, may impair its ability to neutralize reactive lipid peroxidation. The accumulation of lipid peroxidation with intracellular redox imbalance may contribute to asthma exacerbations in individuals with type 2 inflammation. Inhibiting the ferroptotic pathway holds promise as a therapeutic strategy to alleviate asthma exacerbations.
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Affiliation(s)
- Tadao Nagasaki
- Department of Respiratory Medicine and Allergology, Kindai University Nara Hospital, Nara, 630-0293, Japan.
| | - Sally E Wenzel
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Asthma and Environmental Lung Health Institute at UPMC, Pittsburgh, PA, 15261, USA
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3
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Chakraborty S, Mishra A, Choudhuri A, Bhaumik T, Sengupta R. Leveraging the redundancy of S-denitrosylases in response to S-nitrosylation of caspases: Experimental strategies and beyond. Nitric Oxide 2024; 149:18-31. [PMID: 38823434 DOI: 10.1016/j.niox.2024.05.002] [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: 04/18/2024] [Accepted: 05/25/2024] [Indexed: 06/03/2024]
Abstract
Redox-based protein posttranslational modifications, such as S-nitrosylation of critical, active site cysteine thiols have garnered significant clinical attention and research interest, reasoning for one of the crucial biological implications of reactive messenger molecule, nitric oxide in the cellular repertoire. The stringency of the S-(de)nitrosylation-based redox switch governs the activity and contribution of several susceptible enzymes in signal transduction processes and diverse pathophysiological settings, thus establishing it as a transient yet reasonable, and regulated mechanism of NO adduction and release. Notably, endogenous proteases like cytosolic and mitochondrial caspases with a molecular weight ranging from 33 to 55 kDa are susceptible to performing this biochemistry in the presence of major oxidoreductases, which further unveils the enormous redox-mediated regulational control of caspases in the etiology of diseases. In addition to advancing the progress of the current state of understanding of 'redox biochemistry' in the field of medicine and enriching the existing dynamic S-nitrosoproteome, this review stands as a testament to an unprecedented shift in the underpinnings for redundancy and redox relay between the major redoxin/antioxidant systems, fine-tuning of which can command the apoptotic control of caspases at the face of nitro-oxidative stress. These intricate functional overlaps and cellular backups, supported rationally by kinetically favorable reaction mechanisms suggest the physiological relevance of identifying and involving such cognate substrates for cellular S-denitrosylases that can shed light on the bigger picture of extensively proposing targeted therapies and redox-based drug designing to potentially alleviate the side effects of NOx/ROS in disease pathogenesis.
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Affiliation(s)
- Surupa Chakraborty
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Akansha Mishra
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Ankita Choudhuri
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Tamal Bhaumik
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India
| | - Rajib Sengupta
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Action Area II, Rajarhat, Newtown, Kolkata, West Bengal, 700135, India.
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4
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Abdelhamid WG, Mowaad NA, Asaad GF, Galal AF, Mohammed SS, Mostafa OE, Sadek DR, Elkhateb LA. The potential protective effect of Camellia Sinensis in mitigating monosodium glutamate-induced neurotoxicity: biochemical and histological study in male albino rats. Metab Brain Dis 2024; 39:953-966. [PMID: 38869783 PMCID: PMC11233344 DOI: 10.1007/s11011-024-01365-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 05/29/2024] [Indexed: 06/14/2024]
Abstract
Monosodium glutamate (MSG) is the sodium compound derived from glutamic acid. Excessive daily ingestion of MSG leads to elevated amounts of glutamic acid in the bloodstream, which can be detrimental to brain structures. Camellia sinensis, often known as green tea (GT), is a rich source of essential hexogen antioxidants that are necessary for the body. Thirty-two adult male albino rats were divided into four groups (n = 8). Group 1 served as a control -ve group. Group 2 was given GT (1.5 ml/rat/day). Group 3 was given MSG (600 mg/kg/day). Group 4 was given MSG (600 mg/kg/day) and GT (1.5 ml/rat/day). All treatments were given orally for 28 days. MSG administration resulted in significant neurotoxicity in rats that was revealed by the significant reduction of serum concentration of glutathione peroxidase (GPx) and nitric oxide (NO), and the significant elevation of total antioxidant capacity (TAC) accompanied by the significant reduction of levels of serum monoamines (dopamine, serotonin, and norepinephrine) and histological changes in the hippocampus area CA1, dentate gyrus, and cerebellar cortex and positive immunohistochemical staining of glial fibrillary acidic proteins (GFAP) and calretinin. Administration of GT with MSG counteracted the MSG-mediated oxidative stress by significantly increasing serum concentrations of GPX and NO and significantly decreasing concentrations of TAC. Furthermore, GT significantly increased levels of serum monoamines (dopamine, serotonin, and norepinephrine). Moreover, it ameliorated the histological changes, GFAP, and calretinin immunostaining in brain tissues. It is envisaged that GT will serve as a viable protective choice for the inclusion of the neurotoxicity treatment procedure.
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Affiliation(s)
- Walaa G Abdelhamid
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Noha A Mowaad
- Narcotics, Ergogenics and Poisons Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Gihan F Asaad
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt.
| | - Asmaa F Galal
- Narcotics, Ergogenics and Poisons Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Sarah S Mohammed
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Olfat E Mostafa
- Biochemistry Department, Poison Control Center, Ain Shams University Hospitals, Cairo, Egypt
| | - Doaa R Sadek
- Histology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Lobna A Elkhateb
- Histology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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5
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Yang F, Li Q, Yin X. Metagenomic analysis of the effects of salinity on microbial community and functional gene diversity in glacial meltwater estuary, Ny-Alesund, Arctic. Braz J Microbiol 2024; 55:1587-1599. [PMID: 38647870 PMCID: PMC11153410 DOI: 10.1007/s42770-024-01298-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 03/05/2024] [Indexed: 04/25/2024] Open
Abstract
Due to the inflow of meltwater from the Midre Lovénbreen glacier upstream of Kongsfjorden, the nutrient concentration of Kongsfjorden change from the estuary to the interior of the fjord. Our objective was to explore the changes in bacterial community structure and metabolism-related genes from the estuary to fjord by metagenomic analysis. Our data indicate that glacial meltwater input has altered the physicochemical properties of the fjords, with a significant effect, in particular, on fjords salinity, thus altering the relative abundance of some specific bacterial groups. In addition, we suggest that the salinity of a fjord is an important factor affecting the abundance of genes associated with the nitrogen and sulfur cycles in the fjord. Changes in salinity may affect the relative abundance of microbial populations that carry metabolic genes, thus affecting the relative abundance of genes associated with the nitrogen and sulfur cycles.
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Affiliation(s)
- Fan Yang
- Management College, Ocean University of China, Qingdao, China
- Business College, Qingdao University, Qingdao, China
| | - Qinxin Li
- College of Chemistry and Chemical Engineering, Qingdao University, Qingdao, China
| | - Xiaofei Yin
- First Institute of Oceanography, Ministry of Natural Resources, Qingdao, China.
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6
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Durmus H, Burak AM, Goktug S, Aysegul B. Metabolomic modelling and neuroprotective effects of carvacrol against acrylamide toxicity in rat's brain and sciatic nerve. Clin Exp Pharmacol Physiol 2024; 51:e13841. [PMID: 38302077 DOI: 10.1111/1440-1681.13841] [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: 09/13/2023] [Revised: 11/30/2023] [Accepted: 12/18/2023] [Indexed: 02/03/2024]
Abstract
The study aimed to investigate the harmful effects of acrylamide (AA), which forms in carbohydrate-rich foods at temperatures above 120°C, on the central and peripheral nervous systems and to evaluate the potential neuroprotective effects of carvacrol (CRV). Male Wistar Albino rats were subjected to AA (40 mg/kg/bw/day) and CRV (50 mg/kg/bw/day) for 15 days. Following the last administration, evaluations revealed disrupted gait, heightened thermal sensitivity and altered paw withdrawal thresholds in AA-exposed rats. Notably, AA reduced glutathione (GSH) and raised malondialdehyde (MDA) levels in both brain and sciatic nerve tissues. AA raised nuclear factor erythroid 2-related factor 2 (Nrf2), caspase 3 and nuclear factor κB (NF-κB) gene expressions while decreasing NR4A2. CRV co-administration mitigated gait abnormalities, elevated GSH levels and lowered MDA levels in both tissues. CRV also modulated gene expression, reducing Nrf2 and NF-κB while increasing NR4A2. Histopathological signs of AA-induced neurodegeneration and elevated glial fibrillary acidic protein levels observed in brain and sciatic nerve tissues were rectified with simultaneous administration of CRV, thereby demonstrating neuroprotective efficacy in both regions. This study is pioneering in demonstrating CRV's neuroprotective potential against AA-induced neurotoxicity in both central and peripheral nervous systems, effectively addressing limitations in the literature. In conclusion, the study revealed AA-induced neurodegeneration in the brain and sciatic nerve, with CRV significantly mitigating this neurotoxicity. This novel research underscores CRV's promise as a neuroprotective agent against AA-induced adverse effects in both the central and peripheral nervous systems.
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Affiliation(s)
- Hatipoglu Durmus
- Department of Physiology, Faculty of Veterinary Medicine, Selcuk University, Konya, Türkiye
| | - Ates M Burak
- Department of Pathology, Faculty of Veterinary Medicine, Selcuk University, Konya, Türkiye
| | - Senturk Goktug
- Department of Physiology, Faculty of Veterinary Medicine, Aksaray University, Aksaray, Türkiye
| | - Bulut Aysegul
- Department of Pathology, Faculty of Veterinary Medicine, Selcuk University, Konya, Türkiye
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7
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Cadenas-Garrido P, Schonvandt-Alarcos A, Herrera-Quintana L, Vázquez-Lorente H, Santamaría-Quiles A, Ruiz de Francisco J, Moya-Escudero M, Martín-Oliva D, Martín-Guerrero SM, Rodríguez-Santana C, Aragón-Vela J, Plaza-Diaz J. Using Redox Proteomics to Gain New Insights into Neurodegenerative Disease and Protein Modification. Antioxidants (Basel) 2024; 13:127. [PMID: 38275652 PMCID: PMC10812581 DOI: 10.3390/antiox13010127] [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: 12/15/2023] [Revised: 01/16/2024] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
Antioxidant defenses in biological systems ensure redox homeostasis, regulating baseline levels of reactive oxygen and nitrogen species (ROS and RNS). Oxidative stress (OS), characterized by a lack of antioxidant defenses or an elevation in ROS and RNS, may cause a modification of biomolecules, ROS being primarily absorbed by proteins. As a result of both genome and environment interactions, proteomics provides complete information about a cell's proteome, which changes continuously. Besides measuring protein expression levels, proteomics can also be used to identify protein modifications, localizations, the effects of added agents, and the interactions between proteins. Several oxidative processes are frequently used to modify proteins post-translationally, including carbonylation, oxidation of amino acid side chains, glycation, or lipid peroxidation, which produces highly reactive alkenals. Reactive alkenals, such as 4-hydroxy-2-nonenal, are added to cysteine (Cys), lysine (Lys), or histidine (His) residues by a Michael addition, and tyrosine (Tyr) residues are nitrated and Cys residues are nitrosylated by a Michael addition. Oxidative and nitrosative stress have been implicated in many neurodegenerative diseases as a result of oxidative damage to the brain, which may be especially vulnerable due to the large consumption of dioxygen. Therefore, the current methods applied for the detection, identification, and quantification in redox proteomics are of great interest. This review describes the main protein modifications classified as chemical reactions. Finally, we discuss the importance of redox proteomics to health and describe the analytical methods used in redox proteomics.
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Affiliation(s)
- Paula Cadenas-Garrido
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - Ailén Schonvandt-Alarcos
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - Lourdes Herrera-Quintana
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.); (C.R.-S.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Héctor Vázquez-Lorente
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.); (C.R.-S.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Alicia Santamaría-Quiles
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - Jon Ruiz de Francisco
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - Marina Moya-Escudero
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - David Martín-Oliva
- Department of Cell Biology, Faculty of Science, University of Granada, 18071 Granada, Spain;
| | - Sandra M. Martín-Guerrero
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RT, UK
| | - César Rodríguez-Santana
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.); (C.R.-S.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Jerónimo Aragón-Vela
- Department of Health Sciences, Area of Physiology, Building B3, Campus s/n “Las Lagunillas”, University of Jaén, 23071 Jaén, Spain
| | - Julio Plaza-Diaz
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria IBS, Complejo Hospitalario Universitario de Granada, 18071 Granada, Spain
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Dyachenko EI, Bel’skaya LV. The Role of Amino Acids in Non-Enzymatic Antioxidant Mechanisms in Cancer: A Review. Metabolites 2023; 14:28. [PMID: 38248831 PMCID: PMC10818545 DOI: 10.3390/metabo14010028] [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: 12/12/2023] [Revised: 12/27/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Currently, the antioxidant properties of amino acids and their role in the physicochemical processes accompanying oxidative stress in cancer remain unclear. Cancer cells are known to extensively uptake amino acids, which are used as an energy source, antioxidant precursors that reduce oxidative stress in cancer, and as regulators of inhibiting or inducing tumor cell-associated gene expression. This review examines nine amino acids (Cys, His, Phe, Met, Trp, Tyr, Pro, Arg, Lys), which play a key role in the non-enzymatic oxidative process in various cancers. Conventionally, these amino acids can be divided into two groups, in one of which the activity increases (Cys, Phe, Met, Pro, Arg, Lys) in cancer, and in the other, it decreases (His, Trp, Tyr). The review examines changes in the metabolism of nine amino acids in eleven types of oncology. We have identified the main nonspecific mechanisms of changes in the metabolic activity of amino acids, and described direct and indirect effects on the redox homeostasis of cells. In the future, this will help to understand better the nature of life of a cancer cell and identify therapeutic targets more effectively.
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Affiliation(s)
| | - Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, Omsk 644099, Russia;
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9
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Zhang L, Ludden CM, Cullen AJ, Tew KD, Branco de Barros AL, Townsend DM. Nuclear factor kappa B expression in non-small cell lung cancer. Biomed Pharmacother 2023; 167:115459. [PMID: 37716117 PMCID: PMC10591792 DOI: 10.1016/j.biopha.2023.115459] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/18/2023] Open
Abstract
In this mini-review, we discuss the role of NF-κB, a proinflammatory transcription factor, in the expression of genes involved in inflammation, proliferation, and apoptosis pathways, and link it with prognosis of various human cancers, particularly non-small cell lung cancer (NSCLC). We and others have shown that NF-κB activity can be impacted by post-translational S-glutathionylation through reversible formation of a mixed disulfide bond between its cysteine residues and glutathione (GSH). Clinical data analysis showed that high expression of NF-κB correlated with shorter overall survival (OS) in NSCLC patients, suggesting a tumor promotion function for NF-κB. Moreover, NF-κB expression was associated with tumor stage, lymph node metastasis, and 5-year OS in these patients. NF-κB was over-expressed in the cytoplasm of tumor tissue compared to adjacent normal tissues. S-glutathionylation of NF-κB caused negative regulation by interfering with DNA binding activities of NF-κB subunits. In response to oxidants, S-glutathionylation of NF-κB also correlated with enhanced lung inflammation. Thus, S-glutathionylation is an important contributor to NF-κB regulation and clinical results highlight the importance of NF-κB in NSCLC, where NF-κB levels are associated with unfavorable prognosis.
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Affiliation(s)
- Leilei Zhang
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - Claudia M Ludden
- Department of Drug Discovery and Experimental Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Alexander J Cullen
- Department of Drug Discovery and Experimental Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Kenneth D Tew
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - André Luís Branco de Barros
- Department of Clinical and Toxicological Analyses, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Danyelle M Townsend
- Department of Drug Discovery and Experimental Sciences, Medical University of South Carolina, Charleston, SC, USA.
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10
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Wang L, Zhang K, Gao S, Zhang M, Liu T, Cai B, Wang L, Su L, Wu J, Chen S. High-Yield Synthesis of 2'-Fucosyllactose from Glycerol and Glucose in Engineered Escherichia coli. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:15237-15248. [PMID: 37795855 DOI: 10.1021/acs.jafc.3c05015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
2'-Fucosyllactose (2'-FL) is vital for the growth and development of newborns. In this study, we developed a synthesis pathway for 2'-FL in Escherichia coli BL21 (DE3). Then, we optimized the solubility of α-1,2-fucosyltransferase, thereby enhancing the production yield of 2'-FL. Based on this finding, we further enhanced the expression of guanosine inosine kinase Gsk and knocked out the isocitrate lyase regulator gene iclR. This strategy reduced the formation of byproduct acetate during the metabolic process and alleviated carbon source overflow effects in the strain, resulting in further improvement of the yield of 2'-FL. In a 3 L bioreactor, employing fed-batch fermentation with glycerol and glucose as substrates, the engineered strain BWLAI-RSZL exhibited impressive 2'-FL titers of 121.9 and 111.56 g/L, along with productivity levels of 1.57 and 1.31 g/L/h, respectively. The reported 2'-FL titers reached a groundbreaking level, irrespective of the carbon source employed (glycerol or glucose), highlighting the significant potential for large-scale industrial synthesis of 2'-FL.
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Affiliation(s)
- Luyao Wang
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Kang Zhang
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Shengqi Gao
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Mengwei Zhang
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Tongle Liu
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Bohan Cai
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Lei Wang
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Lingqia Su
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Jing Wu
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Sheng Chen
- State Key Laboratory of Food Science and Resources, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
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11
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Zhao Y, Liu Y, Wu J, Kong D, Zhao S, Li G, Li W. Swamp eel aldehyde reductase is involved in response to nitrosative stress via regulating NO/GSH levels. JOURNAL OF FISH BIOLOGY 2023; 103:529-543. [PMID: 37266950 DOI: 10.1111/jfb.15471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 06/01/2023] [Indexed: 06/03/2023]
Abstract
Aldehyde reductase (ALR) plays key roles in the detoxification of toxic aldehyde. In this study, the authors cloned the swamp eel ALR gene using rapid amplification of cDNA ends-PCR (RACE-PCR). The recombinant protein (rALR) was expressed in Escherichia coli and purified using a Ni2+ -NTA chelating column. The rALR protein exhibited efficient reductive activity towards several aldehydes, ketones and S-nitrosoglutathione (GSNO). A spot assay suggested that the recombinant E. coli strain expressing rALR showed better resistance to formaldehyde, sodium nitrite and GSNO stress, suggesting that swamp eel ALR is crucial for redox homeostasis in vivo. Consequently, the authors investigated the effect of rALR on the oxidative parameters of the liver in swamp eels challenged with Aeromonas hydrophila. The hepatic glutathione (GSH) content significantly increased, and the hepatic NO content and levels of reactive oxygen species and reactive nitrogen species significantly decreased when rALR was administered. In addition, the mRNA expression of hepatic Alr, HO1 and Nrf2 was significantly upregulated, whereas the expression levels of NF-κB, IL-1β and NOS1 were significantly downregulated in the rALR-administered group. Collectively, these results suggest that ALR is involved in the response to nitrosative stress by regulating GSH/NO levels in the swamp eel.
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Affiliation(s)
- Yuhe Zhao
- College of Life Sciences, Yangtze University, Jingzhou, China
| | - Yang Liu
- College of Life Sciences, Yangtze University, Jingzhou, China
| | - Jianfen Wu
- College of Life Sciences, Yangtze University, Jingzhou, China
| | - Dan Kong
- College of Life Sciences, Yangtze University, Jingzhou, China
| | - Sifan Zhao
- College of Life Sciences, Yangtze University, Jingzhou, China
| | - Guopan Li
- College of Life Sciences, Yangtze University, Jingzhou, China
| | - Wei Li
- College of Life Sciences, Yangtze University, Jingzhou, China
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12
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Naspinska R, Moreira da Silva MH, Moreira da Silva F. Current Advances in Bovine In Vitro Maturation and Embryo Production Using Different Antioxidants: A Review. J Dev Biol 2023; 11:36. [PMID: 37754838 PMCID: PMC10532407 DOI: 10.3390/jdb11030036] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/18/2023] [Accepted: 08/15/2023] [Indexed: 09/28/2023] Open
Abstract
In vitro maturation (IVM) is one of the most important steps in in vitro embryo production (IVEP). It is a complicated procedure in which nuclear and cytoplasmatic changes in oocytes appear. In order to carry out the in vitro maturation procedure correctly, it is necessary to provide the oocytes with as close to a natural (in vivo) environment as possible. Many factors contribute to the overall poor quality of in vitro-matured oocytes. One important factor may be oxidative stress (OS). The generation of oxidants, such as reactive oxygen species, is common under culture conditions. The solution for OC treatment and prevention is antioxidants. In the last 5 years, many studies have examined different antioxidants and their effects on in vitro maturation of oocytes and embryo production. The aim of this systematic review was to present the achievements of scientific research in the last five years, in which the effects of many antioxidants were tested on bovine oocyte maturation and embryo production.
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Affiliation(s)
| | | | - Fernando Moreira da Silva
- Animal Reproduction, Centro de Investigação e Tecnologia Agrária dos Açores IITA-A, Faculty of Agricultural and Environmental Sciences, University of the Azores, 9701-851 Angra do Heroísmo, Portugal; (R.N.); (M.H.M.d.S.)
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13
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Feng Y, Li T, Li Y, Lin Z, Han X, Pei X, Zhang Y, Li F, Yang J, Shao D, Li C. Glutaredoxin-1 promotes lymphangioleiomyomatosis progression through inhibiting Bim-mediated apoptosis via COX2/PGE2/ERK pathway. Clin Transl Med 2023; 13:e1333. [PMID: 37478294 PMCID: PMC10361546 DOI: 10.1002/ctm2.1333] [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: 03/19/2023] [Revised: 07/03/2023] [Accepted: 07/11/2023] [Indexed: 07/23/2023] Open
Abstract
BACKGROUND Lymphangioleiomyomatosis (LAM) is a female-predominant interstitial lung disease, characterized by progressive cyst formation and respiratory failure. Clinical treatment with the mTORC1 inhibitor rapamycin could relieve partially the respiratory symptoms, but not curative. It is urgent to illustrate the fundamental mechanisms of TSC2 deficiency to the development of LAM, especially mTORC1-independent mechanisms. Glutaredoxin-1 (Glrx), an essential glutathione (GSH)-dependent thiol-oxidoreductase, maintains redox homeostasis and participates in various processes via controlling protein GSH adducts. Redox signalling through protein GSH adducts in LAM remains largely elusive. Here, we demonstrate the underlying mechanism of Glrx in the pathogenesis of LAM. METHODS 1. Abnormal Glrx expression in various kinds of human malignancies was identified by the GEPIA tumour database, and the expression of Glrx in LAM-derived cells was detected by real-time quantitative reverse transcription (RT-qPCR) and immunoblot. 2. Stable Glrx knockdown cell line was established to evaluate cellular impact. 3. Cell viability was determined by CCK8 assay. 4. Apoptotic cell number and intracellular reactive oxygen species (ROS) level were quantified by flow cytometry. 5. Cox2 expression and PGE2 production were detected to clarify the mechanism of Bim expression modulated by Glrx. 6. S-glutathionylated p65 was enriched and detected by immunoprecipitation and the direct regulation of Glrx on p65 was determined. 7. The xenograft animal model was established and photon flux was analyzed using IVIS Spectrum. RESULTS In LAM, TSC2 negatively regulated abnormal Glrx expression and activation in a mTORC1-independent manner. Knockdown of Glrx increased the expression of Bim and the accumulation of ROS, together with elevated S-glutathionylated proteins, contributing to the induction of apoptotic cell death and inhibited cell proliferation. Knockdown of Glrx in TSC2-deficient LAM cells increased GSH adducts on nuclear factor-kappa B p65, which contributed to a decrease in the expression of Cox2 and the biosynthesis of PGE2. Inhibition of PGE2 metabolism attenuated phosphorylation of ERK, which led to the accumulation of Bim, due to the imbalance of its phosphorylation and proteasome degradation. In xenograft tumour models, knockdown of Glrx in TSC2-deficient LAM cells inhibited tumour growth and increased tumour cell apoptosis. CONCLUSIONS Collectively, we provide a novel redox-dependent mechanism in the pathogenesis of LAM and propose that Glrx may be a beneficial strategy for the treatment of LAM or other TSC-related diseases.
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Affiliation(s)
- Ya Feng
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
| | - Tianjiao Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
| | - Yin Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
| | - Zhoujun Lin
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
| | - Xiao Han
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
| | - Xiaolin Pei
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
| | - Yupeng Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
| | - Fei Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
| | - Juan Yang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
| | - Di Shao
- Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, P. R. China
| | - Chenggang Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, P. R. China
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14
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Sadeghi A, Taherifard E, Dehdari Ebrahimi N, Rafiei E, Hadianfard F, Taherifard E. Effects of l-arginine supplementation in patients with sickle cell disease: A systematic review and meta-analysis of clinical trials. Health Sci Rep 2023; 6:e1167. [PMID: 37064309 PMCID: PMC10090802 DOI: 10.1002/hsr2.1167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/06/2023] [Accepted: 03/13/2023] [Indexed: 04/18/2023] Open
Abstract
Background and Aims Previous studies have shown that supplementation of some amino acids such as l-arginine or its precursors could exert beneficial effects in patients with sickle cell disease (SCD). The objective of this study is to systematically review the literature to assess the effect of arginine administration on the clinical and paraclinical parameters of patients with SCD. Methods Four online databases of PubMed, Web of Sciences, Scopus, and Embase were selected for systematic search. Eligible studies were clinical trials that evaluated the effect of arginine usage in patients with SCD. Effects sizes were calculated using weighted mean difference (WMD) and Hedge's g and they were pooled using random-effects modeling with Hartung-Knapp adjustment. Additional analyses were also conducted. Results Twelve studies containing detail of 399 patients with SCD were found to be eligible. The data synthesis showed that l-arginine significantly increased the level of NO metabolites (Hedge's g: 1.50, 0.48-1.82, I 2: 88%) and hemoglobin F (WMD: 1.69%, 0.86-2.52, I 2: 0%) and significantly decreased systolic blood pressure (WMD: -8.46 mmHg, -15.58 to -1.33, I 2: 53%) and aspartate transaminase (Hedge's g: -0.49, -0.73 to -0.26, I 2: 0%). However, there were no significant effects on hemoglobin, reticulocyte, malondialdehyde and diastolic blood pressure, and alanine transaminase. Conclusion Our meta-analysis showed that l-arginine use for SCD could be beneficial, increase hemoglobin F and exert blood pressure-lowering and hepatoprotective properties. However, for a firm conclusion and widespread use of l-arginine for these patients, more studies are needed.
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Affiliation(s)
- Alireza Sadeghi
- Student Research CommitteeShiraz University of Medical SciencesShirazIran
| | - Ehsan Taherifard
- Internal Medicine DepartmentShiraz University of Medical SciencesShirazIran
| | | | - Elham Rafiei
- Student Research CommitteeShiraz University of Medical SciencesShirazIran
| | - Farshad Hadianfard
- Student Research CommitteeShiraz University of Medical SciencesShirazIran
| | - Erfan Taherifard
- Internal Medicine DepartmentShiraz University of Medical SciencesShirazIran
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15
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El-Aswad AF, Aly MI, Alsahaty SA, Basyony ABA. Efficacy evaluation of some fumigants against Fusarium oxysporum and enhancement of tomato growth as elicitor-induced defense responses. Sci Rep 2023; 13:2479. [PMID: 36774421 PMCID: PMC9922316 DOI: 10.1038/s41598-023-29033-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 01/30/2023] [Indexed: 02/13/2023] Open
Abstract
Fusarium wilt, the most serious soil-borne pathogen, is a serious problem for tomato production worldwide. The presented study evaluated the antifungal activity against Fusarium oxysporum f. sp. lycopersici in vitro and in vivo for nine fumigants. In addition, the research examined the possibility of enhancing the growth of tomato plants in order to increase resistance against this disease by using four chemical inducers. The results indicated that at 20 mg/L, the radial growth of the pathogen was inhibited 100% by formaldehyde and > 80% by phosphine. Among the essential oils investigated, neem oil was the most effective, however, it only achieved 40.54% at 500 mg/L. The values of EC50 for all fumigants, except dimethyl disulfide (DMDS) and carbon disulfide (CS2), were lower than those for thiophanate-methyl. Phosphine was the highest efficient. The elicitors can be arranged based on their effectiveness, gibberellic acid (GA3) > sorbic acid > cytokinin (6-benzylaminopurine) > indole-3-butyric acid. The change in root length, fresh weight, and dry weight was greater with soil drench than with foliar application. The fumigant generators formaldehyde, phosphine and 1,4-dichlorobenzene and bio-fumigants citrus and neem oils as well as elicitors gibberellic and sorbic acid could be one of the promising alternatives to methyl bromide against Fusarium oxysporum as an important component of integrated management of Fusarium wilt.
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Affiliation(s)
- Ahmed F El-Aswad
- Pesticide Chemistry and Technology Department, Faculty of Agriculture, Alexandria University, El-Shatby, Alexandria, 21545, Egypt.
| | - Maher I Aly
- Pesticide Chemistry and Technology Department, Faculty of Agriculture, Alexandria University, El-Shatby, Alexandria, 21545, Egypt
| | - Sameh A Alsahaty
- Pesticide Chemistry and Technology Department, Faculty of Agriculture, Alexandria University, El-Shatby, Alexandria, 21545, Egypt
| | - Ayman B A Basyony
- Plant Pathology Department, Faculty of Agriculture, Alexandria University, Alexandria, Egypt
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16
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Alharthi NS, Khan H, Siyal FJ, Shaikh ZA, Arain SP, Eltayeb LB, Mangi AA. Glutathione, Cysteine, and D-Penicillamine Role in Exchange of Silver Metal from the Albumin Metal Complex. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3619308. [PMID: 35978640 PMCID: PMC9377917 DOI: 10.1155/2022/3619308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/05/2022] [Accepted: 07/12/2022] [Indexed: 11/22/2022]
Abstract
The purpose of this study is to investigate the exchange reaction taking place among the bovine serum albumin (BSA), 5,5'-dithiobis-(2-nitrobenzoic acid (ESSE), reduced glutathione, N-acetylcysteine, D-penicillamine (thiolates), and silver metal (AgI). For this purpose, stock solutions of BSA and Ellman's reagent were prepared by dissolving 264 mg of BSA in 5 ml of reaction buffer (0.1 M KH2PO4 at pH 7.8) and 23.8 mg of ESSE in 1.0 ml of reaction buffer which were mixed together. Mixture of BSA-AgI was prepared in a separate procedure by dissolving 0.17 mg of silver nitrate in 1 ml of reaction buffer and then dissolving BSA (200 mg) in the same solution of silver nitrate. Blocking of Cys-34 of BSA with AgI was confirmed by treating different dilutions of BSA-AgI (500 μM) solutions with the solutions of ESSE (85 μM) and ES- (85 μM) and recording the spectra (300-450) with a UV-visible spectrophotometer. The chromatographed AgI-modified BSA ((BSA-S)AgI)) samples (typically 500 μM) were subsequently mixed with thiolates (reduced glutathione, N-acetylcysteine, and D-penicillamine). AgI and modified BSA (typically 500 μM each) were treated with these low molecular weight thiolates and allowed to react overnight followed by chromatographic separation (Sephadex G25). The redox reactions of AgI-modified BSA with various low molecular weight thiols revealed a mechanically important phenomenon. In the case of reduced glutathione and N-acetylcysteine, we observed the rapid release of a commensurate amount of Ellman's anion, indicating that an exchange has taken place and low molecular weight thiols (RSH) substituted AgI species at the Cys-34 of BSA eventually forming disulfide (BSA-SSR) at Cys-34. It can be anticipated from the phase of study involving bovine serum albumin that low molecular weight thiolates (reduced glutathione and N-acetylcysteine) take off AgI which are attached to proteins elsewhere in the physiological system, making these toxic metals free for toxic action.
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Affiliation(s)
- Nahed S. Alharthi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Haroon Khan
- Gomal Centre of Pharmaceutical Sciences Faculty of Pharmacy Gomal University D.I. Khan, 29111, Pakistan
| | - Fahad Jibran Siyal
- Department of Pharmacology, Chandka Medical College, SMBB Medical University Larkana, 77150, Pakistan
| | - Zahid Ali Shaikh
- Department of Medicine, Chandka Medical College, SMBB Medical University Larkana, 77150, Pakistan
| | | | - Lienda Bashier Eltayeb
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Altaf Ali Mangi
- Gomal Centre of Pharmaceutical Sciences Faculty of Pharmacy Gomal University D.I. Khan, 29111, Pakistan
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17
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Effect of solvents and glutathione on the decomposition of the nitrosyl iron complex with N-ethylthiourea ligands: An experimental and theoretical study. J Inorg Biochem 2022; 235:111926. [PMID: 35843200 DOI: 10.1016/j.jinorgbio.2022.111926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 06/24/2022] [Accepted: 07/04/2022] [Indexed: 11/22/2022]
Abstract
Dinitrosyl iron complexes (DNICs) are a depot and potential source of free NO in organisms. Their synthetic analog, N-ethylthiourea DNIC [Fe(SC(NH2)(NHC2H5))2(NO)2]+Cl-∙[Fe(SC(NH2)(NHC2H5))Cl(NO)2]0 (complex 1), as cardioprotective and cytostatic agent is a promising prodrug for the treatment of socially relevant diseases. In this work, transformation mechanism of complex 1 has been studied in anaerobic aqueous solution (pH = 7.0), DMSO, and ethanol. It was shown that the solvent has a significant effect on the decomposition of complex. According to EPR-spectroscopy, only cationic part of complex is found upon its dissolution in water; only neutral part is retained in DMSO, and both fragments are present in ethanol. Effective generation of NO occurs in an aqueous solution. The structures of the decomposition products were proposed for all solvents, their UV-spectra and rate constants were calculated. From the experimental and theoretical data obtained, it follows that complex 1 is most stable in DMSO. Solutions of complex in a DMSO-water mixture can be used to improve its bioavailability in further in vitro and in vivo studies. Also, we have analyzed its interaction with glutathione (GSH), which can participate in the metabolism of this compound. This study shows that complex 1 reacts with GSH to form a new binuclear DNIC with two GS--ligands. It was found that the resulting complex is a more prolonged NO-donor than the initial one: k = 6.1∙10-3·s-1 in buffer, k = 6.4∙10-5 s-1 with GSH. This reaction may prevent S-glutathionylation of the essential enzyme systems and is important for metabolism of complex, associated with its antitumor activity.
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18
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Mooli RGR, Mukhi D, Ramakrishnan SK. Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases. Compr Physiol 2022; 12:3167-3192. [PMID: 35578969 PMCID: PMC10074426 DOI: 10.1002/cphy.c200021] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a "multiple parallel-hit model" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.
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Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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19
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Effects of cadmium on oxidative stress and cell apoptosis in Drosophila melanogaster larvae. Sci Rep 2022; 12:4762. [PMID: 35307728 PMCID: PMC8934349 DOI: 10.1038/s41598-022-08758-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 03/11/2022] [Indexed: 12/22/2022] Open
Abstract
AbstractWith the increase of human activities, cadmium (Cd) pollution has become a global environmental problem affecting biological metabolism in ecosystem. Cd has a very long half-life in humans and is excreted slowly in organs, which poses a serious threat to human health. In order to better understand the toxicity effects of cadmium, third instar larvae of Drosophila melanogaster (Canton-S strain) were exposed to different concentrations (1.125 mg/kg, 2.25 mg/kg, 4.5 mg/kg, and 9 mg/kg) of cadmium. Trypan blue staining showed that intestinal cell damage of Drosophila larvae increased and the comet assay indicated significantly more DNA damage in larvae exposed to high Cd concentrations. The nitroblue tetrazolium (NBT) experiments proved that content of reactive oxygen species (ROS) increased, which indicated Cd exposure could induce oxidative stress. In addition, the expression of mitochondrial adenine nucleotide transferase coding gene (sesB and Ant2) and apoptosis related genes (Debcl, hid, rpr, p53, Sce and Diap1) changed, which may lead to increased apoptosis. These findings confirmed the toxicity effects on oxidative stress and cell apoptosis in Drosophila larvae after early cadmium exposure, providing insights into understanding the effects of heavy metal stress in animal development.
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20
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Antidiabetes, Antimicrobial and Antioxidant studies of mixed β-diketone and diimine Copper(II) complexes. Polyhedron 2022. [DOI: 10.1016/j.poly.2022.115738] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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21
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Li M, Kim C. Chloroplast ROS and stress signaling. PLANT COMMUNICATIONS 2022; 3:100264. [PMID: 35059631 PMCID: PMC8760138 DOI: 10.1016/j.xplc.2021.100264] [Citation(s) in RCA: 119] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 10/25/2021] [Accepted: 11/05/2021] [Indexed: 05/23/2023]
Abstract
Chloroplasts overproduce reactive oxygen species (ROS) under unfavorable environmental conditions, and these ROS are implicated in both signaling and oxidative damage. There is mounting evidence for their roles in translating environmental fluctuations into distinct physiological responses, but their targets, signaling cascades, and mutualism and antagonism with other stress signaling cascades and within ROS signaling remain poorly understood. Great efforts made in recent years have shed new light on chloroplast ROS-directed plant stress responses, from ROS perception to plant responses, in conditional mutants of Arabidopsis thaliana or under various stress conditions. Some articles have also reported the mechanisms underlying the complexity of ROS signaling pathways, with an emphasis on spatiotemporal regulation. ROS and oxidative modification of affected target proteins appear to induce retrograde signaling pathways to maintain chloroplast protein quality control and signaling at a whole-cell level using stress hormones. This review focuses on these seemingly interconnected chloroplast-to-nucleus retrograde signaling pathways initiated by ROS and ROS-modified target molecules. We also discuss future directions in chloroplast stress research to pave the way for discovering new signaling molecules and identifying intersectional signaling components that interact in multiple chloroplast signaling pathways.
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22
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Omidkhah N, Ghodsi R. NO-HDAC dual inhibitors. Eur J Med Chem 2021; 227:113934. [PMID: 34700268 DOI: 10.1016/j.ejmech.2021.113934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/08/2021] [Accepted: 10/17/2021] [Indexed: 12/11/2022]
Abstract
HDAC inhibitors and NO donors have both demonstrated independently broad therapeutic potential in a variety of diseases. Borretto et al. presented the topic of NO-HDAC dual inhibitors for the first time in 2013 as an attractive new topic. Here we collected the general structure of all synthesized NO-HDAC dual inhibitors, lead compounds, synthesis methods and biological features of the most potent dual NO-HDAC inhibitor in each category with the intention of assisting in the synthesis and optimization of new drug-like compounds for diverse diseases. Based on studies done so far, NO-HDAC dual inhibitors have displayed satisfactory results against wound healing (3), heart hypertrophy (3), inflammatory, cardiovascular, neuromuscular illnesses (11a-11e) and cancer (6a-6o, 9a-9d, 10a-10d, 16 and 17). NO-HDAC dual inhibitors can have high therapeutic potential for various diseases due to their new properties, NO properties, HDAC inhibitor properties and also due to the effects of NO on HDAC enzymes.
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Affiliation(s)
- Negar Omidkhah
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Razieh Ghodsi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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23
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Sekmen Cetinel AH, Yalcinkaya T, Akyol TY, Gokce A, Turkan I. Pretreatment of seeds with hydrogen peroxide improves deep-sowing tolerance of wheat seedlings. PLANT PHYSIOLOGY AND BIOCHEMISTRY : PPB 2021; 167:321-336. [PMID: 34392045 DOI: 10.1016/j.plaphy.2021.08.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/08/2021] [Accepted: 08/09/2021] [Indexed: 06/13/2023]
Abstract
Drought is a prevalent natural factor limiting crop production in arid regions across the world. To overcome this limitation, seeds are sown much deeper to boost germination by soil moisture produced by underground water. Seed pretreatment can effectively induce deep-sowing tolerance in plants. In the present study, we evaluated whether H2O2 pretreatment of seeds can initiate metabolic changes and lead to improved deep-sowing tolerance in wheat. Pretreatment with 0.05 μM H2O2 promoted first internode elongation by 13% in the deep-sowing tolerant wheat cultivar "Tir" and by 32% in the sensitive cultivar "Kıraç-66" under deep-sowing conditions, whereas internode elongation was inhibited by diphenyleneiodonium chloride. In contrast to Tir seedlings, H2O2 levels in the first internode of Kıraç-66 seedlings increased under deep-sowing condition in the H2O2-treated group compared to controls. Moreover, these seedlings had significantly lower catalase (CAT), peroxidase (POX), and ascorbate peroxidase (APX) activities but higher NADPH oxidase (NOX) and superoxide dismutase (SOD) activities under the same conditions, which consequently induced greater H2O2 accumulation. Contrary to Tir, both total glutathione and glutathione S-transferase (GST) activity decreased in Kıraç-66 after deep-sowing at 10 cm. However, H2O2 treatment increased the total glutathione amounts and the activities of glutathione-related enzymes (except GST and GPX) in the first internode of Kıraç-66. Taken together, these data support that H2O2 acts as a signaling molecule in the activation of antioxidant enzymes (specifically NOX, SOD, and CAT), regulation of both glutathione-related enzymes and total glutathione content, and upregulation of the cell wall-loosening protein gene TaEXPB23.
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Affiliation(s)
| | - Tolga Yalcinkaya
- Department of Biology, Faculty of Science, Ege University, Bornova, 35100, Izmir, Turkey.
| | - Turgut Yigit Akyol
- Department of Molecular Biology and Genetics, Aarhus University, 8000, Aarhus, Denmark.
| | - Azime Gokce
- Department of Biology, Faculty of Science, Ege University, Bornova, 35100, Izmir, Turkey.
| | - Ismail Turkan
- Department of Biology, Faculty of Science, Ege University, Bornova, 35100, Izmir, Turkey.
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Foglietta F, Pinnelli V, Giuntini F, Barbero N, Panzanelli P, Durando G, Terreno E, Serpe L, Canaparo R. Sonodynamic Treatment Induces Selective Killing of Cancer Cells in an In Vitro Co-Culture Model. Cancers (Basel) 2021; 13:cancers13153852. [PMID: 34359753 PMCID: PMC8345649 DOI: 10.3390/cancers13153852] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/24/2021] [Accepted: 07/26/2021] [Indexed: 11/16/2022] Open
Abstract
Sonodynamic Therapy (SDT) is a new anticancer strategy based on ultrasound (US) technique and is derived from photodynamic therapy (PDT); SDT is still, however, far from clinical application. In order to move this therapy forward from bench to bedside, investigations have been focused on treatment selectivity between cancer cells and normal cells. As a result, the effects of the porphyrin activation by SDT on cancer (HT-29) and normal (HDF 106-05) cells were studied in a co-culture evaluating cell cytotoxicity, reactive oxygen species (ROS) production, mitochondrial function and plasma membrane fluidity according to the bilayer sonophore (BLS) theory. While PDT induced similar effects on both HT-29 and HDF 106-05 cells in co-culture, SDT elicited significant cytotoxicity, ROS production and mitochondrial impairment on HT-29 cells only, whereas HDF 106-05 cells were unaffected. Notably, HT-29 and HDF 106-05 showed different cell membrane fluidity during US exposure. In conclusion, our data demonstrate a marked difference between cancer cells and normal cells in co-culture in term of responsiveness to SDT, suggesting that this different behavior can be ascribed to diversity in plasma membrane properties, such as membrane fluidity, according to the BLS theory.
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Affiliation(s)
- Federica Foglietta
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy; (F.F.); (V.P.); (R.C.)
| | - Vanessa Pinnelli
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy; (F.F.); (V.P.); (R.C.)
| | - Francesca Giuntini
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK;
| | - Nadia Barbero
- Department of Chemistry, NIS Interdepartmental Centre and INSTM Reference Centre, University of Torino, 10125 Torino, Italy;
| | - Patrizia Panzanelli
- Department of Neuroscience Rita Levi Montalcini, University of Torino, 10125 Torino, Italy;
| | - Gianni Durando
- National Institute of Metrological Research (INRIM), 10135 Torino, Italy;
| | - Enzo Terreno
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy;
| | - Loredana Serpe
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy; (F.F.); (V.P.); (R.C.)
- Correspondence: ; Tel.: +39-0116706235
| | - Roberto Canaparo
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy; (F.F.); (V.P.); (R.C.)
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Abd-Elkareem M, Abd El-Rahman MAM, Khalil NSA, Amer AS. Antioxidant and cytoprotective effects of Nigella sativa L. seeds on the testis of monosodium glutamate challenged rats. Sci Rep 2021; 11:13519. [PMID: 34188150 PMCID: PMC8242002 DOI: 10.1038/s41598-021-92977-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 06/14/2021] [Indexed: 02/06/2023] Open
Abstract
Monosodium glutamate (MSG) is one of the most widely spread food additives that might cause male infertility. However, Nigella sativa L. seeds (NSS) could provide a solution. This study was designed to investigate the potential effects of NSS on rats ingesting MSG. To achieve this aim, adult male albino rats were randomly equally assigned into three groups for 21 days: control group received no treatment, MSG group received MSG as 30 g/kg feed, and MSG + NSS group received MSG as 30 g/kg and NSS as 30 g/kg feed. Testis histomorphometry showed marked deterioration by MSG as atrophic seminiferous tubules with degeneration of their lining cells, damaged Leydig cells and decreased germ cells number. Periodic Acid Schiff stain indicated irregular interrupted basement membranes. Glutathione reductase, superoxide dismutase 2 (SOD2), and caspase-3 immuno-expressions increased in testicular cells. Testosterone levels were significantly decreased in MSG challenged rats along with significant increase in luteinizing hormone levels, whereas NSS normalized this hormonal profile. MSG exposure also caused significantly increased lipid peroxides (LPO), glutathione-S-transferase, and total antioxidant capacity (TAC) whereas nitric oxide and SOD2 were significantly decreased. NSS succeeded in rebalance LPO and TAC and ameliorated the histoarchitectural disturbances. NSS mitigated MSG-induced testicular impairment by its antioxidant and cytoprotective activities.
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Affiliation(s)
- Mahmoud Abd-Elkareem
- grid.252487.e0000 0000 8632 679XDepartment of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
| | - Mokhless A. M. Abd El-Rahman
- grid.252487.e0000 0000 8632 679XDepartment of Food Science and Technology, Faculty of Agriculture, Assiut University, Assiut, Egypt
| | - Nasser S. Abou Khalil
- grid.252487.e0000 0000 8632 679XDepartment of Medical Physiology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ayman S. Amer
- grid.252487.e0000 0000 8632 679XDepartment of Human Anatomy and Embryology, Faculty of Medicine, Assiut University, Assiut, Egypt
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PEP-1-GLRX1 Reduces Dopaminergic Neuronal Cell Loss by Modulating MAPK and Apoptosis Signaling in Parkinson's Disease. Molecules 2021; 26:molecules26113329. [PMID: 34206041 PMCID: PMC8198499 DOI: 10.3390/molecules26113329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 11/22/2022] Open
Abstract
Parkinson’s disease (PD) is characterized mainly by the loss of dopaminergic neurons in the substantia nigra (SN) mediated via oxidative stress. Although glutaredoxin-1 (GLRX1) is known as one of the antioxidants involved in cell survival, the effects of GLRX1 on PD are still unclear. In this study, we investigated whether cell-permeable PEP-1-GLRX1 inhibits dopaminergic neuronal cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We showed that PEP-1-GLRX1 protects cell death and DNA damage in MPP+-exposed SH-SY5Y cells via the inhibition of MAPK, Akt, and NF-κB activation and the regulation of apoptosis-related protein expression. Furthermore, we found that PEP-1-GLRX1 was delivered to the SN via the blood–brain barrier (BBB) and reduced the loss of dopaminergic neurons in the MPTP-induced PD model. These results indicate that PEP-1-GLRX1 markedly inhibited the loss of dopaminergic neurons in MPP+- and MPTP-induced cytotoxicity, suggesting that this fusion protein may represent a novel therapeutic agent against PD.
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Abstract
Glutathione (GSH) is the most abundant non-protein thiol, and plays crucial roles in the antioxidant defense system and the maintenance of redox homeostasis in neurons. GSH depletion in the brain is a common finding in patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and can cause neurodegeneration prior to disease onset. Excitatory amino acid carrier 1 (EAAC1), a sodium-dependent glutamate/cysteine transporter that is selectively present in neurons, plays a central role in the regulation of neuronal GSH production. The expression of EAAC1 is posttranslationally controlled by the glutamate transporter-associated protein 3–18 (GTRAP3-18) or miR-96-5p in neurons. The regulatory mechanism of neuronal GSH production mediated by EAAC1 may be a new target in therapeutic strategies for these neurodegenerative diseases. This review describes the regulatory mechanism of neuronal GSH production and its potential therapeutic application in the treatment of neurodegenerative diseases.
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Bago Á, Íñiguez MA, Serrador JM. Nitric Oxide and Electrophilic Cyclopentenone Prostaglandins in Redox signaling, Regulation of Cytoskeleton Dynamics and Intercellular Communication. Front Cell Dev Biol 2021; 9:673973. [PMID: 34026763 PMCID: PMC8137968 DOI: 10.3389/fcell.2021.673973] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/01/2021] [Indexed: 12/16/2022] Open
Abstract
Nitric oxide (NO) and electrophilic cyclopentenone prostaglandins (CyPG) are local mediators that modulate cellular response to oxidative stress in different pathophysiological processes. In particular, there is increasing evidence about their functional role during inflammation and immune responses. Although the mechanistic details about their relationship and functional interactions are still far from resolved, NO and CyPG share the ability to promote redox-based post-translational modification (PTM) of proteins that play key roles in cellular homeostasis, signal transduction and transcription. NO-induced S-nitrosylation and S-glutathionylation as well as cyclopentenone-mediated adduct formation, are a few of the main PTMs by which intra- and inter-cellular signaling are regulated. There is a growing body of evidence indicating that actin and actin-binding proteins are susceptible to covalent PTM by these agents. It is well known that the actin cytoskeleton is key for the establishment of interactions among leukocytes, endothelial and muscle cells, enabling cellular activation and migration. In this review we analyze the current knowledge about the actions exerted by NO and CyPG electrophilic lipids on the regulation of actin dynamics and cytoskeleton organization, and discuss some open questions regarding their functional relevance in the regulation of intercellular communication.
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Affiliation(s)
- Ángel Bago
- Interactions with the Environment Program, Immune System Development and Function Unit, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain
| | - Miguel A Íñiguez
- Interactions with the Environment Program, Immune System Development and Function Unit, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain.,Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain
| | - Juan M Serrador
- Interactions with the Environment Program, Immune System Development and Function Unit, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain
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Kumar A, Kumar V, Dubey AK, Ansari MA, Narayan S, Kumar S, Pandey V, Pande V, Sanyal I. Chickpea glutaredoxin ( CaGrx) gene mitigates drought and salinity stress by modulating the physiological performance and antioxidant defense mechanisms. PHYSIOLOGY AND MOLECULAR BIOLOGY OF PLANTS : AN INTERNATIONAL JOURNAL OF FUNCTIONAL PLANT BIOLOGY 2021; 27:923-944. [PMID: 34092945 PMCID: PMC8140008 DOI: 10.1007/s12298-021-00999-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 04/01/2021] [Accepted: 04/22/2021] [Indexed: 05/23/2023]
Abstract
UNLABELLED Glutaredoxins (Grxs) are short, cysteine-rich glutathione (GSH)-mediated oxidoreductases. In this study, a chickpea (Cicer arietinum L.) glutaredoxin [LOC101493651 (CaGrx)] gene has been selected based on screening experiments with two contrasting varieties of chickpea, PUSA-362 (drought-tolerant) and ICC-1882 (drought-sensitive) under drought and salinity. The tolerant variety showed higher CaGrx gene expression, as compared to less in the sensitive variety, under both the stresses. The CaGrx gene was then over-expressed in Arabidopsis thaliana and were exposed to drought and salinity. The over-expression of CaGrx elevated the activity of glutaredoxin, which induced antioxidant enzymes (glutathione reductase; GR, glutathione peroxidase; GPX, catalase; CAT, ascorbate peroxidase; APX, glutathione-S-transferase; GST, superoxide dismutase; SOD, monodehydroascorbate reductase; MDHAR, and dehydroascorbate reductase; DHAR), antioxidants (GSH and ascorbate) and stress-responsive amino acids (cysteine and proline). Enhancement in the antioxidant defense system possibly administered tolerance in transgenics against both stresses. CaGrx reduced stress markers (H2O2, TBARS, and electrolyte leakage) and enhanced root growth, seed germination, and survival against both stresses. The physiological parameters (net photosynthesis; P N, water use efficiency; WUE, stomatal conductance; g s, transpiration; E, electron transport rate; ETR, and photochemical quenching; qP), chlorophylls and carotenoids, were improved in the transgenics during both stresses, that maintained the photosynthetic apparatus and protected the plants from damage. The enhanced activity of the cysteine biosynthesis enzyme, o-acetylserine (thiol) lyase (OAS-TL), increased the cysteine level in the transgenics, which elevated glutathione biosynthesis to maintain the ascorbate-glutathione cycle under both stresses. This investigation verified that the CaGrx gene provides tolerance against salinity and drought, maintaining physiological and morphological performances, and could be exploited for genetic engineering approaches to overcome both the stresses in various crops. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s12298-021-00999-z.
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Affiliation(s)
- Anil Kumar
- Plant Transgenic Laboratory, Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute, Lucknow, India
- Department of Biotechnology, Bhimtal Campus, Kumaun University, Nainital, India
| | - Varun Kumar
- Plant Transgenic Laboratory, Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Arvind Kumar Dubey
- Plant Transgenic Laboratory, Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute, Lucknow, India
- Department of Biotechnology, Bhimtal Campus, Kumaun University, Nainital, India
| | - Mohd Akram Ansari
- Plant Transgenic Laboratory, Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute, Lucknow, India
- Department of Biotechnology, Bhimtal Campus, Kumaun University, Nainital, India
| | - Shiv Narayan
- Plant Transgenic Laboratory, Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Sanoj Kumar
- Plant Transgenic Laboratory, Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute, Lucknow, India
| | - Vivek Pandey
- Plant Transgenic Laboratory, Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Veena Pande
- Department of Biotechnology, Bhimtal Campus, Kumaun University, Nainital, India
| | - Indraneel Sanyal
- Plant Transgenic Laboratory, Molecular Biology and Biotechnology Division, CSIR-National Botanical Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
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Bacou E, Walk C, Rider S, Litta G, Perez-Calvo E. Dietary Oxidative Distress: A Review of Nutritional Challenges as Models for Poultry, Swine and Fish. Antioxidants (Basel) 2021; 10:525. [PMID: 33801670 PMCID: PMC8066155 DOI: 10.3390/antiox10040525] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 03/19/2021] [Accepted: 03/22/2021] [Indexed: 11/17/2022] Open
Abstract
The redox system is essential for maintaining cellular homeostasis. When redox homeostasis is disrupted through an increase of reactive oxygen species or a decrease of antioxidants, oxidative distress occurs resulting in multiple tissue and systemic responses and damage. Poultry, swine and fish, raised in commercial conditions, are exposed to different stressors that can affect their productivity. Some dietary stressors can generate oxidative distress and alter the health status and subsequent productive performance of commercial farm animals. For several years, researchers used different dietary stressors to describe the multiple and detrimental effects of oxidative distress in animals. Some of these dietary challenge models, including oxidized fats and oils, exposure to excess heavy metals, soybean meal, protein or amino acids, and feeding diets contaminated with mycotoxins are discussed in this review. A better understanding of the oxidative distress mechanisms associated with dietary stressors allows for improved understanding and evaluation of feed additives as mitigators of oxidative distress.
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Affiliation(s)
- Elodie Bacou
- DSM Nutritional Products, Animal Nutrition and Health, F-68128 Village-Neuf, France; (S.R.); (E.P.-C.)
| | - Carrie Walk
- DSM Nutritional Products, Animal Nutrition and Health, Wurmisweg 576, 4303 Kaiseraugst, Switzerland; (C.W.); (G.L.)
| | - Sebastien Rider
- DSM Nutritional Products, Animal Nutrition and Health, F-68128 Village-Neuf, France; (S.R.); (E.P.-C.)
| | - Gilberto Litta
- DSM Nutritional Products, Animal Nutrition and Health, Wurmisweg 576, 4303 Kaiseraugst, Switzerland; (C.W.); (G.L.)
| | - Estefania Perez-Calvo
- DSM Nutritional Products, Animal Nutrition and Health, F-68128 Village-Neuf, France; (S.R.); (E.P.-C.)
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Viedma-Poyatos Á, González-Jiménez P, Langlois O, Company-Marín I, Spickett CM, Pérez-Sala D. Protein Lipoxidation: Basic Concepts and Emerging Roles. Antioxidants (Basel) 2021; 10:295. [PMID: 33669164 PMCID: PMC7919664 DOI: 10.3390/antiox10020295] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 12/13/2022] Open
Abstract
Protein lipoxidation is a non-enzymatic post-translational modification that consists of the covalent addition of reactive lipid species to proteins. This occurs under basal conditions but increases in situations associated with oxidative stress. Protein targets for lipoxidation include metabolic and signalling enzymes, cytoskeletal proteins, and transcription factors, among others. There is strong evidence for the involvement of protein lipoxidation in disease, including atherosclerosis, neurodegeneration, and cancer. Nevertheless, the involvement of lipoxidation in cellular regulatory mechanisms is less understood. Here we review basic aspects of protein lipoxidation and discuss several features that could support its role in cell signalling, including its selectivity, reversibility, and possibilities for regulation at the levels of the generation and/or detoxification of reactive lipids. Moreover, given the great structural variety of electrophilic lipid species, protein lipoxidation can contribute to the generation of multiple structurally and functionally diverse protein species. Finally, the nature of the lipoxidised proteins and residues provides a frameshift for a complex interplay with other post-translational modifications, including redox and redox-regulated modifications, such as oxidative modifications and phosphorylation, thus strengthening the importance of detailed knowledge of this process.
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Affiliation(s)
- Álvaro Viedma-Poyatos
- Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (C.S.I.C.), 28040 Madrid, Spain
| | - Patricia González-Jiménez
- Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (C.S.I.C.), 28040 Madrid, Spain
| | - Ophélie Langlois
- College of Health & Life Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Idoia Company-Marín
- College of Health & Life Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Corinne M Spickett
- College of Health & Life Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Dolores Pérez-Sala
- Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (C.S.I.C.), 28040 Madrid, Spain
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Pezzotti G, Boschetto F, Ohgitani E, Fujita Y, Zhu W, Marin E, McEntire BJ, Bal BS, Mazda O. Silicon nitride: a potent solid-state bioceramic inactivator of ssRNA viruses. Sci Rep 2021; 11:2977. [PMID: 33536558 PMCID: PMC7858580 DOI: 10.1038/s41598-021-82608-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 01/19/2021] [Indexed: 01/30/2023] Open
Abstract
Surface inactivation of human microbial pathogens has a long history. The Smith Papyrus (2600 ~ 2200 B.C.) described the use of copper surfaces to sterilize chest wounds and drinking water. Brass and bronze on doorknobs can discourage microbial spread in hospitals, and metal-base surface coatings are used in hygiene-sensitive environments, both as inactivators and modulators of cellular immunity. A limitation of these approaches is that the reactive oxygen radicals (ROS) generated at metal surfaces also damage human cells by oxidizing their proteins and lipids. Silicon nitride (Si3N4) is a non-oxide ceramic compound with known surface bacterial resistance. We show here that off-stoichiometric reactions at Si3N4 surfaces are also capable of inactivating different types of single-stranded RNA (ssRNA) viruses independent of whether their structure presents an envelop or not. The antiviral property of Si3N4 derives from a hydrolysis reaction at its surface and the subsequent formation of reactive nitrogen species (RNS) in doses that could be metabolized by mammalian cells but are lethal to pathogens. Real-time reverse transcription (RT)-polymerase chain reaction (PCR) tests of viral RNA and in situ Raman spectroscopy suggested that the products of Si3N4 hydrolysis directly react with viral proteins and RNA. Si3N4 may have a role in controlling human epidemics related to ssRNA mutant viruses.
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Affiliation(s)
- Giuseppe Pezzotti
- grid.419025.b0000 0001 0723 4764Ceramic Physics Laboratory, Kyoto Institute of Technology, Sakyo-ku, Matsugasaki, Kyoto, 606–8585 Japan ,grid.410793.80000 0001 0663 3325Department of Orthopedic Surgery, Tokyo Medical University, 6–7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160–0023 Japan ,grid.136593.b0000 0004 0373 3971The Center for Advanced Medical Engineering and Informatics, Osaka University, 2–2 Yamadaoka, Suita, Osaka 565–0854 Japan ,grid.272458.e0000 0001 0667 4960Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, 465 Kajii-cho, Kyoto, 602–8566 Japan ,grid.272458.e0000 0001 0667 4960Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, 602–8566 Japan
| | - Francesco Boschetto
- grid.419025.b0000 0001 0723 4764Ceramic Physics Laboratory, Kyoto Institute of Technology, Sakyo-ku, Matsugasaki, Kyoto, 606–8585 Japan ,grid.272458.e0000 0001 0667 4960Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, 465 Kajii-cho, Kyoto, 602–8566 Japan
| | - Eriko Ohgitani
- grid.272458.e0000 0001 0667 4960Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, 465 Kajii-cho, Kyoto, 602–8566 Japan
| | - Yuki Fujita
- grid.419025.b0000 0001 0723 4764Ceramic Physics Laboratory, Kyoto Institute of Technology, Sakyo-ku, Matsugasaki, Kyoto, 606–8585 Japan
| | - Wenliang Zhu
- grid.419025.b0000 0001 0723 4764Ceramic Physics Laboratory, Kyoto Institute of Technology, Sakyo-ku, Matsugasaki, Kyoto, 606–8585 Japan
| | - Elia Marin
- grid.419025.b0000 0001 0723 4764Ceramic Physics Laboratory, Kyoto Institute of Technology, Sakyo-ku, Matsugasaki, Kyoto, 606–8585 Japan ,grid.272458.e0000 0001 0667 4960Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, 602–8566 Japan
| | - Bryan J. McEntire
- grid.422391.f0000 0004 6010 3714SINTX Technologies Corporation, 1885 West 2100 South, Salt Lake City, UT 84119 USA
| | - B. Sonny Bal
- grid.422391.f0000 0004 6010 3714SINTX Technologies Corporation, 1885 West 2100 South, Salt Lake City, UT 84119 USA
| | - Osam Mazda
- grid.272458.e0000 0001 0667 4960Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, 465 Kajii-cho, Kyoto, 602–8566 Japan
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Mintz J, Vedenko A, Rosete O, Shah K, Goldstein G, Hare JM, Ramasamy R, Arora H. Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics. Vaccines (Basel) 2021; 9:94. [PMID: 33513777 PMCID: PMC7912608 DOI: 10.3390/vaccines9020094] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro- and antitumorigenic effects of NO depend on multiple aspects, including, but not limited to, tissue of generation, the level of production, the oxidative/reductive (redox) environment in which this radical is generated, the presence or absence of NO transduction elements, and the tumor microenvironment. Generally, there are four major categories of NO-based anticancer therapies: NO donors, phosphodiesterase inhibitors (PDE-i), soluble guanylyl cyclase (sGC) activators, and immunomodulators. Of these, NO donors are well studied, well characterized, and also the most promising. In this study, we review the current knowledge in this area, with an emphasis placed on the role of NO as an anticancer therapy and dysregulated molecular interactions during the evolution of cancer, highlighting the strategies that may aid in the targeting of cancer.
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Affiliation(s)
- Joel Mintz
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, FL 33328, USA;
| | - Anastasia Vedenko
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (A.V.); (J.M.H.)
| | - Omar Rosete
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Khushi Shah
- College of Arts and Sciences, University of Miami, Miami, FL 33146, USA;
| | - Gabriella Goldstein
- College of Health Professions and Sciences, University of Central Florida, Orlando, FL 32816, USA;
| | - Joshua M. Hare
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (A.V.); (J.M.H.)
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Medicine, Cardiology Division, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Ranjith Ramasamy
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Himanshu Arora
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (A.V.); (J.M.H.)
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Oskouei Z, Mehri S, Kalalinia F, Hosseinzadeh H. Evaluation of the effect of thymoquinone in d-galactose-induced memory impairments in rats: Role of MAPK, oxidative stress, and neuroinflammation pathways and telomere length. Phytother Res 2020; 35:2252-2266. [PMID: 33325602 DOI: 10.1002/ptr.6982] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 11/08/2020] [Accepted: 12/03/2020] [Indexed: 12/19/2022]
Abstract
D-galactose (d-gal) induces aging and memory impairment via oxidative stress and neuroinflammation pathways. This study evaluated the neuroprotective activity of thymoquinone (TQ) against d-gal. d-gal (400 mg/kg, SC), d-gal plus TQ (2.5, 5, 10 mg/kg, i.p.), and TQ alone (2.5 and 10 mg/kg) for 8 weeks were administered to rats. The effect of TQ on learning and memory were studied using the Morris water maze test. Malondialdehyde (MDA) and glutathione (GSH) levels were determined in the hippocampus. The levels of MAPKs (p-ERK/ERK, p-P38/P38), cAMP response elements binding (p-CREB/CREB), advanced glycation end products (AGEs), inflammatory markers (TNFα, IL-1β), glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF) were analyzed by western blotting. Telomere length was evaluated using real-time PCR. Memory and learning impairment, MDA enhancement, GSH reduction, and neuroinflammation via increasing the TNFα, IL-1β, and GFAP contents were observed in d-gal group. TQ with d-gal, improved memory impairment, reduced oxidative stress, and alleviated neuroinflammation. The elevated level of AGEs decreased by TQ compared to d-gal. No changes were observed in the levels of p-ERK/ERK, p-CREB/CREB, p-P38/P38, BDNF, and telomere length following administration of d-gal or TQ plus d-gal. TQ improved memory deficits of d-gal through anti-oxidative and anti-inflammatory mechanisms.
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Affiliation(s)
- Zahra Oskouei
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soghra Mehri
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Kalalinia
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Khan FH, Dervan E, Bhattacharyya DD, McAuliffe JD, Miranda KM, Glynn SA. The Role of Nitric Oxide in Cancer: Master Regulator or NOt? Int J Mol Sci 2020; 21:ijms21249393. [PMID: 33321789 PMCID: PMC7763974 DOI: 10.3390/ijms21249393] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Nitric oxide (NO) is a key player in both the development and suppression of tumourigenesis depending on the source and concentration of NO. In this review, we discuss the mechanisms by which NO induces DNA damage, influences the DNA damage repair response, and subsequently modulates cell cycle arrest. In some circumstances, NO induces cell cycle arrest and apoptosis protecting against tumourigenesis. NO in other scenarios can cause a delay in cell cycle progression, allowing for aberrant DNA repair that promotes the accumulation of mutations and tumour heterogeneity. Within the tumour microenvironment, low to moderate levels of NO derived from tumour and endothelial cells can activate angiogenesis and epithelial-to-mesenchymal transition, promoting an aggressive phenotype. In contrast, high levels of NO derived from inducible nitric oxide synthase (iNOS) expressing M1 and Th1 polarised macrophages and lymphocytes may exert an anti-tumour effect protecting against cancer. It is important to note that the existing evidence on immunomodulation is mainly based on murine iNOS studies which produce higher fluxes of NO than human iNOS. Finally, we discuss different strategies to target NO related pathways therapeutically. Collectively, we present a picture of NO as a master regulator of cancer development and progression.
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Affiliation(s)
- Faizan H. Khan
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Eoin Dervan
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Dibyangana D. Bhattacharyya
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Jake D. McAuliffe
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Katrina M. Miranda
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA;
| | - Sharon A. Glynn
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
- Correspondence:
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Vo QV, Bay MV, Nam PC, Quang DT, Flavel M, Hoa NT, Mechler A. Theoretical and Experimental Studies of the Antioxidant and Antinitrosant Activity of Syringic Acid. J Org Chem 2020; 85:15514-15520. [PMID: 33150788 DOI: 10.1021/acs.joc.0c02258] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Syringic acid (SA) is a natural phenolic acid found in vegetables, fruits, and other plant-based foods. A range of biological activities were proposed for this compound including anticancer, antimicrobial, anti-inflammation, and anti-diabetic activities, as well as antioxidant and antinitrosant properties. In this study, the focus is on the latter two. The HO•, HOO•, NO, and NO2 scavenging activities of SA were evaluated in physiological environments by kinetic and thermodynamic calculations. The computed rate constants of the HO• radical scavenging of SA were 4.63 × 109 and 9.77 × 107 M-1 s-1 in polar and nonpolar solvents, respectively. A comparison with the experimentally determined rate constant in aqueous solution yields a kcalculated/kexperimental ratio of 0.3, thus the computed kinetic data are reasonably accurate. SA exhibited excellent HOO• and NO2 scavenging activity in water (koverall(HOO•) = 1.53 × 108 M-1 s-1 and koverall(NO2) = 1.98 × 108 M-1 s-1), whereas it did not show NO scavenging activity in any of the studied environments. In lipid medium, SA exhibited weak activity. Thus, in polar environments, the HOO• radical scavenging of SA is 1.53 times higher than that of ascorbic acid. Consistently, SA is a promising antioxidant and antinitrosant agent in polar environments.
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Affiliation(s)
- Quan V Vo
- The University of Danang-University of Technology and Education, Danang 550000, Vietnam
| | - Mai Van Bay
- Department of Chemistry, The University of Danang-University of Science and Education, Danang 550000, Vietnam
| | - Pham Cam Nam
- Department of Chemical Engineering, The University of Danang-University of Science and Technology, Danang 550000, Vietnam
| | - Duong Tuan Quang
- University of Education, Hue University, Hue City 530000, Vietnam
| | - Matthew Flavel
- TPM Bioactives Division, The Product Makers Pty Ltd., Melbourne 3173, Australia.,School of Life Sciences, La Trobe University, Victoria 3086, Australia
| | - Nguyen Thi Hoa
- The University of Danang-University of Technology and Education, Danang 550000, Vietnam
| | - Adam Mechler
- Department of Chemistry and Physics, La Trobe University, Victoria 3086, Australia
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Type III intermediate filaments as targets and effectors of electrophiles and oxidants. Redox Biol 2020; 36:101582. [PMID: 32711378 PMCID: PMC7381704 DOI: 10.1016/j.redox.2020.101582] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 05/05/2020] [Accepted: 05/13/2020] [Indexed: 12/20/2022] Open
Abstract
Intermediate filaments (IFs) play key roles in cell mechanics, signaling and homeostasis. Their assembly and dynamics are finely regulated by posttranslational modifications. The type III IFs, vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP), are targets for diverse modifications by oxidants and electrophiles, for which their conserved cysteine residue emerges as a hot spot. Pathophysiological examples of these modifications include lipoxidation in cell senescence and rheumatoid arthritis, disulfide formation in cataracts and nitrosation in endothelial shear stress, although some oxidative modifications can also be detected under basal conditions. We previously proposed that cysteine residues of vimentin and GFAP act as sensors for oxidative and electrophilic stress, and as hinges influencing filament assembly. Accumulating evidence indicates that the structurally diverse cysteine modifications, either per se or in combination with other posttranslational modifications, elicit specific functional outcomes inducing distinct assemblies or network rearrangements, including filament stabilization, bundling or fragmentation. Cysteine-deficient mutants are protected from these alterations but show compromised cellular performance in network assembly and expansion, organelle positioning and aggresome formation, revealing the importance of this residue. Therefore, the high susceptibility to modification of the conserved cysteine of type III IFs and its cornerstone position in filament architecture sustains their role in redox sensing and integration of cellular responses. This has deep pathophysiological implications and supports the potential of this residue as a drug target.
Type III intermediate filaments can be modified by many oxidants and electrophiles. Oxidative modifications of type III IFs occur in normal and pathological conditions. The conserved cysteine residue acts as a hub for redox/electrophilic modifications. Cysteine modifications elicit structure-dependent type III IF rearrangements. Type III intermediate filaments act as sensors for oxidative and electrophilic stress.
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Liang J, Ziegler JD, Jahraus B, Orlik C, Blatnik R, Blank N, Niesler B, Wabnitz G, Ruppert T, Hübner K, Balta E, Samstag Y. Piperlongumine Acts as an Immunosuppressant by Exerting Prooxidative Effects in Human T Cells Resulting in Diminished T H17 but Enhanced T reg Differentiation. Front Immunol 2020; 11:1172. [PMID: 32595640 PMCID: PMC7303365 DOI: 10.3389/fimmu.2020.01172] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 05/12/2020] [Indexed: 12/29/2022] Open
Abstract
Piperlongumine (PL), a natural small molecule derived from the Piper longum Linn plant, has received growing interest as a prooxidative drug with promising anticancer properties. Yet, the influence of PL on primary human T cells remained elusive. Knowledge of this is of crucial importance, however, since T cells in particular play a critical role in tumor control. Therefore, we investigated the effects of PL on the survival and function of primary human peripheral blood T cells (PBTs). While PL was not cytotoxic to PBTs, it interfered with several stages of T cell activation as it inhibited T cell/APC immune synapse formation, co-stimulation-induced upregulation of CD69 and CD25, T cell proliferation and the secretion of proinflammatory cytokines. PL-induced immune suppression was prevented in the presence of thiol-containing antioxidants. In line with this finding, PL increased the levels of intracellular reactive oxygen species and decreased glutathione in PBTs. Diminished intracellular glutathione was accompanied by a decrease in S-glutathionylation on actin suggesting a global alteration of the antioxidant response. Gene expression analysis demonstrated that TH17-related genes were predominantly inhibited by PL. Consistently, the polarization of primary human naïve CD4+ T cells into TH17 subsets was significantly diminished while differentiation into Treg cells was substantially increased upon PL treatment. This opposed consequence for TH17 and Treg cells was again abolished by thiol-containing antioxidants. Taken together, PL may act as a promising agent for therapeutic immunosuppression by exerting prooxidative effects in human T cells resulting in a diminished TH17 but enhanced Treg cell differentiation.
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Affiliation(s)
- Jie Liang
- Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany
| | - Jacqueline D. Ziegler
- Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany
| | - Beate Jahraus
- Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany
| | - Christian Orlik
- Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany
| | - Renata Blatnik
- Mass Spectrometry Core Facility, Center for Molecular Biology (ZMBH), Heidelberg University, Heidelberg, Germany
| | - Norbert Blank
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University, Heidelberg, Germany
| | - Beate Niesler
- Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany
- nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany
| | - Guido Wabnitz
- Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany
| | - Thomas Ruppert
- Mass Spectrometry Core Facility, Center for Molecular Biology (ZMBH), Heidelberg University, Heidelberg, Germany
| | - Katrin Hübner
- Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany
| | - Emre Balta
- Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany
| | - Yvonne Samstag
- Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany
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Regulatory thiol oxidation in chloroplast metabolism, oxidative stress response and environmental signaling in plants. Biochem J 2020; 477:1865-1878. [DOI: 10.1042/bcj20190124] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 05/04/2020] [Accepted: 05/05/2020] [Indexed: 12/28/2022]
Abstract
The antagonism between thiol oxidation and reduction enables efficient control of protein function and is used as central mechanism in cellular regulation. The best-studied mechanism is the dithiol-disulfide transition in the Calvin Benson Cycle in photosynthesis, including mixed disulfide formation by glutathionylation. The adjustment of the proper thiol redox state is a fundamental property of all cellular compartments. The glutathione redox potential of the cytosol, stroma, matrix and nucleoplasm usually ranges between −300 and −320 mV. Thiol reduction proceeds by short electron transfer cascades consisting of redox input elements and redox transmitters such as thioredoxins. Thiol oxidation ultimately is linked to reactive oxygen species (ROS) and reactive nitrogen species (RNS). Enhanced ROS production under stress shifts the redox network to more positive redox potentials. ROS do not react randomly but primarily with few specific redox sensors in the cell. The most commonly encountered reaction within the redox regulatory network however is the disulfide swapping. The thiol oxidation dynamics also involves transnitrosylation. This review compiles present knowledge on this network and its central role in sensing environmental cues with focus on chloroplast metabolism.
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Chen HJC, Lai PY, Wu DC. Analysis of cysteine glutathionylation in hemoglobin of gastric cancer patients using nanoflow liquid chromatography/triple-stage mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2020; 34 Suppl 1:e8588. [PMID: 31509281 DOI: 10.1002/rcm.8588] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 09/03/2019] [Accepted: 09/03/2019] [Indexed: 06/10/2023]
Abstract
Glutathione is an intracellular antioxidant capable of scavenging free radicals and detoxifying electrophiles from endogenous and exogenous sources via the free thiol group. Post-translational glutathionylation at cysteine residues of proteins can affect the structure and cause a functional change of proteins. Protein glutathionylation has been proven to reflect the cellular redox status. Our previous report indicates that the levels of glutathionylation in hemoglobin from peripheral blood of smokers are significantly higher than in nonsmokers. In this study, a nanoflow liquid chromatography/nanospray ionization triple-stage mass spectrometric (nanoLC/NSI-MS3 ) method with a linear ion trap mass spectrometer was employed to quantify glutathionylated peptides in the trypsin digests of hemoglobin from gastric cancer patients. We compare the extent of glutathionylation in hemoglobin from nonsmoking gastric cancer patients with that from nonsmoking healthy adults. Using a carboxymethylated peptide as the reference peptide, the relative quantification of each glutathionylated peptide was measured as the peak area ratio of the modified peptide versus the sum of the peak areas of the modified and the carboxymethylated parent peptide in the selected reaction monitoring chromatograms. Using this method, we found that the extents of glutathionylation at Cys-104 of the α-globin and Cys-93 of β-globulin hemoglobin from 10 gastric cancer patients were significantly higher than those from 14 normal individuals with p values <0.0001. Our results suggest the possibility of using the extent of cysteine glutathionylation at β-93 of hemoglobin as an oxidative stress biomarker candidate for gastric cancer.
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Affiliation(s)
- Hauh-Jyun Candy Chen
- Department of Chemistry and Biochemistry, National Chung Cheng University, 168 University Road, Ming-Hsiung, Chia-Yi, 62142, Taiwan
| | - Pang-Yen Lai
- Department of Chemistry and Biochemistry, National Chung Cheng University, 168 University Road, Ming-Hsiung, Chia-Yi, 62142, Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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Matsui R, Ferran B, Oh A, Croteau D, Shao D, Han J, Pimentel DR, Bachschmid MM. Redox Regulation via Glutaredoxin-1 and Protein S-Glutathionylation. Antioxid Redox Signal 2020; 32:677-700. [PMID: 31813265 PMCID: PMC7047114 DOI: 10.1089/ars.2019.7963] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Significance: Over the past several years, oxidative post-translational modifications of protein cysteines have been recognized for their critical roles in physiology and pathophysiology. Cells have harnessed thiol modifications involving both oxidative and reductive steps for signaling and protein processing. One of these stages requires oxidation of cysteine to sulfenic acid, followed by two reduction reactions. First, glutathione (reduced glutathione [GSH]) forms a S-glutathionylated protein, and second, enzymatic or chemical reduction removes the modification. Under physiological conditions, these steps confer redox signaling and protect cysteines from irreversible oxidation. However, oxidative stress can overwhelm protein S-glutathionylation and irreversibly modify cysteine residues, disrupting redox signaling. Critical Issues: Glutaredoxins mainly catalyze the removal of protein-bound GSH and help maintain protein thiols in a highly reduced state without exerting direct antioxidant properties. Conversely, glutathione S-transferase (GST), peroxiredoxins, and occasionally glutaredoxins can also catalyze protein S-glutathionylation, thus promoting a dynamic redox environment. Recent Advances: The latest studies of glutaredoxin-1 (Glrx) transgenic or knockout mice demonstrate important distinct roles of Glrx in a variety of pathologies. Endogenous Glrx is essential to maintain normal hepatic lipid homeostasis and prevent fatty liver disease. Further, in vivo deletion of Glrx protects lungs from inflammation and bacterial pneumonia-induced damage, attenuates angiotensin II-induced cardiovascular hypertrophy, and improves ischemic limb vascularization. Meanwhile, exogenous Glrx administration can reverse pathological lung fibrosis. Future Directions: Although S-glutathionylation modifies many proteins, these studies suggest that S-glutathionylation and Glrx regulate specific pathways in vivo, and they implicate Glrx as a potential novel therapeutic target to treat diverse disease conditions. Antioxid. Redox Signal. 32, 677-700.
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Affiliation(s)
- Reiko Matsui
- Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Beatriz Ferran
- Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Albin Oh
- Cardiology, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Dominique Croteau
- Cardiology, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Di Shao
- Helens Clinical Research Center, Chongqing, China
| | - Jingyan Han
- Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - David Richard Pimentel
- Cardiology, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Markus Michael Bachschmid
- Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
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Wolf C, López del Amo V, Arndt S, Bueno D, Tenzer S, Hanschmann EM, Berndt C, Methner A. Redox Modifications of Proteins of the Mitochondrial Fusion and Fission Machinery. Cells 2020; 9:cells9040815. [PMID: 32230997 PMCID: PMC7226787 DOI: 10.3390/cells9040815] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/19/2020] [Accepted: 03/24/2020] [Indexed: 02/07/2023] Open
Abstract
Mitochondrial fusion and fission tailors the mitochondrial shape to changes in cellular homeostasis. Players of this process are the mitofusins, which regulate fusion of the outer mitochondrial membrane, and the fission protein DRP1. Upon specific stimuli, DRP1 translocates to the mitochondria, where it interacts with its receptors FIS1, MFF, and MID49/51. Another fission factor of clinical relevance is GDAP1. Here, we identify and discuss cysteine residues of these proteins that are conserved in phylogenetically distant organisms and which represent potential sites of posttranslational redox modifications. We reveal that worms and flies possess only a single mitofusin, which in vertebrates diverged into MFN1 and MFN2. All mitofusins contain four conserved cysteines in addition to cysteine 684 in MFN2, a site involved in mitochondrial hyperfusion. DRP1 and FIS1 are also evolutionarily conserved but only DRP1 contains four conserved cysteine residues besides cysteine 644, a specific site of nitrosylation. MFF and MID49/51 are only present in the vertebrate lineage. GDAP1 is missing in the nematode genome and contains no conserved cysteine residues. Our analysis suggests that the function of the evolutionarily oldest proteins of the mitochondrial fusion and fission machinery, the mitofusins and DRP1 but not FIS1, might be altered by redox modifications.
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Affiliation(s)
- Christina Wolf
- Institute of Molecular Medicine, University Medical Center of the Johannes-Gutenberg University Mainz, 55131 Mainz, Germany; (C.W.); (D.B.)
| | - Víctor López del Amo
- Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA;
| | - Sabine Arndt
- Institute for Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, 55131 Mainz, Germany; (S.A.); (S.T.)
| | - Diones Bueno
- Institute of Molecular Medicine, University Medical Center of the Johannes-Gutenberg University Mainz, 55131 Mainz, Germany; (C.W.); (D.B.)
| | - Stefan Tenzer
- Institute for Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, 55131 Mainz, Germany; (S.A.); (S.T.)
| | - Eva-Maria Hanschmann
- Department of Neurology, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany; (E.-M.H.); (C.B.)
| | - Carsten Berndt
- Department of Neurology, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany; (E.-M.H.); (C.B.)
| | - Axel Methner
- Institute of Molecular Medicine, University Medical Center of the Johannes-Gutenberg University Mainz, 55131 Mainz, Germany; (C.W.); (D.B.)
- Correspondence:
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Kadam K, Khole VV, Ghosalkar K, Jagtap D, Yarramala DS, Ramachandran B. Thiol based mechanism internalises interacting partners to outer dense fibers in sperm. Free Radic Biol Med 2020; 148:170-181. [PMID: 31923584 DOI: 10.1016/j.freeradbiomed.2019.12.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/04/2019] [Accepted: 12/23/2019] [Indexed: 11/19/2022]
Abstract
The sperm tail outer dense fibres (ODFs) contribute passive structural role in sperm motility. The level of disulphide cross-linking of ODFs and their structural thickness determines flagellar bending curvature and motility. During epididymal maturation, proteins are internalized to modify ODF disulphide cross-linking and enable motility. Sperm thiol status is further altered during capacitation in female tract. This suggests that components in female reproductive tract acting on thiol/disulphides could be capable of modulating the tail stiffness to facilitate modulation of the sperm tail rigidity and waveform en route to fertilization. Understanding the biochemical properties and client proteins of ODFs in reproductive tract fluids will help bridge this gap. Using recombinant ODF2 (aka Testis Specific Antigen of 70 kDa) as bait, we identified client proteins in male and female reproductive fluids. A thiol-based interaction and internalization indicates sperm can harness reproductive tract fluids for proteins that interact with ODFs and likely modulate the tail stiffness en route to fertilization.
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Affiliation(s)
- Kaushiki Kadam
- Department of Gamete Immunobiology, National Institute for Research in Reproductive Health, J.M Street, Parel, Mumbai, 400012, India.
| | - Vrinda V Khole
- Department of Gamete Immunobiology, National Institute for Research in Reproductive Health, J.M Street, Parel, Mumbai, 400012, India
| | - Kanaka Ghosalkar
- Department of Gamete Immunobiology, National Institute for Research in Reproductive Health, J.M Street, Parel, Mumbai, 400012, India
| | - Dhanashree Jagtap
- Structural Biology Department, National Institute for Research in Reproductive Health, J.M Street, Parel, Mumbai, 400012, India
| | - Deepthi S Yarramala
- Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400 076, India
| | - Bini Ramachandran
- Thermo Fisher Scientific India Pvt. Ltd, 403-404, Delphi 'B' Wing, Hiranandani Business Park, Powai, Mumbai, 400076, India
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Dicarbonyl Stress and S-Glutathionylation in Cerebrovascular Diseases: A Focus on Cerebral Cavernous Malformations. Antioxidants (Basel) 2020; 9:antiox9020124. [PMID: 32024152 PMCID: PMC7071005 DOI: 10.3390/antiox9020124] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/25/2020] [Accepted: 01/29/2020] [Indexed: 02/07/2023] Open
Abstract
Dicarbonyl stress is a dysfunctional state consisting in the abnormal accumulation of reactive α-oxaldehydes leading to increased protein modification. In cells, post-translational changes can also occur through S-glutathionylation, a highly conserved oxidative post-translational modification consisting of the formation of a mixed disulfide between glutathione and a protein cysteine residue. This review recapitulates the main findings supporting a role for dicarbonyl stress and S-glutathionylation in the pathogenesis of cerebrovascular diseases, with specific emphasis on cerebral cavernous malformations (CCM), a vascular disease of proven genetic origin that may give rise to various clinical signs and symptoms at any age, including recurrent headaches, seizures, focal neurological deficits, and intracerebral hemorrhage. A possible interplay between dicarbonyl stress and S-glutathionylation in CCM is also discussed.
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Mishra D, Patel V, Banerjee D. Nitric Oxide and S-Nitrosylation in Cancers: Emphasis on Breast Cancer. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2020; 14:1178223419882688. [PMID: 32030066 PMCID: PMC6977095 DOI: 10.1177/1178223419882688] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022]
Abstract
Nitric oxide (NO) is a ubiquitous, endogenously produced, water-soluble signaling molecule playing critical roles in physiological processes. Nitric oxide plays pleiotropic roles in cancer and, depending on its local concentration, may lead to either tumor progression or tumor suppression. Addition of NO group to a cysteine residue within a protein, termed as S-nitrosylation, plays diverse regulatory roles and affects processes such as metabolism, apoptosis, protein phosphorylation, and regulation of transcription factors. The process of S-nitrosylation has been associated with development of different cancers, including breast cancer. The present review discusses different mechanisms through which NO acts, with special emphasis on breast cancers, and provides detailed insights into reactive nitrogen species, posttranslational modifications of proteins mediated by NO, dual nature of NO in cancers, and the implications of S-nitrosylation in cancers. Our review will generate interest in exploring molecular regulation by NO in different cancers and will have significant therapeutic implications in the management and treatment of breast cancer.
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Affiliation(s)
- Deepshikha Mishra
- Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Vaibhav Patel
- Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,School of Graduate Studies, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Debabrata Banerjee
- Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,School of Graduate Studies, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
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Oxidative Modifications in Advanced Atherosclerotic Plaques: A Focus on In Situ Protein Sulfhydryl Group Oxidation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6169825. [PMID: 31998439 PMCID: PMC6973184 DOI: 10.1155/2020/6169825] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/17/2019] [Accepted: 12/26/2019] [Indexed: 12/21/2022]
Abstract
Although oxidative stress has been long associated with the genesis and progression of the atherosclerotic plaque, scanty data on its in situ effects on protein sulfhydryl group modifications are available. Within the arterial wall, protein sulfhydryls and low-molecular-weight (LMW) thiols are involved in the cell regulation of both Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) levels and are a target for several posttranslational oxidative modifications that take place inside the atherosclerotic plaque, probably contributing to both atherogenesis and atherosclerotic plaque progression towards complicated lesions. Advanced carotid plaques are characterized by very high intraplaque GSH levels, due to cell lysis during apoptotic and/or necrotic events, probably responsible for the altered equilibrium among protein sulfhydryls and LMW thiols. Some lines of evidence show that the prooxidant environment present in atherosclerotic tissue could modify filtered proteins also by protein-SH group oxidation, and demonstrate that particularly albumin, once filtered, represents a harmful source of homocysteine and cysteinylglycine inside the plaque. The oxidative modification of protein sulfhydryls, with particular emphasis to protein thiolation by LMW thiols and its association with atherosclerosis, is the main topic of this review.
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The Influence of Light on Reactive Oxygen Species and NF-кB in Disease Progression. Antioxidants (Basel) 2019; 8:antiox8120640. [PMID: 31842333 PMCID: PMC6943569 DOI: 10.3390/antiox8120640] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/29/2019] [Accepted: 12/02/2019] [Indexed: 12/17/2022] Open
Abstract
Reactive oxygen species (ROS) are important secondary metabolites that play major roles in signaling pathways, with their levels often used as analytical tools to investigate various cellular scenarios. They potentially damage genetic material and facilitate tumorigenesis by inhibiting certain tumor suppressors. In diabetic conditions, substantial levels of ROS stimulate oxidative stress through specialized precursors and enzymatic activity, while minimum levels are required for proper wound healing. Photobiomodulation (PBM) uses light to stimulate cellular mechanisms and facilitate the removal of oxidative stress. Photodynamic therapy (PDT) generates ROS to induce selective tumor destruction. The regulatory roles of PBM via crosstalk between ROS and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) are substantial for the appropriate management of various conditions.
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48
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Bilska-Wilkosz A, Kotańska M, Górny M, Filipek B, Iciek M. Can Lipoic Acid Attenuate Cardiovascular Disturbances Induced by Ethanol and Disulfiram Administration Separately or Jointly in Rats? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1974982. [PMID: 31885774 PMCID: PMC6893278 DOI: 10.1155/2019/1974982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 10/24/2019] [Accepted: 11/02/2019] [Indexed: 11/27/2022]
Abstract
The exogenous lipoic acid (LA) is successfully used as a drug in the treatment of many diseases. It is assumed that after administration, LA is transported to the intracellular compartments and reduced to dihydrolipoic acid (DHLA) which is catalyzed by NAD(P)H-dependent enzymes. The purpose of this study was to investigate whether LA can attenuate cardiovascular disturbances induced by ethanol (EtOH) and disulfiram (DSF) administration separately or jointly in rats. For this purpose, we measured systolic and diastolic blood pressure, recorded electrocardiogram (ECG), and estimated mortality of rats. We also studied the activity of aldehyde dehydrogenase (ALDH) in the rat liver. It was shown for the first time that LA partially attenuated the cardiac arrhythmia (extrasystoles and atrioventricular blocks) induced by EtOH and reduced the EtOH-induced mortality of animals, which suggests that LA may have a potential for use in cardiac disturbance in conditions of acute EtOH intoxication. The administration of EtOH, LA, and DSF separately or jointly affected the ALDH activity in the rat liver since a significant decrease in the activity of the enzyme was observed in all treatment groups. The results indicating that LA is an inhibitor of ALDH activity are very surprising.
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Affiliation(s)
- Anna Bilska-Wilkosz
- Chair of Medical Biochemistry, Jagiellonian University, Medical College, 7 Kopernika Street, PL 31-034 Kraków, Poland
| | - Magdalena Kotańska
- Department of Pharmacodynamics, Jagiellonian University, Medical College, 9 Medyczna Street, PL 30-688 Kraków, Poland
| | - Magdalena Górny
- Chair of Medical Biochemistry, Jagiellonian University, Medical College, 7 Kopernika Street, PL 31-034 Kraków, Poland
| | - Barbara Filipek
- Department of Pharmacodynamics, Jagiellonian University, Medical College, 9 Medyczna Street, PL 30-688 Kraków, Poland
| | - Małgorzata Iciek
- Chair of Medical Biochemistry, Jagiellonian University, Medical College, 7 Kopernika Street, PL 31-034 Kraków, Poland
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49
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Pokidova ОV, Emel’yanova NS, Psikha BL, Sanina NA, Kulikov AV, Kotel’nikov AI, Aldoshin SM. Transformation of mononuclear dinitrosyl iron complex (DNIC) with thiourea in glutathione aqueous solution. J Mol Struct 2019. [DOI: 10.1016/j.molstruc.2019.05.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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50
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Rajendran S, Shen X, Glawe J, Kolluru GK, Kevil CG. Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Growth and Remodeling. Compr Physiol 2019; 9:1213-1247. [PMID: 31187898 DOI: 10.1002/cphy.c180026] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ischemic vascular remodeling occurs in response to stenosis or arterial occlusion leading to a change in blood flow and tissue perfusion. Altered blood flow elicits a cascade of molecular and cellular physiological responses leading to vascular remodeling of the macro- and micro-circulation. Although cellular mechanisms of vascular remodeling such as arteriogenesis and angiogenesis have been studied, therapeutic approaches in these areas have had limited success due to the complexity and heterogeneous constellation of molecular signaling events regulating these processes. Understanding central molecular players of vascular remodeling should lead to a deeper understanding of this response and aid in the development of novel therapeutic strategies. Hydrogen sulfide (H2 S) and nitric oxide (NO) are gaseous signaling molecules that are critically involved in regulating fundamental biochemical and molecular responses necessary for vascular growth and remodeling. This review examines how NO and H2 S regulate pathophysiological mechanisms of angiogenesis and arteriogenesis, along with important chemical and experimental considerations revealed thus far. The importance of NO and H2 S bioavailability, their synthesis enzymes and cofactors, and genetic variations associated with cardiovascular risk factors suggest that they serve as pivotal regulators of vascular remodeling responses. © 2019 American Physiological Society. Compr Physiol 9:1213-1247, 2019.
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Affiliation(s)
| | - Xinggui Shen
- Departments of Pathology, LSU Health Sciences Center, Shreveport
| | - John Glawe
- Departments of Pathology, LSU Health Sciences Center, Shreveport
| | - Gopi K Kolluru
- Departments of Pathology, LSU Health Sciences Center, Shreveport
| | - Christopher G Kevil
- Departments of Pathology, LSU Health Sciences Center, Shreveport.,Departments of Cellular Biology and Anatomy, LSU Health Sciences Center, Shreveport.,Departments of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport
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