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1
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Sherwood AM, Yasseen BA, DeBlasi JM, Caldwell S, DeNicola GM. Distinct roles for the thioredoxin and glutathione antioxidant systems in Nrf2-Mediated lung tumor initiation and progression. Redox Biol 2025; 83:103653. [PMID: 40334547 DOI: 10.1016/j.redox.2025.103653] [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: 04/04/2025] [Accepted: 04/29/2025] [Indexed: 05/09/2025] Open
Abstract
Redox regulators are emerging as critical mediators of lung tumorigenesis. NRF2 and its negative regulator KEAP1 are commonly mutated in human lung cancers, leading to NRF2 accumulation and constitutive expression of NRF2 target genes, many of which are at the interface between antioxidant function and anabolic processes that support cellular proliferation. Nrf2 activation promotes lung tumor initiation and early progression in murine models of lung cancer, but which Nrf2 targets mediate these phenotypes is unknown. Nrf2 regulates two parallel antioxidant systems mediated by thioredoxin reductase 1 (TXNRD1) and glutathione reductase (GSR), which promote the reduction of protein antioxidant thioredoxin (TXN) and tripeptide antioxidant glutathione (GSH), respectively. We deleted TXNRD1 and GSR alone, or in combination, in lung tumors harboring mutations in KrasG12D and Nrf2D29H. We found that tumor initiation was promoted by expression of GSR, but not TXNRD1, regardless of Nrf2 status. In contrast, Nrf2D29H tumors, but not Nrf2WT, were dependent on TXNRD1 for tumor progression, while GSR was dispensable. Simultaneous deletion of GSR and TXNRD1 reduced initiation and progression independent of Nrf2 status, but surprisingly did not completely abrogate tumor formation. Thus, the thioredoxin and glutathione antioxidant systems play unique roles in tumor initiation and progression.
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Affiliation(s)
- Amanda M Sherwood
- Department of Metabolism and Physiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Basma A Yasseen
- Department of Metabolism and Physiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Janine M DeBlasi
- Department of Metabolism and Physiology, Moffitt Cancer Center, Tampa, FL, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA
| | - Samantha Caldwell
- Department of Metabolism and Physiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Gina M DeNicola
- Department of Metabolism and Physiology, Moffitt Cancer Center, Tampa, FL, USA.
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Wan S, Liang C, Wu C, Wang S, Wang J, Xu L, Zhang X, Hou Y, Xia Y, Xu L, Huang X. Disulfidptosis in tumor progression. Cell Death Discov 2025; 11:205. [PMID: 40295497 PMCID: PMC12038022 DOI: 10.1038/s41420-025-02495-9] [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: 11/27/2024] [Revised: 04/10/2025] [Accepted: 04/15/2025] [Indexed: 04/30/2025] Open
Abstract
Disulfidptosis, a regulated cell death modality driven by the cystine transporter solute carrier family 7 member 11 (SLC7A11), is characterized by actin cytoskeleton collapse under glucose starvation. This review systematically elucidates the pivotal role of disulfidptosis in tumor metabolic reprogramming, with a focus on its molecular mechanisms and distinctions from other cell death pathways. The core mechanisms include SLC7A11-mediated cystine overload and NRF2/c-Myc-regulated pentose phosphate pathway activation. By integrating multiomics data and single-cell transcriptomics, we comprehensively decipher the heterogeneous expression patterns of disulfidptosis-related genes (DRGs) and their dynamic interplay with immune microenvironment remodeling. Furthermore, the coexpression networks of DRGs and disulfidptosis-related long noncoding RNAs (DRLs) offer novel insights into tumor diagnosis, prognosis, and targeted therapy. Therapeutically, SLC7A11 inhibitors (e.g., HG106) and glucose transporter inhibitors (e.g., BAY-876) demonstrate efficacy by exploiting metabolic vulnerabilities, whereas natural compounds synergizing with immune checkpoint blockade provide strategies to counteract immunosuppressive microenvironments. Through interdisciplinary collaboration and clinical translation, disulfidptosis research holds transformative potential in redefining precision oncology.
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Affiliation(s)
- Senlin Wan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Changming Liang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Chengwei Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Song Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Jiawei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Lishuai Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Xu Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Yinfen Hou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Yabin Xia
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Li Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Xiaoxu Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China.
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China.
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Ghaffari MK, Sefati N, Esmaeilpour T, Salari V, Oblak D, Simon C. The impact of ketamine and thiopental anesthesia on ultraweak photon emission and oxidative-nitrosative stress in rat brains. Front Syst Neurosci 2025; 19:1502589. [PMID: 40191280 PMCID: PMC11968709 DOI: 10.3389/fnsys.2025.1502589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 02/28/2025] [Indexed: 04/09/2025] Open
Abstract
Anesthetics such as ketamine and thiopental, commonly used for inducing unconsciousness, have distinct effects on neuronal activity, metabolism, and cardiovascular and respiratory systems. Ketamine increases heart rate and blood pressure while preserving respiratory function, whereas thiopental decreases both and can cause respiratory depression. This study investigates the impact of ketamine (100 mg/kg) and thiopental (45 mg/kg) on ultraweak photon emission (UPE), oxidative-nitrosative stress, and antioxidant capacity in isolated rat brains. To our knowledge, no previous study has investigated and compared UPE in the presence and absence of anesthesia. Here, we compare the effects of ketamine and thiopental anesthetics with each other and with a non-anesthetized control group. Ketamine increased UPE, lipid peroxidation, and antioxidant enzyme activity while reducing thiol levels. Conversely, thiopental decreased UPE, oxidative markers, and antioxidant enzyme activity, while increasing thiol levels. UPE was negatively correlated with thiol levels and positively correlated with oxidative stress markers. These findings suggest that the contrasting effects of ketamine and thiopental on UPE are linked to their differing impacts on brain oxidative stress and antioxidant capacity. This research suggests a potential method to monitor brain oxidative stress via UPE during anesthesia, and opens up new ways for understanding and managing anesthetic effects.
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Affiliation(s)
- Mahdi Khorsand Ghaffari
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Niloofar Sefati
- Department of Anatomy, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Tahereh Esmaeilpour
- Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahid Salari
- Department of Physics and Astronomy, University of Calgary, Calgary, AB, Canada
- Institute for Quantum Science and Technology, University of Calgary, Calgary, AB, Canada
| | - Daniel Oblak
- Department of Physics and Astronomy, University of Calgary, Calgary, AB, Canada
- Institute for Quantum Science and Technology, University of Calgary, Calgary, AB, Canada
| | - Christoph Simon
- Department of Physics and Astronomy, University of Calgary, Calgary, AB, Canada
- Institute for Quantum Science and Technology, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
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Guo Q, Pan J, Guo X, Zhao M, Du H, Wang M, Deponte M, Zhong X, Xiao L, Feng Y, Xia N. Toxoplasma survives the loss of key enzymes of peroxide and glutathione metabolism. FASEB J 2025; 39:e70416. [PMID: 40059453 DOI: 10.1096/fj.202402341r] [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: 10/01/2024] [Revised: 01/24/2025] [Accepted: 02/14/2025] [Indexed: 05/13/2025]
Abstract
Toxoplasma gondii is an obligate intracellular protozoan parasite that replicates rapidly in a variety of host cells. The parasite encodes diverse enzymes of glutathione and peroxide metabolism, but their physiological roles remain poorly understood. Herein, we shed a new perspective on the functions and relevance of the peroxiredoxin and glutathione metabolism in the zoonotic pathogen T. gondii. We show that two cytosolic peroxidases (TgPRX1, TgPRX2), a mitochondrial peroxiredoxin (TgPRX3), and the cytosolic glutathione reductase (TgGR2), glutamate-cysteine ligase (TgGCL), and glutathione synthetase (TgGS) are not required for the lytic cycle of T. gondii under standard growth conditions. However, mutants lacking the gene for either TgPRX1 or TgGR2 exhibited increased susceptibility to exogenous hydrogen peroxide compared to wild-type parasites. Furthermore, we found that the combined deletion of TgPRX1 and TgPRX2 led to a notable impairment of parasite growth, suggesting a functional redundancy between the two peroxidases. Finally, our results show that the apicoplast glutathione reductase (TgGR1) is required for normal parasite growth in vitro and in vivo but is not essential for parasite survival. Our findings highlight that the redox metabolism of Toxoplasma is surprisingly robust and flexible, allowing the parasite to survive under the loss of several key enzymes of peroxide and glutathione metabolism.
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Affiliation(s)
- Qinghong Guo
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Jiajia Pan
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Xuefang Guo
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Meng Zhao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Huiyu Du
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Mengting Wang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Marcel Deponte
- Faculty of Chemistry, Comparative Biochemistry, RPTU Kaiserslautern, Kaiserslautern, Germany
| | - Xinhua Zhong
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Materials and Energy, South China Agricultural University, Guangzhou, China
| | - Lihua Xiao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yaoyu Feng
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Ningbo Xia
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
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Jia M, Li F, Wu T, Chen N. Exerkines: Potential regulators of ferroptosis. JOURNAL OF SPORT AND HEALTH SCIENCE 2025; 14:101032. [PMID: 39988270 PMCID: PMC12002844 DOI: 10.1016/j.jshs.2025.101032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 11/03/2024] [Accepted: 12/13/2024] [Indexed: 02/25/2025]
Abstract
Ferroptosis is a programmed cell death, and its mechanism involves multiple metabolic pathways, such as iron and lipid metabolism, and redox homeostasis. Exerkines are important mediators that optimize cellular homeostasis and maintain physiological health during exercise stimulation. This article comprehensively examines the mechanisms and regulatory networks for governing ferroptosis and summarizes the impact of exercise and exerkines on ferroptosis under varying load intensities and disease contexts. Notably, despite its significant efficacy and minimal side effects, the therapeutic and prognostic potential of exercise in ferroptosis-related diseases remains largely unexplored. This article, by summarizing recent progresses in the regulation of exerkines-mediated ferroptosis, could further uncover the preventive or alleviative mechanisms of some diseases upon exercise interventions, which will be beneficial to design exercise interventional strategies for alleviating disease progression through the regulation of ferroptosis.
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Affiliation(s)
- Min Jia
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China
| | - Fengxing Li
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China
| | - Tong Wu
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China.
| | - Ning Chen
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China.
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6
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Vašková J, Kováčová G, Pudelský J, Palenčár D, Mičková H. Methylglyoxal Formation-Metabolic Routes and Consequences. Antioxidants (Basel) 2025; 14:212. [PMID: 40002398 PMCID: PMC11852113 DOI: 10.3390/antiox14020212] [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: 12/18/2024] [Revised: 02/04/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Methylglyoxal (MGO), a by-product of glycolysis, plays a significant role in cellular metabolism, particularly under stress conditions. However, MGO is a potent glycotoxin, and its accumulation has been linked to the development of several pathological conditions due to oxidative stress, including diabetes mellitus and neurodegenerative diseases. This paper focuses on the biochemical mechanisms by which MGO contributes to oxidative stress, particularly through the formation of advanced glycation end products (AGEs), its interactions with antioxidant systems, and its involvement in chronic diseases like diabetes, neurodegeneration, and cardiovascular disorders. MGO exerts its effects through multiple signaling pathways, including NF-κB, MAPK, and Nrf2, which induce oxidative stress. Additionally, MGO triggers apoptosis primarily via intrinsic and extrinsic pathways, while endoplasmic reticulum (ER) stress is mediated through PERK-eIF2α and IRE1-JNK signaling. Moreover, the activation of inflammatory pathways, particularly through RAGE and NF-κB, plays a crucial role in the pathogenesis of these conditions. This study points out the connection between oxidative and carbonyl stress due to increased MGO formation, and it should be an incentive to search for a marker that could have prognostic significance or could be a targeted therapeutic intervention in various diseases.
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Affiliation(s)
- Janka Vašková
- Department of Medical Biology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 11 Košice, Slovakia
| | - Gabriela Kováčová
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik, 040 11 Košice, Slovakia; (G.K.)
| | - Jakub Pudelský
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik, 040 11 Košice, Slovakia; (G.K.)
| | - Drahomír Palenčár
- Department of Plastic Surgery, Faculty of Medicine, Comenius University Bratislava, 813 72 Bratislava, Slovakia
| | - Helena Mičková
- Department of Medical Biology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 11 Košice, Slovakia
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Fan S, Wang K, Zhang T, Deng D, Shen J, Zhao B, Fu D, Chen X. Mechanisms and Therapeutic Potential of GPX4 in Pain Modulation. Pain Ther 2025; 14:21-45. [PMID: 39503961 PMCID: PMC11751247 DOI: 10.1007/s40122-024-00673-8] [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: 08/14/2024] [Accepted: 10/04/2024] [Indexed: 01/23/2025] Open
Abstract
Pain, a complex symptom encompassing both sensory and emotional dimensions, constitutes a significant global public health issue. Oxidative stress is a pivotal factor in the complex pathophysiology of pain, with glutathione peroxidase 4 (GPX4) recognized as a crucial antioxidant enzyme involved in both antioxidant defense mechanisms and ferroptosis pathways. This review systematically explores GPX4's functions across various pain models, including neuropathic, inflammatory, low back, and cancer-related pain. Specifically, the focus includes GPX4's physiological roles, antioxidant defense mechanisms, regulation of ferroptosis, involvement in signal transduction pathways, and metabolic regulation. By summarizing current research, we highlight the potential of GPX4-targeted therapies in pain management.
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Affiliation(s)
- Shiwen Fan
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
- Department of Anesthesiology, First Affiliated Hospital of Shihezi University, Shihezi, 832002, China
| | - Kaixin Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Tianhao Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Daling Deng
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Jiwei Shen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Bowen Zhao
- Department of Anesthesiology, First Affiliated Hospital of Shihezi University, Shihezi, 832002, China
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Daan Fu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
| | - Xiangdong Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
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Zimmermann J, Lang L, Calabrese G, Laporte H, Amponsah PS, Michalk C, Sukmann T, Oestreicher J, Tursch A, Peker E, Owusu TNE, Weith M, Roma LP, Deponte M, Riemer J, Morgan B. Tsa1 is the dominant peroxide scavenger and a source of H 2O 2-dependent GSSG production in yeast. Free Radic Biol Med 2025; 226:408-420. [PMID: 39515595 DOI: 10.1016/j.freeradbiomed.2024.11.004] [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: 09/03/2024] [Revised: 10/30/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024]
Abstract
Hydrogen peroxide (H2O2) is an important biological molecule, functioning both as a second messenger in cell signaling and, especially at higher concentrations, as a cause of cell damage. Cells harbor multiple enzymes that have peroxide reducing activity in vitro. However, the contribution of each of these enzymes towards peroxide scavenging in vivo is less clear. Therefore, to directly investigate in vivo peroxide scavenging, we used the genetically encoded peroxide probes, roGFP2-Tsa2ΔCR and HyPer7, to systematically screen the peroxide scavenging capacity of baker's yeast thiol and heme peroxidase mutants. We show that the 2-Cys peroxiredoxin Tsa1 alone is responsible for almost all exogenous H2O2 and tert-butyl hydroperoxide scavenging. Furthermore, Tsa1 can become an important source of H2O2-dependent cytosolic glutathione disulfide production. The two catalases and cytochrome c peroxidase only produce observable scavenging defects at higher H2O2 concentrations when these three heme peroxidases are removed in combination. We also analyzed the reduction of Tsa1 in vitro, revealing that the enzyme is efficiently reduced by thioredoxin-1 with a rate constant of 2.8 × 106 M-1s-1 but not by glutaredoxin-2. Tsa1 reduction by reduced glutathione occurs nonenzymatically with a rate constant of 2.9 M-1s-1. Hence, the observed Tsa1-dependent glutathione disulfide production in yeast probably requires the oxidation of thioredoxins. Our findings clarify the importance of the various thiol and heme peroxidases for peroxide removal and suggest that most thiol peroxidases have alternative or specialized functions in specific subcellular compartments.
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Affiliation(s)
- Jannik Zimmermann
- Institute of Biochemistry, Centre for Human and Molecular Biology (ZHMB), Saarland University, 66123, Saarbrücken, Germany
| | - Lukas Lang
- Faculty of Chemistry, Comparative Biochemistry, RPTU Kaiserslautern, D-67663, Kaiserslautern, Germany
| | - Gaetano Calabrese
- Institute for Biochemistry, Redox Biochemistry, University of Cologne, Zuelpicher Str. 47a/R. 3.49, 50674, Cologne, Germany
| | - Hugo Laporte
- Institute of Biochemistry, Centre for Human and Molecular Biology (ZHMB), Saarland University, 66123, Saarbrücken, Germany
| | - Prince S Amponsah
- Institute of Biochemistry, Centre for Human and Molecular Biology (ZHMB), Saarland University, 66123, Saarbrücken, Germany; Cellular Biochemistry, RPTU Kaiserslautern, 67663, Kaiserslautern, Germany
| | - Christoph Michalk
- Cellular Biochemistry, RPTU Kaiserslautern, 67663, Kaiserslautern, Germany
| | - Tobias Sukmann
- Institute of Biochemistry, Centre for Human and Molecular Biology (ZHMB), Saarland University, 66123, Saarbrücken, Germany
| | - Julian Oestreicher
- Institute of Biochemistry, Centre for Human and Molecular Biology (ZHMB), Saarland University, 66123, Saarbrücken, Germany
| | - Anja Tursch
- Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Esra Peker
- Institute for Biochemistry, Redox Biochemistry, University of Cologne, Zuelpicher Str. 47a/R. 3.49, 50674, Cologne, Germany
| | - Theresa N E Owusu
- Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Matthias Weith
- Institute for Biochemistry, Redox Biochemistry, University of Cologne, Zuelpicher Str. 47a/R. 3.49, 50674, Cologne, Germany
| | - Leticia Prates Roma
- Institute of Biophysics, Centre for Human and Molecular Biology (ZHMB), Saarland University, 66424, Homburg, Germany
| | - Marcel Deponte
- Faculty of Chemistry, Comparative Biochemistry, RPTU Kaiserslautern, D-67663, Kaiserslautern, Germany.
| | - Jan Riemer
- Institute for Biochemistry, Redox Biochemistry, University of Cologne, Zuelpicher Str. 47a/R. 3.49, 50674, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
| | - Bruce Morgan
- Institute of Biochemistry, Centre for Human and Molecular Biology (ZHMB), Saarland University, 66123, Saarbrücken, Germany.
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Madabeni A, Bortoli M, Nogara PA, Ribaudo G, Dalla Tiezza M, Flohé L, Rocha JBT, Orian L. 50 Years of Organoselenium Chemistry, Biochemistry and Reactivity: Mechanistic Understanding, Successful and Controversial Stories. Chemistry 2024; 30:e202403003. [PMID: 39304519 PMCID: PMC11639659 DOI: 10.1002/chem.202403003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 09/22/2024]
Abstract
In 1973, two major discoveries changed the face of selenium chemistry: the identification of the first mammal selenoenzyme, glutathione peroxidase 1, and the discovery of the synthetic utility of the so-called selenoxide elimination. While the chemical mechanism behind the catalytic activity of glutathione peroxidases appears to be mostly unveiled, little is known about the mechanisms of other selenoproteins and, for some of them, even the function lies in the dark. In chemistry, the capacity of organoselenides of catalyzing hydrogen peroxide activation for the practical manipulation of organic functional groups has been largely explored, and some mechanistic details have been clearly elucidated. As a paradox, despite the long-standing experience in the field, the nature of the active oxidant in various reactions still remains matter of debate. While many successes characterize these fields, the pharmacological use of organoselenides still lacks any true application, and while some organoselenides were found to be non-toxic and safe to use, to date no therapeutically approved use was granted. In this review, some fundamental and chronologically aligned topics spanning organoselenium biochemistry, chemistry and pharmacology are discussed, focusing on the current mechanistic picture describing their activity as either bioactive compounds or catalysts.
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Affiliation(s)
- Andrea Madabeni
- Dipartimento di Scienze ChimicheUniversità degli Studi di PadovaVia Marzolo 135131PadovaItaly
| | - Marco Bortoli
- Department of Chemistry and Hylleraas Centre for Quantum Molecular SciencesUniversity of OsloOslo0315Norway
| | - Pablo A. Nogara
- Instituto Federal de Educação, Ciência e Tecnologia Sul-rio-grandense (IFSul)Av. Leonel de Moura Brizola, 250196418-400Bagé, RSBrasil
| | - Giovanni Ribaudo
- Dipartimento di Medicina Molecolare e TraslazionaleUniversità degli Studi di BresciaViale Europa 1125123BresciaItaly
| | - Marco Dalla Tiezza
- Dipartimento di Scienze ChimicheUniversità degli Studi di PadovaVia Marzolo 135131PadovaItaly
| | - Leopold Flohé
- Department of Molecular MedicineUniversity of PadovaItaly
- Departamento de BioquímicaUniversidad de la RepúblicaMontevideoUruguay
| | - João B. T. Rocha
- Departamento de BioquímicaUniversidade Federaldo Rio Grande do Sul (UFRGS)90035-003Porto Alegre, RSBrazil
| | - Laura Orian
- Dipartimento di Scienze ChimicheUniversità degli Studi di PadovaVia Marzolo 135131PadovaItaly
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10
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Hussain S, Gupta G, Shahwan M, Bansal P, Kaur H, Deorari M, Pant K, Ali H, Singh SK, Rama Raju Allam VS, Paudel KR, Dua K, Kumarasamy V, Subramaniyan V. Non-coding RNA: A key regulator in the Glutathione-GPX4 pathway of ferroptosis. Noncoding RNA Res 2024; 9:1222-1234. [PMID: 39036600 PMCID: PMC11259992 DOI: 10.1016/j.ncrna.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/26/2024] [Accepted: 05/19/2024] [Indexed: 07/23/2024] Open
Abstract
Ferroptosis, a form of regulated cell death, has emerged as a crucial process in diverse pathophysiological states, encompassing cancer, neurodegenerative ailments, and ischemia-reperfusion injury. The glutathione (GSH)-dependent lipid peroxidation pathway, chiefly governed by glutathione peroxidase 4 (GPX4), assumes an essential part in driving ferroptosis. GPX4, as the principal orchestrator of ferroptosis, has garnered significant attention across cancer, cardiovascular, and neuroscience domains over the past decade. Noteworthy investigations have elucidated the indispensable functions of ferroptosis in numerous diseases, including tumorigenesis, wherein robust ferroptosis within cells can impede tumor advancement. Recent research has underscored the complex regulatory role of non-coding RNAs (ncRNAs) in regulating the GSH-GPX4 network, thus influencing cellular susceptibility to ferroptosis. This exhaustive review endeavors to probe into the multifaceted processes by which ncRNAs control the GSH-GPX4 network in ferroptosis. Specifically, we delve into the functions of miRNAs, lncRNAs, and circRNAs in regulating GPX4 expression and impacting cellular susceptibility to ferroptosis. Moreover, we discuss the clinical implications of dysregulated interactions between ncRNAs and GPX4 in several conditions, underscoring their capacity as viable targets for therapeutic intervention. Additionally, the review explores emerging strategies aimed at targeting ncRNAs to modulate the GSH-GPX4 pathway and manipulate ferroptosis for therapeutic advantage. A comprehensive understanding of these intricate regulatory networks furnishes insights into innovative therapeutic avenues for diseases associated with perturbed ferroptosis, thereby laying the groundwork for therapeutic interventions targeting ncRNAs in ferroptosis-related pathological conditions.
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Affiliation(s)
- Sadique Hussain
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Gaurav Gupta
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, 346, United Arab Emirates
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
| | - Moyad Shahwan
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, 346, United Arab Emirates
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, 346, United Arab Emirates
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka, 560069, India
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh, 247341, India
- Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand, 831001, India
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Kumud Pant
- Graphic Era (Deemed to be University), Clement Town, Dehradun, 248002, India
- Graphic Era Hill University, Clement Town, Dehradun, 248002, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
- Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, 2007, Australia
- School of Medical and Life Sciences, Sunway University, 47500 Sunway City, Malaysia
| | | | - Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, NSW, 2007, Australia
| | - Kamal Dua
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, 2007, Australia
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, P.O. Box: 123 Broadway, Ultimo, NSW, 2007, Australia
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Vetriselvan Subramaniyan
- Pharmacology Unit, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor Darul Ehsan, Malaysia
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11
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Pawluk H, Tafelska-Kaczmarek A, Sopońska M, Porzych M, Modrzejewska M, Pawluk M, Kurhaluk N, Tkaczenko H, Kołodziejska R. The Influence of Oxidative Stress Markers in Patients with Ischemic Stroke. Biomolecules 2024; 14:1130. [PMID: 39334896 PMCID: PMC11430825 DOI: 10.3390/biom14091130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/27/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Stroke is the second leading cause of death worldwide, and its incidence is rising rapidly. Acute ischemic stroke is a subtype of stroke that accounts for the majority of stroke cases and has a high mortality rate. An effective treatment for stroke is to minimize damage to the brain's neural tissue by restoring blood flow to decreased perfusion areas of the brain. Many reports have concluded that both oxidative stress and excitotoxicity are the main pathological processes associated with ischemic stroke. Current measures to protect the brain against serious damage caused by stroke are insufficient. For this reason, it is important to investigate oxidative and antioxidant strategies to reduce oxidative damage. This review focuses on studies assessing the concentration of oxidative stress biomarkers and the level of antioxidants (enzymatic and non-enzymatic) and their impact on the clinical prognosis of patients after stroke. Mechanisms related to the production of ROS/RNS and the role of oxidative stress in the pathogenesis of ischemic stroke are presented, as well as new therapeutic strategies aimed at reducing the effects of ischemia and reperfusion.
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Affiliation(s)
- Hanna Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Agnieszka Tafelska-Kaczmarek
- Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Torun, Poland
| | - Małgorzata Sopońska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Marta Porzych
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Martyna Modrzejewska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Mateusz Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
| | - Natalia Kurhaluk
- Institute of Biology, Pomeranian University in Slupsk, Arciszewski 22B, 76-200 Slupsk, Poland
| | - Halina Tkaczenko
- Institute of Biology, Pomeranian University in Slupsk, Arciszewski 22B, 76-200 Slupsk, Poland
| | - Renata Kołodziejska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland
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12
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Kalinina E. Glutathione-Dependent Pathways in Cancer Cells. Int J Mol Sci 2024; 25:8423. [PMID: 39125992 PMCID: PMC11312684 DOI: 10.3390/ijms25158423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
The most abundant tripeptide-glutathione (GSH)-and the major GSH-related enzymes-glutathione peroxidases (GPxs) and glutathione S-transferases (GSTs)-are highly significant in the regulation of tumor cell viability, initiation of tumor development, its progression, and drug resistance. The high level of GSH synthesis in different cancer types depends not only on the increasing expression of the key enzymes of the γ-glutamyl cycle but also on the changes in transport velocity of its precursor amino acids. The ability of GPxs to reduce hydroperoxides is used for cellular viability, and each member of the GPx family has a different mechanism of action and site for maintaining redox balance. GSTs not only catalyze the conjugation of GSH to electrophilic substances and the reduction of organic hydroperoxides but also take part in the regulation of cellular signaling pathways. By catalyzing the S-glutathionylation of key target proteins, GSTs are involved in the regulation of major cellular processes, including metabolism (e.g., glycolysis and the PPP), signal transduction, transcription regulation, and the development of resistance to anticancer drugs. In this review, recent findings in GSH synthesis, the roles and functions of GPxs, and GST isoforms in cancer development are discussed, along with the search for GST and GPx inhibitors for cancer treatment.
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Affiliation(s)
- Elena Kalinina
- T.T. Berezov Department of Biochemistry, Peoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
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13
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Feng L, Sun J, Xia L, Shi Q, Hou Y, Zhang L, Li M, Fan C, Sun B. Ferroptosis mechanism and Alzheimer's disease. Neural Regen Res 2024; 19:1741-1750. [PMID: 38103240 PMCID: PMC10960301 DOI: 10.4103/1673-5374.389362] [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: 05/08/2023] [Revised: 07/05/2023] [Accepted: 09/09/2023] [Indexed: 12/18/2023] Open
Abstract
Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms. This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms. Ferroptosis is a classic regulatory mode of cell death. Extensive studies of regulatory cell death in Alzheimer's disease have yielded increasing evidence that ferroptosis is closely related to the occurrence, development, and prognosis of Alzheimer's disease. This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferroptosis in Alzheimer's disease. Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer's disease.
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Affiliation(s)
- Lina Feng
- Shandong Key Laboratory of TCM Multi-Target Intervention and Disease Control, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
| | - Jingyi Sun
- Shandong Key Laboratory of TCM Multi-Target Intervention and Disease Control, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
| | - Ling Xia
- Shandong Key Laboratory of TCM Multi-Target Intervention and Disease Control, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
| | - Qiang Shi
- Shandong Key Laboratory of TCM Multi-Target Intervention and Disease Control, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
| | - Yajun Hou
- Shandong Key Laboratory of TCM Multi-Target Intervention and Disease Control, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
| | - Lili Zhang
- Department of Internal Medicine, Taian Traffic Hospital, Taian, Shandong Province, China
| | - Mingquan Li
- Department of Neurology, the Third Affiliated Clinical Hospital of Changchun University of Chinese Medicine, Changchun, Jilin Province, China
| | - Cundong Fan
- Shandong Key Laboratory of TCM Multi-Target Intervention and Disease Control, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
| | - Baoliang Sun
- Shandong Key Laboratory of TCM Multi-Target Intervention and Disease Control, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
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14
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Caetano Filho FF, Paulino LRF, Bezerra VS, Azevedo VAN, Barroso PAA, Costa FC, Amorim GG, Silva JRV. Thymol increases primordial follicle activation, protects stromal cells, collagen fibers and down-regulates expression of mRNA for superoxide dismutase 1, catalase and periredoxin 6 in cultured bovine ovarian tissues. Anim Reprod Sci 2024; 266:107514. [PMID: 38824841 DOI: 10.1016/j.anireprosci.2024.107514] [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: 02/28/2024] [Revised: 05/14/2024] [Accepted: 05/25/2024] [Indexed: 06/04/2024]
Abstract
This study aims to investigate the influence of thymol on primordial follicle growth and survival, as well as on collagen fibers and stromal cells density in bovine ovarian tissues cultured in vitro. The activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), the thiol levels and the expression of mRNAs for SOD1, CAT, periredoxin 6 (PRDX6) and GPX1 were also investigated. Ovarian cortical tissues were cultured in α-MEM+ alone or with thymol (400, 800, 1600 or 3200 μg/mL) for six days. Before and after culture, the tissues were processed for histological analysis to evaluate follicular activation, growth, morphology, ovarian stromal cell density and collagen fibers. The levels of mRNA for SOD1, CAT, GPX1 and PRDX6 were evaluated by real-time PCR. The results show that tissues cultured with thymol (400 and 800 µg/mL) had increased percentages of normal follicles, when compared to tissues cultured in other treatments. At concentrations of 400 and 800 µg/mL, thymol maintained the rate of normal follicles similar to the uncultured control. In addition, 400 µg/mL thymol increased follicle activation, collagen fibers and stromal cell density of when compared to tissues cultured in control medium. The presence of 800 µg/mL thymol in culture medium increased CAT activity, while 400 or 800 µg/mL thymol reduced mRNA levels for SOD1, CAT and PRDX6, but did not alter GPX1 expression. In conclusion, 400 µg/mL thymol increases primordial follicle activation, preserves stromal cells, collagen fibers, and down-regulates expression of mRNA for SOD1, CAT and PRDX6 in cultured bovine ovarian tissues.
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Affiliation(s)
- Francisco F Caetano Filho
- Laboratory of Biotechnology and Physiology of Reproduction (LABIREP), Federal University of Ceará, Sobral, CE, Brazil
| | - Lais R F Paulino
- Laboratory of Biotechnology and Physiology of Reproduction (LABIREP), Federal University of Ceará, Sobral, CE, Brazil
| | - Vitória S Bezerra
- Laboratory of Biotechnology and Physiology of Reproduction (LABIREP), Federal University of Ceará, Sobral, CE, Brazil
| | - Venância A N Azevedo
- Laboratory of Biotechnology and Physiology of Reproduction (LABIREP), Federal University of Ceará, Sobral, CE, Brazil
| | - Pedro A A Barroso
- Laboratory of Biotechnology and Physiology of Reproduction (LABIREP), Federal University of Ceará, Sobral, CE, Brazil
| | - Francisco C Costa
- Laboratory of Biotechnology and Physiology of Reproduction (LABIREP), Federal University of Ceará, Sobral, CE, Brazil
| | - Geovany G Amorim
- Nucleus of Studies in Bioactive Phytochemicals (NEFB), Vale do Acaraú State University, Sobral, Ceará, Brazil
| | - José R V Silva
- Laboratory of Biotechnology and Physiology of Reproduction (LABIREP), Federal University of Ceará, Sobral, CE, Brazil.
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15
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Masanta S, Wiesyk A, Panja C, Pilch S, Ciesla J, Sipko M, De A, Enkhbaatar T, Maslanka R, Skoneczna A, Kucharczyk R. Fmp40 ampylase regulates cell survival upon oxidative stress by controlling Prx1 and Trx3 oxidation. Redox Biol 2024; 73:103201. [PMID: 38795545 PMCID: PMC11140801 DOI: 10.1016/j.redox.2024.103201] [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: 04/21/2024] [Revised: 05/16/2024] [Accepted: 05/19/2024] [Indexed: 05/28/2024] Open
Abstract
Reactive oxygen species (ROS), play important roles in cellular signaling, nonetheless are toxic at higher concentrations. Cells have many interconnected, overlapped or backup systems to neutralize ROS, but their regulatory mechanisms remain poorly understood. Here, we reveal an essential role for mitochondrial AMPylase Fmp40 from budding yeast in regulating the redox states of the mitochondrial 1-Cys peroxiredoxin Prx1, which is the only protein shown to neutralize H2O2 with the oxidation of the mitochondrial glutathione and the thioredoxin Trx3, directly involved in the reduction of Prx1. Deletion of FMP40 impacts a cellular response to H2O2 treatment that leads to programmed cell death (PCD) induction and an adaptive response involving up or down regulation of genes encoding, among others the catalase Cta1, PCD inducing factor Aif1, and mitochondrial redoxins Trx3 and Grx2. This ultimately perturbs the reduced glutathione and NADPH cellular pools. We further demonstrated that Fmp40 AMPylates Prx1, Trx3, and Grx2 in vitro and interacts with Trx3 in vivo. AMPylation of the threonine residue 66 in Trx3 is essential for this protein's proper endogenous level and its precursor forms' maturation under oxidative stress conditions. Additionally, we showed the Grx2 involvement in the reduction of Trx3 in vivo. Taken together, Fmp40, through control of the reduction of mitochondrial redoxins, regulates the hydrogen peroxide, GSH and NADPH signaling influencing the yeast cell survival.
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Affiliation(s)
- Suchismita Masanta
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland
| | - Aneta Wiesyk
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland
| | - Chiranjit Panja
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland
| | - Sylwia Pilch
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland
| | - Jaroslaw Ciesla
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland
| | - Marta Sipko
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland
| | - Abhipsita De
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland
| | - Tuguldur Enkhbaatar
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland
| | - Roman Maslanka
- Institute of Biology, College of Natural Sciences, University of Rzeszow, Rzeszow, Poland
| | - Adrianna Skoneczna
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland
| | - Roza Kucharczyk
- Institute of Biochemistry and Biophysics PAS, Warsaw, 02-106, Pawinskiego 5A, Poland.
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16
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Xu Z, Chen L, Luo Y, Wei YM, Wu NY, Luo LF, Wei YB, Huang J. Advances in metal-organic framework-based nanozymes in ROS scavenging medicine. NANOTECHNOLOGY 2024; 35:362006. [PMID: 38865988 DOI: 10.1088/1361-6528/ad572a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/12/2024] [Indexed: 06/14/2024]
Abstract
Reactive oxygen species (ROS) play important roles in regulating various physiological functions in the human body, however, excessive ROS can cause serious damage to the human body, considering the various limitations of natural enzymes as scavengers of ROS in the body, the development of better materials for the scavenging of ROS is of great significance to the biomedical field, and nanozymes, as a kind of nanomaterials which can show the activity of natural enzymes. Have a good potential for the development in the area of ROS scavenging. Metal-organic frameworks (MOFs), which are porous crystalline materials with a periodic network structure composed of metal nodes and organic ligands, have been developed with a variety of active nanozymes including catalase-like, superoxide dismutase-like, and glutathione peroxidase-like enzymes due to the adjustability of active sites, structural diversity, excellent biocompatibility, and they have shown a wide range of applications and prospects. In the present review, we first introduce three representative natural enzymes for ROS scavenging in the human body, methods for the detection of relevant enzyme-like activities and mechanisms of enzyme-like clearance are discussed, meanwhile, we systematically summarize the progress of the research on MOF-based nanozymes, including the design strategy, mechanism of action, and medical application, etc. Finally, the current challenges of MOF-based nanozymes are summarized, and the future development direction is anticipated. We hope that this review can contribute to the research of MOF-based nanozymes in the medical field related to the scavenging of ROS.
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Affiliation(s)
- Zhong Xu
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Liang Chen
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Yan Luo
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Yan-Mei Wei
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Ning-Yuan Wu
- Guangxi Medical University Life Sciences Institute, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Lan-Fang Luo
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Yong-Biao Wei
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Jin Huang
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, People's Republic of China
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17
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Arnér ESJ, Schmidt EE. Unresolved questions regarding cellular cysteine sources and their possible relationships to ferroptosis. Adv Cancer Res 2024; 162:1-44. [PMID: 39069366 PMCID: PMC11785257 DOI: 10.1016/bs.acr.2024.04.001] [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] [Indexed: 07/30/2024]
Abstract
Cysteine is required for synthesis of glutathione (GSH), coenzyme A, other sulfur-containing metabolites, and most proteins. In most cells, cysteine comes from extracellular disulfide sources including cystine, glutathione-disulfide, and peptides. The thioredoxin reductase-1 (TrxR1)- or glutathione-disulfide reductase (GSR)-driven enzymatic systems can fuel cystine reduction via thioredoxins, glutaredoxins, or other thioredoxin-fold proteins. Free cystine enters cells thorough the cystine-glutamate antiporter, xCT, but systemically, plasma glutathione-disulfide might predominate as a cystine source. Erastin, inhibiting both xCT and voltage-dependent anion channels, induces ferroptotic cell death, so named because this type of cell death is antagonized by iron-chelators. Many cancer cells seem to be predisposed to ferroptosis, which has been proposed as a targetable cancer liability. Ferroptosis is associated with lipid peroxidation and loss of either glutathione peroxidase-4 (GPX4) or ferroptosis suppressor protein-1 (FSP1), which each prevent accumulation of lipid peroxides. It has been suggested that an xCT inhibition-induced cellular cysteine-deficiency lowers GSH levels, starving GPX4 for reducing power and allowing membrane lipid peroxides to accumulate, thereby causing ferroptosis. Aspects of ferroptosis are however not fully understood and need to be further scrutinized, for example that neither disruption of GSH synthesis, loss of GSH, nor disruption of glutathione disulfide reductase (GSR), triggers ferroptosis in animal models. Here we reevaluate the relationships between Erastin, xCT, GPX4, cellular cysteine and GSH, RSL3 or ML162, and ferroptosis. We conclude that, whereas both Cys and ferroptosis are potential liabilities in cancer, their relationship to each other remains insufficiently understood.
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Affiliation(s)
- Elias S J Arnér
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Selenoprotein Research and the National Tumor Biology Laboratory, National Institutes of Oncology, Budapest, Hungary
| | - Edward E Schmidt
- Laboratory of Redox Biology, University of Veterinary Medicine, Budapest, Hungary; Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, United States.
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Fu Y, Song Y, Jiang D, Pan J, Li W, Zhang X, Chen W, Tian Y, Shen X, Huang Y. Comprehensive Transcriptomic and Metabolomic Analysis Revealed the Functional Differences in Pigeon Lactation between Male and Female during the Reproductive Cycle. Animals (Basel) 2023; 14:75. [PMID: 38200806 PMCID: PMC10778231 DOI: 10.3390/ani14010075] [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: 11/07/2023] [Revised: 12/07/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
Lactation is a unique reproductive behavior in pigeons, with the crop serving as the organ responsible for secreting pigeon milk. Both male and female pigeons can produce crop milk and rear their offspring through a division of labor. Since the time of the secretion of pigeon crop milk is different in the process of feeding the young, whether the metabolism and formation of pigeon milk use the same mechanism is a very interesting scientific question. However, the metabolic dynamics and underlying genetic mechanisms involved in the formation of pigeon crop milk remain unclear, particularly during the incubation-feeding reproductive cycle. In this study, we integrated lactation-associated metabolism and transcriptome data from the crop tissues of both male and female pigeons during the brooding and feeding stages. We mapped the changes in metabolites related to milk formation in the crop tissues during these stages. Through metabolome profiling, we identified 1413 metabolites among 18 crop tissues. During the breeding cycles, the concentrations of estrone, L-ergothioneine, and L-histidine exhibited the most dynamic changes in females. In contrast, estrone, L-anserine, 1-methylhistidine, homovanillate, oxidized glutathione, and reducing glutathione showed the most dynamic changes in males. Gender-specific differences were observed in the metabolome, with several metabolites significantly differing between males and females, many of which were correlated with cytokine binding, immunity, and cytochrome P450 activity. Using this dataset, we constructed complex regulatory networks, enabling us to identify important metabolites and key genes involved in regulating the formation of pigeon milk in male and female pigeons, respectively. Additionally, we investigated gender-associated differences in the crop metabolites of pigeons. Our study revealed differences in the modulation of pigeon crop milk metabolism between males and females and shed light on the potential functions of male and female pigeon milk in the growth, development, and immunity of young pigeons, an area that has not been previously explored. In conclusion, our results provide new insights into the metabolic regulation of pigeon crop milk formation during the brooding and breeding stages. Furthermore, our findings lay the foundation for the accurate development of artificial pigeon milk.
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Affiliation(s)
- Yuting Fu
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Waterfowl Healthy Breeding Engineering Research Center, Guangdong Higher Education Institute, Guangzhou 510225, China
| | - Yan Song
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Waterfowl Healthy Breeding Engineering Research Center, Guangdong Higher Education Institute, Guangzhou 510225, China
| | - Danli Jiang
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Waterfowl Healthy Breeding Engineering Research Center, Guangdong Higher Education Institute, Guangzhou 510225, China
| | - Jianqiu Pan
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Waterfowl Healthy Breeding Engineering Research Center, Guangdong Higher Education Institute, Guangzhou 510225, China
| | - Wanyan Li
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Waterfowl Healthy Breeding Engineering Research Center, Guangdong Higher Education Institute, Guangzhou 510225, China
| | - Xumeng Zhang
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Waterfowl Healthy Breeding Engineering Research Center, Guangdong Higher Education Institute, Guangzhou 510225, China
| | - Wenbin Chen
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Yunbo Tian
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Waterfowl Healthy Breeding Engineering Research Center, Guangdong Higher Education Institute, Guangzhou 510225, China
| | - Xu Shen
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Waterfowl Healthy Breeding Engineering Research Center, Guangdong Higher Education Institute, Guangzhou 510225, China
| | - Yunmao Huang
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510225, China; (Y.F.); (Y.S.); (D.J.); (J.P.); (W.L.); (X.Z.); (W.C.); (Y.T.)
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
- Waterfowl Healthy Breeding Engineering Research Center, Guangdong Higher Education Institute, Guangzhou 510225, China
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19
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Bischoff E, Lang L, Zimmermann J, Luczak M, Kiefer AM, Niedner-Schatteburg G, Manolikakes G, Morgan B, Deponte M. Glutathione kinetically outcompetes reactions between dimedone and a cyclic sulfenamide or physiological sulfenic acids. Free Radic Biol Med 2023; 208:165-177. [PMID: 37541455 DOI: 10.1016/j.freeradbiomed.2023.08.005] [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: 07/07/2023] [Revised: 07/31/2023] [Accepted: 08/01/2023] [Indexed: 08/06/2023]
Abstract
Dimedone and its derivates are used as selective probes for the nucleophilic detection of sulfenic acids in biological samples. Qualitative analyses suggested that dimedone also reacts with cyclic sulfenamides. Furthermore, under physiological conditions, dimedone must compete with the highly concentrated nucleophile glutathione. We therefore quantified the reaction kinetics for a cyclic sulfenamide model peptide and the sulfenic acids of glutathione and a model peroxiredoxin in the presence or absence of dimedone and glutathione. We show that the cyclic sulfenamide is stabilized at lower pH and that it reacts with dimedone. While reactions between dimedone and sulfenic acids or the cyclic sulfenamide have similar rate constants, glutathione kinetically outcompetes dimedone as a nucleophile by several orders of magnitude. Our comparative in vitro and intracellular analyses challenge the selectivity of dimedone. Consequently, the dimedone labeling of cysteinyl residues inside living cells points towards unidentified reaction pathways or unknown, kinetically competitive redox species.
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Affiliation(s)
- Eileen Bischoff
- Fachbereich Chemie & Landesforschungszentrum OPTIMAS, RPTU Kaiserslautern, Erwin-Schrödinger Straße 54, D-67663, Kaiserslautern, Germany
| | - Lukas Lang
- Fachbereich Chemie & Landesforschungszentrum OPTIMAS, RPTU Kaiserslautern, Erwin-Schrödinger Straße 54, D-67663, Kaiserslautern, Germany
| | - Jannik Zimmermann
- Zentrum für Human- und Molekularbiologie (ZHMB), Universität des Saarlandes, Biochemie Campus, Geb. B2.2, D-66123, Saarbrücken, Germany
| | - Maximilian Luczak
- Fachbereich Chemie & Landesforschungszentrum OPTIMAS, RPTU Kaiserslautern, Erwin-Schrödinger Straße 54, D-67663, Kaiserslautern, Germany
| | - Anna Maria Kiefer
- Fachbereich Biologie, RPTU Kaiserslautern, Paul-Ehrlich Straße 23, D-67663, Kaiserslautern, Germany
| | - Gereon Niedner-Schatteburg
- Fachbereich Chemie & Landesforschungszentrum OPTIMAS, RPTU Kaiserslautern, Erwin-Schrödinger Straße 54, D-67663, Kaiserslautern, Germany
| | - Georg Manolikakes
- Fachbereich Chemie & Landesforschungszentrum OPTIMAS, RPTU Kaiserslautern, Erwin-Schrödinger Straße 54, D-67663, Kaiserslautern, Germany
| | - Bruce Morgan
- Zentrum für Human- und Molekularbiologie (ZHMB), Universität des Saarlandes, Biochemie Campus, Geb. B2.2, D-66123, Saarbrücken, Germany
| | - Marcel Deponte
- Fachbereich Chemie & Landesforschungszentrum OPTIMAS, RPTU Kaiserslautern, Erwin-Schrödinger Straße 54, D-67663, Kaiserslautern, Germany.
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20
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Grayson C, Mailloux RJ. Coenzyme Q 10 and nicotinamide nucleotide transhydrogenase: Sentinels for mitochondrial hydrogen peroxide signaling. Free Radic Biol Med 2023; 208:260-271. [PMID: 37573896 DOI: 10.1016/j.freeradbiomed.2023.08.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/21/2023] [Accepted: 08/08/2023] [Indexed: 08/15/2023]
Abstract
Mitochondria use hydrogen peroxide (H2O2) as a mitokine for cell communication. H2O2 output for signaling depends on its rate of production and degradation, both of which are strongly affected by the redox state of the coenzyme Q10 (CoQ) pool and NADPH availability. Here, we propose the CoQ pool and nicotinamide nucleotide transhydrogenase (NNT) have evolved to be central modalities for mitochondrial H2O2 signaling. Both factors play opposing yet equally important roles in dictating H2O2 availability because they are connected to one another by two central parameters in bioenergetics: electron supply and Δp. The CoQ pool is the central point of convergence for electrons from various dehydrogenases and the electron transport chain (ETC). The increase in Δp creates a significant amount of protonic backpressure on mitochondria to promote H2O2 genesis through CoQ pool reduction. These same factors also drive the activity of NNT, which uses electrons and the Δp to eliminate H2O2. In this way, electron supply and the magnitude of the Δp manifests as a redox connection between the two sentinels, CoQ and NNT, which serve as opposing yet equally important forces required for budgeting H2O2. Taken together, CoQ and NNT are sentinels linked through mitochondrial bioenergetics to manage H2O2 availability for interorganelle and intercellular redox signaling.
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Affiliation(s)
- Cathryn Grayson
- The School of Human Nutrition, Faculty of Agricultural and Environmental Sciences, McGill University, Ste.-Anne-de-Bellevue, Quebec, Canada
| | - Ryan J Mailloux
- The School of Human Nutrition, Faculty of Agricultural and Environmental Sciences, McGill University, Ste.-Anne-de-Bellevue, Quebec, Canada.
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21
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Xu T, Zhu Q, Huang Q, Gu Q, Zhu Y, Tang M, Tian S, Wang L, Yan F, Ge J, Sha W, Lin X. FGF21 prevents neuronal cell ferroptosis after spinal cord injury by activating the FGFR1/β-Klotho pathway. Brain Res Bull 2023; 202:110753. [PMID: 37660729 DOI: 10.1016/j.brainresbull.2023.110753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/12/2023] [Accepted: 08/31/2023] [Indexed: 09/05/2023]
Abstract
Spinal cord injury (SCI) is a kind of traumatic nervous system disease caused by neuronal death, causing symptoms like sensory, motor, and autonomic nerve dysfunction. The recovery of neurological function has always been a intractable problem that has greatly distressed individuals and society. Although the involvement of iron-dependent lipid peroxidation leading to nerve cell ferroptosis in SCI progression has been reported, the underlying mechanisms remain unaddressed. Thus, this study aimed to investigate the potential of recombinant human FGF21 (rhFGF21) in inhibiting ferroptosis of nerve cells and improving limb function after SCI, along with its underlying mechanisms. In vivo animal model showed that FGFR1, p-FGFR1, and β-Klotho protein gradually increased over time after injury, reaching a peak on the third day. Moreover, rhFGF21 treatment significantly reduced ACSL4, increased GPX4 expression, reduced iron deposition, and inhibited ferroptosis. Meanwhile, rhFGF21 decreased cell apoptosis following acute spinal cord damage. In contrast, FGFR1 inhibitor PD173074 partially reversed the rhFGF21-induced therapeutic effects. Overall, this work revealed that rhFGF21 activates the FGFR1/β-Klotho pathway to decrease ferroptosis of nerve cells, suggesting that FGF21 could be a new therapeutic target for SCI neurological rehabilitation.
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Affiliation(s)
- Tianli Xu
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China; Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China
| | - Qiancheng Zhu
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China; Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China
| | - Qun Huang
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China; Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China
| | - Qi Gu
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China; Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China
| | - Yi Zhu
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China; Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China
| | - Mengjie Tang
- Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China; Department of Endocrinology, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China
| | - Shoujin Tian
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China; Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China
| | - Liming Wang
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China
| | - Fei Yan
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China
| | - Jianfei Ge
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China; Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China
| | - Weiping Sha
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China; Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China.
| | - Xiaolong Lin
- Department of Orthopaedic Surgery, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, China; Orthopaedics Laboratory, The First People's Hospital of Zhangjiagang City, Suzhou 215600, China.
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22
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Orrico F, Laurance S, Lopez AC, Lefevre SD, Thomson L, Möller MN, Ostuni MA. Oxidative Stress in Healthy and Pathological Red Blood Cells. Biomolecules 2023; 13:1262. [PMID: 37627327 PMCID: PMC10452114 DOI: 10.3390/biom13081262] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Red cell diseases encompass a group of inherited or acquired erythrocyte disorders that affect the structure, function, or production of red blood cells (RBCs). These disorders can lead to various clinical manifestations, including anemia, hemolysis, inflammation, and impaired oxygen-carrying capacity. Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms, plays a significant role in the pathophysiology of red cell diseases. In this review, we discuss the most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and finally, the role of oxidative stress in different red cell diseases, including sickle cell disease, glucose 6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency, highlighting the underlying mechanisms leading to pathological RBC phenotypes.
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Affiliation(s)
- Florencia Orrico
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (F.O.); (A.C.L.); (M.N.M.)
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay;
- Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Sandrine Laurance
- Université Paris Cité and Université des Antilles, UMR_S1134, BIGR, Inserm, F-75014 Paris, France; (S.L.); (S.D.L.)
| | - Ana C. Lopez
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (F.O.); (A.C.L.); (M.N.M.)
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay;
- Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Sophie D. Lefevre
- Université Paris Cité and Université des Antilles, UMR_S1134, BIGR, Inserm, F-75014 Paris, France; (S.L.); (S.D.L.)
| | - Leonor Thomson
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay;
- Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Matias N. Möller
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (F.O.); (A.C.L.); (M.N.M.)
- Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Mariano A. Ostuni
- Université Paris Cité and Université des Antilles, UMR_S1134, BIGR, Inserm, F-75014 Paris, France; (S.L.); (S.D.L.)
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23
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Xu J, Wang XL, Zeng HF, Han ZY. Methionine alleviates heat stress-induced ferroptosis in bovine mammary epithelial cells through the Nrf2 pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 256:114889. [PMID: 37079940 DOI: 10.1016/j.ecoenv.2023.114889] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 03/24/2023] [Accepted: 04/08/2023] [Indexed: 05/03/2023]
Abstract
Heat stress (HS) triggers mammary gland degradation, accompanied by apoptosis and autophagy in bovine mammary epithelial cells, negatively affecting milk performance and mammary gland health. Ferroptosis is iron-mediated regulated cell death caused by over production of lipid peroxides, however, the relationship between ferroptosis and HS in bovine mammary epithelial cells has not been clarified. Methionine (Met) plays a notable role in alleviating HS affecting the mammary glands in dairy cows, but the underlying mechanisms require further exploration. Therefore, we evaluated the regulatory effect and mechanism of Met in alleviating HS-induced ferroptosis by using bovine mammary epithelial cell line (MAC-T) as an in vitro model. The results showed that Met improved cell vitality, restored mitochondrial function; reduced the content of various reactive oxygen species (ROS), especially hydrogen peroxide (H2O2) and superoxide anion (O2·-); had positive effects on antioxidant enzyme activity, namely glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). More importantly, Met reduced labile iron protein (LIP) levels; increased iron storage and simultaneously decreased the levels of lipid reactive oxygen species (lipid ROS) and malondialdehyde (MDA), which all caused by HS in MAC-T. Mechanistically, Met increased the protein expression levels of glutathione peroxidase 4 (GPX4), solute carrier family 7, member 11 (SLC7A11) and ferritin heavy chain 1 (FTH1) by activating nuclear factor E2-related factor 2 (Nrf2) expression. Additionally, the protection effect of Met was cut off in MAC-T cells after interference with Nrf2, manifesting in decresing the protein expression levels of GPX4, SLC7A11 and FTH1,and increasing the levels of LIP and lipid ROS. Our findings indicate that Met eases HS-induced ferroptosis in MAC-T through the Nrf2 pathway, revealing that Met produces a marked effect on easing HS-induced bovine mammary gland injury in dairy cows.
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Affiliation(s)
- Jie Xu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Xin-Ling Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Han-Fang Zeng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhao-Yu Han
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
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24
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Koeberle SC, Kipp AP, Stuppner H, Koeberle A. Ferroptosis-modulating small molecules for targeting drug-resistant cancer: Challenges and opportunities in manipulating redox signaling. Med Res Rev 2023; 43:614-682. [PMID: 36658724 PMCID: PMC10947485 DOI: 10.1002/med.21933] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/07/2022] [Accepted: 01/03/2023] [Indexed: 01/21/2023]
Abstract
Ferroptosis is an iron-dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis-inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapy-resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis-inducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane-bound lipid hydroperoxides, (ii) the cystine/glutamate antiporter system Xc - that is central for glutathione regeneration, (iii) the redox-protective transcription factor nuclear factor erythroid 2-related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase-1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis-inducing lead structures and provide a comprehensive overview of structurally diverse biogenic and bioinspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.
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Affiliation(s)
- Solveigh C. Koeberle
- Michael Popp Institute, Center for Molecular Biosciences Innsbruck (CMBI)University of InnsbruckTirolInnsbruckAustria
- Department of Molecular Nutritional Physiology, Institute of Nutritional SciencesFriedrich Schiller University JenaThüringenJenaGermany
| | - Anna P. Kipp
- Department of Molecular Nutritional Physiology, Institute of Nutritional SciencesFriedrich Schiller University JenaThüringenJenaGermany
| | - Hermann Stuppner
- Unit of Pharmacognosy, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck (CMBI)University of InnsbruckTirolInnsbruckAustria
| | - Andreas Koeberle
- Michael Popp Institute, Center for Molecular Biosciences Innsbruck (CMBI)University of InnsbruckTirolInnsbruckAustria
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25
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Hewitt OH, Degnan SM. Antioxidant enzymes that target hydrogen peroxide are conserved across the animal kingdom, from sponges to mammals. Sci Rep 2023; 13:2510. [PMID: 36781921 PMCID: PMC9925728 DOI: 10.1038/s41598-023-29304-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 02/02/2023] [Indexed: 02/15/2023] Open
Abstract
Oxygen is the sustenance of aerobic life and yet is highly toxic. In early life, antioxidants functioned solely to defend against toxic effects of reactive oxygen species (ROS). Later, as aerobic metabolisms evolved, ROS became essential for signalling. Thus, antioxidants are multifunctional and must detoxify, but also permit ROS signalling for vital cellular processes. Here we conduct metazoan-wide genomic assessments of three enzymatic antioxidant families that target the predominant ROS signaller, hydrogen peroxide: namely, monofunctional catalases (CAT), peroxiredoxins (PRX), and glutathione peroxidases (GPX). We reveal that the two most evolutionary ancient families, CAT and PRX, exhibit metazoan-wide conservation. In the basal animal lineage, sponges (phylum Porifera), we find all three antioxidant families, but with GPX least abundant. Poriferan CATs are distinct from bilaterian CATs, but the evolutionary divergence is small. Amongst PRXs, subfamily PRX6 is the most conserved, whilst subfamily AhpC-PRX1 is the largest; PRX4 is the only core member conserved from sponges to mammals and may represent the ancestral animal AhpC-PRX1. Conversely, for GPX, the most recent family to arise, only the cysteine-dependent subfamily GPX7 is conserved across metazoans, and common across Porifera. Our analyses illustrate that the fundamental functions of antioxidants have resulted in gene conservation throughout the animal kingdom.
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Affiliation(s)
- Olivia H Hewitt
- School of Biological Sciences and Centre for Marine Science, University of Queensland, St Lucia, QLD, 4072, Australia.
| | - Sandie M Degnan
- School of Biological Sciences and Centre for Marine Science, University of Queensland, St Lucia, QLD, 4072, Australia.
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26
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Cardozo G, Mastrogiovanni M, Zeida A, Viera N, Radi R, Reyes AM, Trujillo M. Mitochondrial Peroxiredoxin 3 Is Rapidly Oxidized and Hyperoxidized by Fatty Acid Hydroperoxides. Antioxidants (Basel) 2023; 12:antiox12020408. [PMID: 36829967 PMCID: PMC9952270 DOI: 10.3390/antiox12020408] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/19/2023] [Accepted: 01/28/2023] [Indexed: 02/11/2023] Open
Abstract
Human peroxiredoxin 3 (HsPrx3) is a thiol-based peroxidase responsible for the reduction of most hydrogen peroxide and peroxynitrite formed in mitochondria. Mitochondrial disfunction can lead to membrane lipoperoxidation, resulting in the formation of lipid-bound fatty acid hydroperoxides (LFA-OOHs) which can be released to become free fatty acid hydroperoxides (fFA-OOHs). Herein, we report that HsPrx3 is oxidized and hyperoxidized by fFA-OOHs including those derived from arachidonic acid and eicosapentaenoic acid peroxidation at position 15 with remarkably high rate constants of oxidation (>3.5 × 107 M-1s-1) and hyperoxidation (~2 × 107 M-1s-1). The endoperoxide-hydroperoxide PGG2, an intermediate in prostanoid synthesis, oxidized HsPrx3 with a similar rate constant, but was less effective in causing hyperoxidation. Biophysical methodologies suggest that HsPrx3 can bind hydrophobic structures. Indeed, molecular dynamic simulations allowed the identification of a hydrophobic patch near the enzyme active site that can allocate the hydroperoxide group of fFA-OOHs in close proximity to the thiolate in the peroxidatic cysteine. Simulations performed using available and herein reported kinetic data indicate that HsPrx3 should be considered a main target for mitochondrial fFA-OOHs. Finally, kinetic simulation analysis support that mitochondrial fFA-OOHs formation fluxes in the range of nM/s are expected to contribute to HsPrx3 hyperoxidation, a modification that has been detected in vivo under physiological and pathological conditions.
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Affiliation(s)
- Giuliana Cardozo
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas, Universidad de la República, Montevideo 11800, Uruguay
| | - Mauricio Mastrogiovanni
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas, Universidad de la República, Montevideo 11800, Uruguay
| | - Ari Zeida
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas, Universidad de la República, Montevideo 11800, Uruguay
| | - Nicolás Viera
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas, Universidad de la República, Montevideo 11800, Uruguay
| | - Rafael Radi
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas, Universidad de la República, Montevideo 11800, Uruguay
| | - Aníbal M. Reyes
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas, Universidad de la República, Montevideo 11800, Uruguay
- Correspondence: (A.M.R.); (M.T.)
| | - Madia Trujillo
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas, Universidad de la República, Montevideo 11800, Uruguay
- Correspondence: (A.M.R.); (M.T.)
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Vašková J, Kočan L, Vaško L, Perjési P. Glutathione-Related Enzymes and Proteins: A Review. Molecules 2023; 28:molecules28031447. [PMID: 36771108 PMCID: PMC9919958 DOI: 10.3390/molecules28031447] [Citation(s) in RCA: 87] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
The tripeptide glutathione is found in all eukaryotic cells, and due to the compartmentalization of biochemical processes, its synthesis takes place exclusively in the cytosol. At the same time, its functions depend on its transport to/from organelles and interorgan transport, in which the liver plays a central role. Glutathione is determined as a marker of the redox state in many diseases, aging processes, and cell death resulting from its properties and reactivity. It also uses other enzymes and proteins, which enables it to engage and regulate various cell functions. This paper approximates the role of these systems in redox and detoxification reactions such as conjugation reactions of glutathione-S-transferases, glyoxylases, reduction of peroxides through thiol peroxidases (glutathione peroxidases, peroxiredoxins) and thiol-disulfide exchange reactions catalyzed by glutaredoxins.
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Affiliation(s)
- Janka Vašková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 040 11 Košice, Slovakia
- Correspondence: (J.V.); (P.P.); Tel.: +42-155-234-3232 (J.V.)
| | - Ladislav Kočan
- Clinic of Anaesthesiology and Intensive Care Medicine, East Slovak Institute of Cardiovascular Disease, 040 11 Košice, Slovakia
| | - Ladislav Vaško
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 040 11 Košice, Slovakia
| | - Pál Perjési
- Institute of Pharmaceutical Chemistry, University of Pécs, 7600 Pécs, Hungary
- Correspondence: (J.V.); (P.P.); Tel.: +42-155-234-3232 (J.V.)
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28
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Chen M, Shi Z, Sun Y, Ning H, Gu X, Zhang L. Prospects for Anti-Tumor Mechanism and Potential Clinical Application Based on Glutathione Peroxidase 4 Mediated Ferroptosis. Int J Mol Sci 2023; 24:1607. [PMID: 36675129 PMCID: PMC9864218 DOI: 10.3390/ijms24021607] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/10/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Ferroptosis, characterized by excessive iron accumulation and lipid peroxidation, is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other known cell death types, such as apoptosis, necrosis, and autophagy. Emerging evidence shows that glutathione peroxidase 4 (GPX4), a critical core regulator of ferroptosis, plays an essential role in protecting cells from ferroptosis by removing the product of iron-dependent lipid peroxidation. The fast-growing studies on ferroptosis in cancer have boosted a perspective on its use in cancer therapeutics. In addition, significant progress has been made in researching and developing tumor therapeutic drugs targeting GPX4 based on ferroptosis, especially in acquired drug resistance. Selenium modulates GPX4-mediated ferroptosis, and its existing form, selenocysteine (Sec), is the active center of GPX4. This review explored the structure and function of GPX4, with the overarching goal of revealing its mechanism and potential application in tumor therapy through regulating ferroptosis. A deeper understanding of the mechanism and application of GPX4-mediated ferroptosis in cancer therapy will provide new strategies for the research and development of antitumor drugs.
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Affiliation(s)
- Mingliang Chen
- School of Basic Medical Science, Henan University, Kaifeng 475004, China
| | - Zhihao Shi
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
| | - Yuqiu Sun
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
| | - Haoran Ning
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
| | - Xinyu Gu
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
| | - Lei Zhang
- School of Basic Medical Science, Henan University, Kaifeng 475004, China
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29
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Möller M, Orrico F, Villar S, López AC, Silva N, Donzé M, Thomson L, Denicola A. Oxidants and Antioxidants in the Redox Biochemistry of Human Red Blood Cells. ACS OMEGA 2023; 8:147-168. [PMID: 36643550 PMCID: PMC9835686 DOI: 10.1021/acsomega.2c06768] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/09/2022] [Indexed: 06/01/2023]
Abstract
Red blood cells (RBCs) are exposed to both external and internal sources of oxidants that challenge their integrity and compromise their physiological function and supply of oxygen to tissues. Autoxidation of oxyhemoglobin is the main source of endogenous RBC oxidant production, yielding superoxide radical and then hydrogen peroxide. In addition, potent oxidants from other blood cells and the surrounding endothelium can reach the RBCs. Abundant and efficient enzymatic systems and low molecular weight antioxidants prevent most of the damage to the RBCs and also position the RBCs as a sink of vascular oxidants that allow the body to maintain a healthy circulatory system. Among the antioxidant enzymes, the thiol-dependent peroxidase peroxiredoxin 2, highly abundant in RBCs, is essential to keep the redox balance. A great part of the RBC antioxidant activity is supported by an active glucose metabolism that provides reducing power in the form of NADPH via the pentose phosphate pathway. There are several RBC defects and situations that generate oxidative stress conditions where the defense mechanisms are overwhelmed, and these include glucose-6-phosphate dehydrogenase deficiencies (favism), hemoglobinopathies like sickle cell disease and thalassemia, as well as packed RBCs for transfusion that suffer from storage lesions. These oxidative stress-associated pathologies of the RBCs underline the relevance of redox balance in these anucleated cells that lack a mechanism of DNA-inducible antioxidant response and rely on a complex and robust network of antioxidant systems.
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Affiliation(s)
- Matias
N. Möller
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Florencia Orrico
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
- Laboratorio
de Enzimología, Instituto de Química Biológica,
Facultad de Ciencias, Universidad de la
República, Montevideo 11400, Uruguay
| | - Sebastián
F. Villar
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Ana C. López
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
- Laboratorio
de Enzimología, Instituto de Química Biológica,
Facultad de Ciencias, Universidad de la
República, Montevideo 11400, Uruguay
| | - Nicolás Silva
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
- Laboratorio
de Enzimología, Instituto de Química Biológica,
Facultad de Ciencias, Universidad de la
República, Montevideo 11400, Uruguay
- Departamento
de Medicina Transfusional, Hospital de Clínicas, Facultad de
Medicina, Universidad de la República, Montevideo 11600, Uruguay
| | - Marcel Donzé
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Leonor Thomson
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
- Laboratorio
de Enzimología, Instituto de Química Biológica,
Facultad de Ciencias, Universidad de la
República, Montevideo 11400, Uruguay
| | - Ana Denicola
- Laboratorio
de Fisicoquímica Biológica, Instituto de Química
Biológica, Facultad de Ciencias,
Universidad de la República, Montevideo 11400, Uruguay
- Centro
de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
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Dumoulin B, Heydeck D, Jähn D, Lassé M, Sofi S, Ufer C, Kuhn H. Male guanine-rich RNA sequence binding factor 1 knockout mice (Grsf1 -/-) gain less body weight during adolescence and adulthood. Cell Biosci 2022; 12:199. [PMID: 36494688 PMCID: PMC9733283 DOI: 10.1186/s13578-022-00922-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 11/02/2022] [Indexed: 12/13/2022] Open
Abstract
The guanine-rich RNA sequence binding factor 1 (GRSF1) is an RNA-binding protein of the heterogenous nuclear ribonucleoprotein H/F (hnRNP H/F) family that binds to guanine-rich RNA sequences forming G-quadruplex structures. In mice and humans there are single copy GRSF1 genes, but multiple transcripts have been reported. GRSF1 has been implicated in a number of physiological processes (e.g. embryogenesis, erythropoiesis, redox homeostasis, RNA metabolism) but also in the pathogenesis of viral infections and hyperproliferative diseases. These postulated biological functions of GRSF1 originate from in vitro studies rather than complex in vivo systems. To assess the in vivo relevance of these findings, we created systemic Grsf1-/- knockout mice lacking exons 4 and 5 of the Grsf1 gene and compared the basic functional characteristics of these animals with those of wildtype controls. We found that Grsf1-deficient mice are viable, reproduce normally and have fully functional hematopoietic systems. Up to an age of 15 weeks they develop normally but when male individuals grow older, they gain significantly less body weight than wildtype controls in a gender-specific manner. Profiling Grsf1 mRNA expression in different mouse tissues we observed high concentrations in testis. Comparison of the testicular transcriptomes of Grsf1-/- mice and wildtype controls confirmed near complete knock-out of Grsf1 but otherwise subtle differences in transcript regulations. Comparative testicular proteome analyses suggested perturbed mitochondrial respiration in Grsf1-/- mice which may be related to compromised expression of complex I proteins. Here we present, for the first time, an in vivo complete Grsf1 knock-out mouse with comprehensive physiological, transcriptomic and proteomic characterization to improve our understanding of the GRSF1 beyond in vitro cell culture models.
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Affiliation(s)
- Bernhard Dumoulin
- grid.6363.00000 0001 2218 4662Department of Biochemistry, Charité - University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany ,grid.13648.380000 0001 2180 3484Present Address: Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dagmar Heydeck
- grid.6363.00000 0001 2218 4662Department of Biochemistry, Charité - University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
| | - Desiree Jähn
- grid.6363.00000 0001 2218 4662Department of Biochemistry, Charité - University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
| | - Moritz Lassé
- grid.13648.380000 0001 2180 3484Present Address: Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sajad Sofi
- grid.6363.00000 0001 2218 4662Department of Biochemistry, Charité - University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany ,grid.5685.e0000 0004 1936 9668Present Address: Department of Biology, University of York, York, YO10 5DD UK
| | - Christoph Ufer
- grid.6363.00000 0001 2218 4662Department of Biochemistry, Charité - University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
| | - Hartmut Kuhn
- grid.6363.00000 0001 2218 4662Department of Biochemistry, Charité - University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
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Vogelsang L, Dietz KJ. Plant thiol peroxidases as redox sensors and signal transducers in abiotic stress acclimation. Free Radic Biol Med 2022; 193:764-778. [PMID: 36403735 DOI: 10.1016/j.freeradbiomed.2022.11.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022]
Abstract
The temporal and spatial patterns of reactive oxygen species (ROS) in cells and tissues decisively determine the plant acclimation response to diverse abiotic and biotic stresses. Recent progress in developing dynamic cell imaging probes provides kinetic information on changes in parameters like H2O2, glutathione (GSH/GSSG) and NAD(P)H/NAD(P)+, that play a crucial role in tuning the cellular redox state. Central to redox-based regulation is the thiol-redox regulatory network of the cell that integrates reductive information from metabolism and oxidative ROS signals. Sensitive proteomics allow for monitoring changes in redox-related posttranslational modifications. Thiol peroxidases act as sensitive peroxide and redox sensors and play a central role in this signal transduction process. Peroxiredoxins (PRX) and glutathione peroxidases (GPX) are the two main thiol peroxidases and their function in ROS sensing and redox signaling in plants is emerging at present and summarized in this review. Depending on their redox state, PRXs and GPXs act as redox-dependent binding partners, direct oxidants of target proteins and oxidants of thiol redox transmitters that in turn oxidize target proteins. With their versatile functions, the multiple isoforms of plant thiol peroxidases play a central role in plant stress acclimation, e.g. to high light or osmotic stress, but also in ROS-mediated immunity and development.
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Affiliation(s)
- Lara Vogelsang
- Biochemistry and Physiology of Plants, W5-134, Bielefeld University, 33615, Bielefeld, Germany
| | - Karl-Josef Dietz
- Biochemistry and Physiology of Plants, W5-134, Bielefeld University, 33615, Bielefeld, Germany.
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Thomas C, Wurzer L, Malle E, Ristow M, Madreiter-Sokolowski CT. Modulation of Reactive Oxygen Species Homeostasis as a Pleiotropic Effect of Commonly Used Drugs. FRONTIERS IN AGING 2022; 3:905261. [PMID: 35821802 PMCID: PMC9261327 DOI: 10.3389/fragi.2022.905261] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 05/18/2022] [Indexed: 01/17/2023]
Abstract
Age-associated diseases represent a growing burden for global health systems in our aging society. Consequently, we urgently need innovative strategies to counteract these pathological disturbances. Overwhelming generation of reactive oxygen species (ROS) is associated with age-related damage, leading to cellular dysfunction and, ultimately, diseases. However, low-dose ROS act as crucial signaling molecules and inducers of a vaccination-like response to boost antioxidant defense mechanisms, known as mitohormesis. Consequently, modulation of ROS homeostasis by nutrition, exercise, or pharmacological interventions is critical in aging. Numerous nutrients and approved drugs exhibit pleiotropic effects on ROS homeostasis. In the current review, we provide an overview of drugs affecting ROS generation and ROS detoxification and evaluate the potential of these effects to counteract the development and progression of age-related diseases. In case of inflammation-related dysfunctions, cardiovascular- and neurodegenerative diseases, it might be essential to strengthen antioxidant defense mechanisms in advance by low ROS level rises to boost the individual ROS defense mechanisms. In contrast, induction of overwhelming ROS production might be helpful to fight pathogens and kill cancer cells. While we outline the potential of ROS manipulation to counteract age-related dysfunction and diseases, we also raise the question about the proper intervention time and dosage.
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Affiliation(s)
- Carolin Thomas
- Laboratory of Energy Metabolism Institute of Translational Medicine Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Lia Wurzer
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Ernst Malle
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Michael Ristow
- Laboratory of Energy Metabolism Institute of Translational Medicine Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
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Zuo J, Zhang Z, Luo M, Zhou L, Nice EC, Zhang W, Wang C, Huang C. Redox signaling at the crossroads of human health and disease. MedComm (Beijing) 2022; 3:e127. [PMID: 35386842 PMCID: PMC8971743 DOI: 10.1002/mco2.127] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/25/2022] [Accepted: 03/01/2022] [Indexed: 02/06/2023] Open
Abstract
Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, we reveal the roles of ROS as multifaceted physiological modulators to mediate redox signaling and sustain redox homeostasis. In addition, we also emphasize the detailed OS mechanisms involved in the initiation and development of several important diseases. ROS as a double-edged sword in disease progression suggest two different therapeutic strategies to treat redox-relevant diseases, in which targeting ROS sources and redox-related effectors to manipulate redox homeostasis will largely promote precision medicine. Therefore, a comprehensive understanding of the redox signaling networks under physiological and pathological conditions will facilitate the development of redox medicine and benefit patients with redox-relevant diseases.
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Affiliation(s)
- Jing Zuo
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
| | - Maochao Luo
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
| | - Edouard C. Nice
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
| | - Wei Zhang
- West China Biomedical Big Data CenterWest China HospitalSichuan UniversityChengduP. R. China
- Mental Health Center and Psychiatric LaboratoryThe State Key Laboratory of BiotherapyWest China Hospital of Sichuan UniversityChengduP. R. China
| | - Chuang Wang
- Department of PharmacologyProvincial Key Laboratory of Pathophysiology, Ningbo University School of MedicineNingboZhejiangP. R. China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
- Department of PharmacologyProvincial Key Laboratory of Pathophysiology, Ningbo University School of MedicineNingboZhejiangP. R. China
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Reactive Human Plasma Glutathione Peroxidase Mutant with Diselenide Bond Succeeds in Tetramer Formation. Antioxidants (Basel) 2022; 11:antiox11061083. [PMID: 35739980 PMCID: PMC9220127 DOI: 10.3390/antiox11061083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/25/2022] [Accepted: 05/27/2022] [Indexed: 12/05/2022] Open
Abstract
Plasma glutathione peroxidase (GPx3) belongs to the GPx superfamily, and it is the only known secreted selenocysteine (Sec)−containing GPx in humans. It exists as a glycosylated homotetramer and catalyzes the reduction of hydrogen peroxide and lipid peroxides, depending on the Sec in its active center. In this study, a previously reported chimeric tRNAUTuT6 was used for the incorporation of Sec at the UAG amber codon, and the mature form of human GPx3 (hGPx3) without the signal peptide was expressed in amber−less E. coli C321.ΔA.exp. Reactive Sec−hGPx3, able to reduce H2O2 and tert−butyl hydroperoxide (t−BuOOH), was produced with high purity and yield. Study of the quaternary structure suggested that the recombinant Sec−hGPx3 contained an intra−molecular disulfide bridge but failed to form tetramer. Mutational and structural analysis of the mutants with three Cys residues, individually or jointly replaced with Ser, indicated that the formation of intra−molecular disulfide bridges involved structure conformational changes. The secondary structure containing Cys77 and Cys132 was flexible and could form a disulfide bond, or form a sulfhydryl–selenyl bond with Sec49 in relative mutants. Mutation of Cys8 and Cys132 to Sec8 and Sec132 could fix the oligomerization loop through the formation of diselenide bond, which, in turn, facilitated tetramer formation and noticeably improved the GPx activity. This research provides an important foundation for the further catalysis and functional study of hGPx3.
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Meireles DA, da Silva Neto JF, Domingos RM, Alegria TGP, Santos LCM, Netto LES. Ohr - OhrR, a neglected and highly efficient antioxidant system: Structure, catalysis, phylogeny, regulation, and physiological roles. Free Radic Biol Med 2022; 185:6-24. [PMID: 35452809 DOI: 10.1016/j.freeradbiomed.2022.04.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 03/09/2022] [Accepted: 04/02/2022] [Indexed: 12/24/2022]
Abstract
Ohrs (organic hydroperoxide resistance proteins) are antioxidant enzymes that play central roles in the response of microorganisms to organic peroxides. Here, we describe recent advances in the structure, catalysis, phylogeny, regulation, and physiological roles of Ohr proteins and of its transcriptional regulator, OhrR, highlighting their unique features. Ohr is extremely efficient in reducing fatty acid peroxides and peroxynitrite, two oxidants relevant in host-pathogen interactions. The highly reactive Cys residue of Ohr, named peroxidatic Cys (Cp), composes together with an arginine and a glutamate the catalytic triad. The catalytic cycle of Ohrs involves a condensation between a sulfenic acid (Cp-SOH) and the thiol of the second conserved Cys, leading to the formation of an intra-subunit disulfide bond, which is then reduced by dihydrolipoamide or lipoylated proteins. A structural switch takes place during catalysis, with the opening and closure of the active site by the so-called Arg-loop. Ohr is part of the Ohr/OsmC super-family that also comprises OsmC and Ohr-like proteins. Members of the Ohr, OsmC and Ohr-like subgroups present low sequence similarities among themselves, but share a high structural conservation, presenting two Cys residues in their active site. The pattern of gene expression is also distinct among members of the Ohr/OsmC subfamilies. The expression of ohr genes increases upon organic hydroperoxides treatment, whereas the signals for the upregulation of osmC are entry into the stationary phase and/or osmotic stress. For many ohr genes, the upregulation by organic hydroperoxides is mediated by OhrR, a Cys-based transcriptional regulator that only binds to its target DNAs in its reduced state. Since Ohrs and OhrRs are involved in virulence of some microorganisms and are absent in vertebrate and vascular plants, they may represent targets for novel therapeutic approaches based on the disruption of this key bacterial organic peroxide defense system.
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Affiliation(s)
- Diogo A Meireles
- Laboratório de Fisiologia e Bioquímica de Microrganismos (LFBM) da Universidade Estadual do Norte Fluminense Darcy Ribeiro, Brazil
| | - José F da Silva Neto
- Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Brazil
| | | | - Thiago G P Alegria
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, Brazil
| | - Lene Clara M Santos
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, Brazil
| | - Luis Eduardo S Netto
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, Brazil.
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Mycothiol Peroxidase Activity as a Part of the Self-Resistance Mechanisms against the Antitumor Antibiotic Cosmomycin D. Microbiol Spectr 2022; 10:e0049322. [PMID: 35510858 PMCID: PMC9241694 DOI: 10.1128/spectrum.00493-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Antibiotic-producing microorganisms usually require one or more self-resistance determinants to survive antibiotic production. The effectors of these mechanisms are proteins that inactivate the antibiotic, facilitate its transport, or modify the target to render it insensitive to the molecule. Streptomyces bacteria biosynthesize various bioactive natural products and possess resistance systems for most metabolites, which are coregulated with antibiotic biosynthesis genes. Streptomyces olindensis strain DAUFPE 5622 produces the antitumor antibiotic cosmomycin D (COSD), a member of the anthracycline family. In this study, we propose three self-resistance mechanisms, anchored or based in the COSD biosynthetic gene cluster. These include cosIJ (an ABC transporter), cosU (a UvrA class IIa protein), and a new self-resistance mechanism encoded by cosP, which shows response against peroxides by the enzyme mycothiol peroxidase (MPx). Activity-based investigations of MPx and its mutant enzyme confirmed peroxidation during the production of COSD. Overexpression of the ABC transporter, the UvrA class IIa protein, and the MPx led to an effective response against toxic anthracyclines, such as cosmomycins. Our findings help to understand how thiol peroxidases play an antioxidant role in the anthracycline producer S. olindensis DAUFPE 5622, a mechanism which has been reported for neoplastic cells that are resistant to doxorubicin (DOX). IMPORTANCE Anthracycline compounds are DNA intercalating agents widely used in cancer chemotherapeutic protocols. This work focused on the self-resistance mechanisms developed by the cosmomycin-producing bacterium Streptomyces olindensis. Our findings showed that cysteine peroxidases, such as mycothiol peroxidase, encoded by the gene cosP, protected S. olindensis against peroxidation during cosmomycin production. This observation can contribute to much better understanding of resistance both in the producers, eventually enhancing production, and in some tumoral cell lines.
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Gladysheva IV, Cherkasov SV, Khlopko YA, Plotnikov AO. Genome Characterization and Probiotic Potential of Corynebacterium amycolatum Human Vaginal Isolates. Microorganisms 2022; 10:microorganisms10020249. [PMID: 35208706 PMCID: PMC8878833 DOI: 10.3390/microorganisms10020249] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 11/17/2022] Open
Abstract
The vaginal microbiome of healthy women contains nondiphtheria corynebacteria. The role and functions of nondiphtheria corynebacteria in the vaginal biotope are still under study. We sequenced and analysed the genomes of three vaginal C. amycolatum strains isolated from healthy women. Previous studies have shown that these strains produced metabolites that significantly increased the antagonistic activity of peroxide-producing lactic acid bacteria against pathogenic and opportunistic microorganisms and had strong antimicrobial activity against opportunistic pathogens. Analysis of the C. amycolatum genomes revealed the genes responsible for adaptation and survival in the vaginal environment, including acid and oxidative stress resistance genes. The genes responsible for the production of H2O2 and the synthesis of secondary metabolites, essential amino acids and vitamins were identified. A cluster of genes encoding the synthesis of bacteriocin was revealed in one of the annotated genomes. The obtained results allow us to consider the studied strains as potential probiotics that are capable of preventing the growth of pathogenic microorganisms and supporting colonisation resistance in the vaginal biotope.
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Mitochondrial Management of Reactive Oxygen Species. Antioxidants (Basel) 2021; 10:antiox10111824. [PMID: 34829696 PMCID: PMC8614740 DOI: 10.3390/antiox10111824] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 01/10/2023] Open
Abstract
Mitochondria in aerobic eukaryotic cells are both the site of energy production and the formation of harmful species, such as radicals and other reactive oxygen species, known as ROS. They contain an efficient antioxidant system, including low-molecular-mass molecules and enzymes that specialize in removing various types of ROS or repairing the oxidative damage of biological molecules. Under normal conditions, ROS production is low, and mitochondria, which are their primary target, are slightly damaged in a similar way to other cellular compartments, since the ROS released by the mitochondria into the cytosol are negligible. As the mitochondrial generation of ROS increases, they can deactivate components of the respiratory chain and enzymes of the Krebs cycle, and mitochondria release a high amount of ROS that damage cellular structures. More recently, the feature of the mitochondrial antioxidant system, which does not specifically deal with intramitochondrial ROS, was discovered. Indeed, the mitochondrial antioxidant system detoxifies exogenous ROS species at the expense of reducing the equivalents generated in mitochondria. Thus, mitochondria are also a sink of ROS. These observations highlight the importance of the mitochondrial antioxidant system, which should be considered in our understanding of ROS-regulated processes. These processes include cell signaling and the progression of metabolic and neurodegenerative disease.
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Trenz TS, Delaix CL, Turchetto-Zolet AC, Zamocky M, Lazzarotto F, Margis-Pinheiro M. Going Forward and Back: The Complex Evolutionary History of the GPx. BIOLOGY 2021; 10:biology10111165. [PMID: 34827158 PMCID: PMC8614756 DOI: 10.3390/biology10111165] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 01/15/2023]
Abstract
Simple Summary Glutathione peroxidases (GPxs) are considered as one of the main antioxidant enzymes, which reduce peroxides into less toxic compounds. This family of enzymes is found in most eukaryotic organisms, but it is highly divergent regarding its structure, catalytic mechanism, and substrate usage. Furthermore, it is still unclear how these enzymes are dispersed in the animal kingdom. Through robust phylogenetic and sequence analyses, we show that all GPx genes originated from a common ancestor and evolved independently across different kingdoms. In Metazoa, GPx genes expanded into three main groups before the rise of bilaterian animals, and they were further expanded in vertebrates. These expansions allowed GPx enzymes to diversify, not only structurally, but also functionally. Our study contributes to the understanding of how this abundant class of antioxidant enzymes evolved. The evolution of GPxs appears to be a continuous process, leading to the diversification of their functions. Abstract There is large diversity among glutathione peroxidase (GPx) enzymes regarding their function, structure, presence of the highly reactive selenocysteine (SeCys) residue, substrate usage, and reducing agent preference. Moreover, most vertebrate GPxs are very distinct from non-animal GPxs, and it is still unclear if they came from a common GPx ancestor. In this study, we aimed to unveil how GPx evolved throughout different phyla. Based on our phylogenetic trees and sequence analyses, we propose that all GPx encoding genes share a monomeric common ancestor and that the SeCys amino acid was incorporated early in the evolution of the metazoan kingdom. In addition, classical GPx and the cysteine-exclusive GPx07 have been present since non-bilaterian animals, but they seem to have been lost throughout evolution in different phyla. Therefore, the birth-and-death of GPx family members (like in other oxidoreductase families) seems to be an ongoing process, occurring independently across different kingdoms and phyla.
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Affiliation(s)
- Thomaz Stumpf Trenz
- Programa de Pós-Graduação em Biologia Celular e Molecular, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91509-900, Brazil;
| | - Camila Luiza Delaix
- Graduação em Biotecnologia, Departamento de Biologia Molecular e Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91509-900, Brazil;
| | - Andreia Carina Turchetto-Zolet
- Programa de Pós-Graduação em Genética e Biologia Molecular, Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91509-900, Brazil;
| | - Marcel Zamocky
- Laboratory of Phylogenomic Ecology, Institute of Molecular Biology, Slovak Academy of Sciences, Dúbravská cesta 21, 84551 Bratislava, Slovakia;
- Department of Chemistry, Institute of Biochemistry, University of Natural Resources and Life Sciences, Vienna, Muthgasse 18, 1190 Vienna, Austria
| | - Fernanda Lazzarotto
- Programa de Pós-Graduação em Biologia Celular e Molecular, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91509-900, Brazil;
- Correspondence: (F.L.); (M.M.-P.)
| | - Márcia Margis-Pinheiro
- Programa de Pós-Graduação em Biologia Celular e Molecular, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91509-900, Brazil;
- Programa de Pós-Graduação em Genética e Biologia Molecular, Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91509-900, Brazil;
- Correspondence: (F.L.); (M.M.-P.)
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Cheff DM, Muotri AR, Stockwell BR, Schmidt EE, Ran Q, Kartha RV, Johnson SC, Mittal P, Arnér ESJ, Wigby KM, Hall MD, Ramesh SK. Development of therapies for rare genetic disorders of GPX4: roadmap and opportunities. Orphanet J Rare Dis 2021; 16:446. [PMID: 34688299 PMCID: PMC8542321 DOI: 10.1186/s13023-021-02048-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 09/19/2021] [Indexed: 01/14/2023] Open
Abstract
Background Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming. Main body The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies. Conclusion The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-02048-0.
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Affiliation(s)
- Dorian M Cheff
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.,Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Alysson R Muotri
- Department of Pediatrics, University of California, San Diego, San Diego, CA, USA.,Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA
| | - Brent R Stockwell
- Department of Biological Sciences, Columbia University, New York, NY, USA.,Department of Chemistry, Columbia University, New York, NY, USA
| | - Edward E Schmidt
- Department of Microbiology and Immunology, Montana State University, Bozeman, MT, USA
| | - Qitao Ran
- Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, San Antonio, TX, USA.,Research and Development Service, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Reena V Kartha
- Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
| | - Simon C Johnson
- Department of Neurology, University of Washington, Seattle, WA, USA.,Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.,Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
| | | | - Elias S J Arnér
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.,Department of Selenoprotein Research, National Institute of Oncology, Budapest, 1521, Hungary
| | - Kristen M Wigby
- Department of Pediatrics, Division of Genetics, San Diego and Rady Children's Hospital-San Diego, University of California, San Diego, CA, USA.,Rady Children's Institute for Genomic Medicine, San Diego, CA, USA
| | - Matthew D Hall
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
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Physiological Functions of Thiol Peroxidases (Gpx1 and Prdx2) during Xenopus laevis Embryonic Development. Antioxidants (Basel) 2021; 10:antiox10101636. [PMID: 34679770 PMCID: PMC8533462 DOI: 10.3390/antiox10101636] [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: 09/29/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 11/18/2022] Open
Abstract
Glutathione peroxidase 1 (Gpx1) and peroxiredoxin 2 (Prdx2) belong to the thiol peroxidase family of antioxidants, and have been studied for their antioxidant functions and roles in cancers. However, the physiological significance of Gpx1 and Prdx2 during vertebrate embryogenesis are lacking. Currently, we investigated the functional roles of Gpx1 and Prdx2 during vertebrate embryogenesis using Xenopus laevis as a vertebrate model. Our investigations revealed the zygotic nature of gpx1 having its localization in the eye region of developing embryos, whereas prdx2 exhibited a maternal nature and were localized in embryonic ventral blood islands. Furthermore, the gpx1-morphants exhibited malformed eyes with incompletely detached lenses. However, the depletion of prdx2 has not established its involvement with embryogenesis. A molecular analysis of gpx1-depleted embryos revealed the perturbed expression of a cryba1-lens-specific marker and also exhibited reactive oxygen species (ROS) accumulation in the eye regions of gpx1-morphants. Additionally, transcriptomics analysis of gpx1-knockout embryos demonstrated the involvement of Wnt, cadherin, and integrin signaling pathways in the development of malformed eyes. Conclusively, our findings indicate the association of gpx1 with a complex network of embryonic developmental pathways and ROS responses, but detailed investigation is a prerequisite in order to pinpoint the mechanistic details of these interactions.
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Sharapov MG, Gudkov SV, Lankin VZ. Hydroperoxide-Reducing Enzymes in the Regulation of Free-Radical Processes. BIOCHEMISTRY. BIOKHIMIIA 2021; 86:1256-1274. [PMID: 34903155 DOI: 10.1134/s0006297921100084] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The review presents current concepts of the molecular mechanisms of oxidative stress development and describes main stages of the free-radical reactions in oxidative stress. Endogenous and exogenous factors of the oxidative stress development, including dysfunction of cell oxidoreductase systems, as well as the effects of various external physicochemical factors, are discussed. The review also describes the main components of the antioxidant defense system and stages of its evolution, with a special focus on peroxiredoxins, glutathione peroxidases, and glutathione S-transferases, which share some phylogenetic, structural, and catalytic properties. The substrate specificity, as well as the similarities and differences in the catalytic mechanisms of these enzymes, are discussed in detail. The role of peroxiredoxins, glutathione peroxidases, and glutathione S-transferases in the regulation of hydroperoxide-mediated intracellular and intercellular signaling and interactions of these enzymes with receptors and non-receptor proteins are described. An important contribution of hydroperoxide-reducing enzymes to the antioxidant protection and regulation of such cell processes as growth, differentiation, and apoptosis is demonstrated.
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Affiliation(s)
- Mars G Sharapov
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
| | - Sergey V Gudkov
- Prokhorov Institute of General Physics, Russian Academy of Sciences, Moscow, 119991, Russia.,Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, 603022, Russia.,All-Russian Research Institute of Phytopathology, Bolshiye Vyazemy, 143050, Russia
| | - Vadim Z Lankin
- National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
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Protective Effects and Mechanisms of Recombinant Human Glutathione Peroxidase 4 on Isoproterenol-Induced Myocardial Ischemia Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6632813. [PMID: 34539971 PMCID: PMC8443360 DOI: 10.1155/2021/6632813] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 07/26/2021] [Accepted: 08/21/2021] [Indexed: 01/15/2023]
Abstract
Ischemic heart disease (IHD) is a cardiovascular disease with high fatality rate, and its pathogenesis is closely related to oxidative stress. Reactive oxygen species (ROS) in oxidative stress can lead to myocardial ischemia (MI) injury in many ways. Therefore, the application of antioxidants may be an effective way to prevent IHD. In recent years, glutathione peroxidase 4 (GPx4) has received increasing attention due to its antioxidant effect. In a previous study, we used the new chimeric tRNAUTuT6 to express highly active recombinant human GPx4 (rhGPx4) in amber-less Escherichia coli. In this study, we established an isoproterenol- (ISO-) induced MI injury model in rats and an in vitro model to research the protective effect and mechanism of rhGPx4 on MI injury. The results showed that rhGPx4 could reduce the area of myocardial infarction and ameliorate the pathological injury of heart tissue, significantly reduce ISO-induced abnormalities on electrocardiogram (ECG) and cardiac serum biomarkers, protect mitochondrial function, and attenuate cardiac oxidative stress injury. In an in vitro model, the results also confirmed that rhGPx4 could inhibit ISO-induced oxidative stress injury and cardiomyocyte apoptosis. The mechanism of action of rhGPx4 involves not only the inhibition of lipid peroxidation by eliminating ROS but also keeping a normal level of endogenous antioxidant enzymes by eliminating ROS, thereby preventing oxidative stress injury in cardiomyocytes. Additionally, rhGPx4 could inhibit cardiomyocyte apoptosis through a mitochondria-dependent pathway. In short, rhGPx4, a recombinant antioxidant enzyme, can play an important role in the prevention of IHD and may have great potential for application.
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Glutathione peroxidase-1 regulates ASK1-dependent apoptosis via interaction with TRAF2 in RIPK3-negative cancer cells. Exp Mol Med 2021; 53:1080-1091. [PMID: 34158609 PMCID: PMC8257591 DOI: 10.1038/s12276-021-00642-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 05/13/2021] [Accepted: 05/17/2021] [Indexed: 12/26/2022] Open
Abstract
Glutathione peroxidase (GPx) is a selenocysteine-containing peroxidase enzyme that defends mammalian cells against oxidative stress, but the role of GPx signaling is poorly characterized. Here, we show that GPx type 1 (GPx1) plays a key regulatory role in the apoptosis signaling pathway. The absence of GPx1 augmented TNF-α-induced apoptosis in various RIPK3-negative cancer cells by markedly elevating the level of cytosolic H2O2, which is derived from mitochondria. At the molecular level, the absence of GPx1 led to the strengthened sequential activation of sustained JNK and caspase-8 expression. Two signaling mechanisms are involved in the GPx1-dependent regulation of the apoptosis pathway: (1) GPx1 regulates the level of cytosolic H2O2 that oxidizes the redox protein thioredoxin 1, blocking ASK1 activation, and (2) GPx1 interacts with TRAF2 and interferes with the formation of the active ASK1 complex. Inducible knockdown of GPx1 expression impaired the tumorigenic growth of MDA-MB-231 cells (>70% reduction, P = 0.0034) implanted in mice by promoting apoptosis in vivo. Overall, this study reveals the apoptosis-related signaling function of a GPx family enzyme highly conserved in aerobic organisms. An antioxidative enzyme that plays a critical role in regulating whether cells program their own death offers a promising new target for anti-cancer therapies. Glutathione peroxidase-1 (GPX1) is involved in cleaning up reactive metabolic byproducts such as hydrogen peroxide inside cells. Sang Won Kang and colleagues at Ewha Womans University in Seoul, South Korea, showed that this stress-response enzyme also suppresses the induction of normal programmed cell death mechanisms in a variety of cancer cells. The researchers detailed the molecular partners involved in GPX1-mediated signaling inside cancer cells, and demonstrated that genetically reducing GPX1 expression dramatically reduces tumor growth in a mouse model of breast cancer. Drugs with similar inhibitory effects on GPX1 activity might therefore also help shrink tumors in human cancer patients.
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Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death. Cancers (Basel) 2021; 13:cancers13102411. [PMID: 34067602 PMCID: PMC8156203 DOI: 10.3390/cancers13102411] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/10/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse underlying the need of new therapeutic approaches. Plasma cells are prone to produce large amounts of immunoglobulins causing the production of intracellular ROS. Although adapted to high level of ROS, MM cells die when exposed to drugs increasing ROS production either directly or by inhibiting antioxidant enzymes. In this review, we discuss the efficacy of ROS-generating drugs for inducing MM cell death and counteracting acquired drug resistance specifically toward proteasome inhibitors.
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Evaluating the Effects of MKAVCFSL Derived from Bighead Carp (Hypophthalmichthys nobilis) Flesh on Antioxidant Activity in Caco-2 Cells In Vitro. J FOOD QUALITY 2021. [DOI: 10.1155/2021/9975586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The effect of an antioxidative peptide Met-Lys-Ala-Val-Cys-Phe-Ser-Leu (MKAVCFSL) on oxidative stress in Caco-2 cell lines was investigated. Caco-2 cells exposed to excess oxidative stress could be restored when pretreated with the peptide. Reactive oxygen species (ROS) and malondialdehyde (MDA) within the cells could be scavenged by MKAVCFSL. The peptide could also enhance the activity of glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD), while catalase (CAT) activity did not show a significant difference between treatment and control samples. Meanwhile, it was observed that peptide treatment increased the concentration of glutathione (GSH). Yet the content of glutathione disulfide (GSSG) was hardly affected. The stability of MKAVCFSL was also assessed and an intact peptide was observed after simulated gastrointestinal digestion. Part of the peptide was hydrolyzed into fragments including MKA, FSL, AVCFSL, and MKAVCF. This study demonstrated that MKAVCFSL derived from bighead carp hydrolysates could ameliorate oxidative stress to protect the Caco-2 cells.
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Bessières B, Cruz E, Alberini CM. Metabolomic profiling reveals a differential role for hippocampal glutathione reductase in infantile memory formation. eLife 2021; 10:68590. [PMID: 34825649 PMCID: PMC8626085 DOI: 10.7554/elife.68590] [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: 03/19/2021] [Accepted: 11/09/2021] [Indexed: 01/12/2023] Open
Abstract
The metabolic mechanisms underlying the formation of early-life episodic memories remain poorly characterized. Here, we assessed the metabolomic profile of the rat hippocampus at different developmental ages both at baseline and following episodic learning. We report that the hippocampal metabolome significantly changes over developmental ages and that learning regulates differential arrays of metabolites according to age. The infant hippocampus had the largest number of significant changes following learning, with downregulation of 54 metabolites. Of those, a large proportion was associated with the glutathione-mediated cellular defenses against oxidative stress. Further biochemical, molecular, and behavioral assessments revealed that infantile learning evokes a rapid and persistent increase in the activity of neuronal glutathione reductase, the enzyme that regenerates reduced glutathione from its oxidized form. Inhibition of glutathione reductase selectively impaired long-term memory formation in infant but not in juvenile and adult rats, confirming its age-specific role. Thus, metabolomic profiling revealed that the hippocampal glutathione-mediated antioxidant pathway is differentially required for the formation of infantile memory.
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Affiliation(s)
| | - Emmanuel Cruz
- Center for Neural Science, New York UniversityNew YorkUnited States
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Kuang Y, Guo X, Guo A, Ran X, He Y, Zhang Y, Guo L. Single-molecule enzymatic reaction dynamics and mechanisms of GPX3 and TRXh9 from Arabidopsis thaliana. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2020; 243:118778. [PMID: 32810779 DOI: 10.1016/j.saa.2020.118778] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/16/2020] [Accepted: 07/19/2020] [Indexed: 06/11/2023]
Abstract
Glutathione peroxidases (GPXs) regulate the levels of reactive oxygen species in cells and tissues. During the redox cycling, the plant GPX is regenerated by thioredoxins (TRXs) as reductant rather than glutathione as the electron donor. However, the direct experimental observation on the interaction dynamics between GPXs and TRXs has not been reported, and the redox mechanism is unclear. In this work, the protein interactions between oxidized AtGPX3 and reduced AtTRXh9 have been studied using single-molecule fluorescence resonance energy transfer (smFRET). The obtained results indicate there are four processes in these two protein interaction, including biological recognition, binding, intermediate and unbinding state. Two enzymatic reaction intermediate states have been identified in the dissociation of AtGPX3-AtTRXh9 complex from binding to unbinding state, suggesting two types of interaction pathways and intermediate complexes. In particular, the dynamical study reveals that the redox reaction between oxidized AtGPX3 and reduced AtTRXh9 is realized through the forming and breaking of disulfide bonds via the active sites of Cys4 and Cys57 in AtTRXh9. These findings are of significant for deep understanding the redox reaction and mechanism between GPXs and TRXs enzymes, and studying other protein dynamics at single-molecule level.
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Affiliation(s)
- Yanmin Kuang
- State Key Laboratory of Crop Stress Adaptation and Improvement, Henan University, Kaifeng 475004, China; School of Physics and Electronics, International Joint Research Laboratory of New Energy Materials and Devices of Henan Province, Henan University, Kaifeng 475004, China
| | - Xing Guo
- School of Physics and Electronics, International Joint Research Laboratory of New Energy Materials and Devices of Henan Province, Henan University, Kaifeng 475004, China
| | - Aiyu Guo
- State Key Laboratory of Crop Stress Adaptation and Improvement, Henan University, Kaifeng 475004, China
| | - Xia Ran
- State Key Laboratory of Crop Stress Adaptation and Improvement, Henan University, Kaifeng 475004, China; School of Physics and Electronics, International Joint Research Laboratory of New Energy Materials and Devices of Henan Province, Henan University, Kaifeng 475004, China
| | - Yulu He
- School of Physics and Electronics, International Joint Research Laboratory of New Energy Materials and Devices of Henan Province, Henan University, Kaifeng 475004, China
| | - Yu Zhang
- State Key Laboratory of Crop Stress Adaptation and Improvement, Henan University, Kaifeng 475004, China
| | - Lijun Guo
- State Key Laboratory of Crop Stress Adaptation and Improvement, Henan University, Kaifeng 475004, China; School of Physics and Electronics, International Joint Research Laboratory of New Energy Materials and Devices of Henan Province, Henan University, Kaifeng 475004, China.
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Abstract
Significance: In humans, imbalances in the reduction-oxidation (redox) status of cells are associated with many pathological states. In addition, many therapeutics and prophylactics used as interventions for diverse pathologies either directly modulate oxidant levels or otherwise influence endogenous cellular redox systems. Recent Advances: The cellular machineries that maintain redox homeostasis or that function within antioxidant defense systems rely heavily on the regulated reactivities of sulfur atoms either within or derived from the amino acids cysteine and methionine. Recent advances have substantially advanced our understanding of the complex and essential chemistry of biological sulfur-containing molecules. Critical Issues: The redox machineries that maintain cellular homeostasis under diverse stresses can consume large amounts of energy to generate reducing power and/or large amounts of sulfur-containing nutrients to replenish or sustain intracellular stores. By understanding the metabolic pathways underlying these responses, one can better predict how to protect cells from specific stresses. Future Directions: Here, we summarize the current state of knowledge about the impacts of different stresses on cellular metabolism of sulfur-containing molecules. This analysis suggests that there remains more to be learned about how cells use sulfur chemistry to respond to stresses, which could in turn lead to advances in therapeutic interventions for some exposures or conditions.
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Affiliation(s)
- Colin G Miller
- Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, USA
| | - Edward E Schmidt
- Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, USA
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50
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Structural and functional characterization of the glutathione peroxidase-like thioredoxin peroxidase from the fungus Trichoderma reesei. Int J Biol Macromol 2020; 167:93-100. [PMID: 33259843 DOI: 10.1016/j.ijbiomac.2020.11.179] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/13/2020] [Accepted: 11/25/2020] [Indexed: 11/22/2022]
Abstract
Glutathione peroxidases (GPx) are a family of enzymes with the ability to reduce organic and inorganic hydroperoxides to the corresponding alcohols using glutathione or thioredoxin as an electron donor. Here, we report the functional and structural characterization of a GPx identified in Trichoderma reesei (TrGPx). TrGPx was recombinantly expressed in a bacterial host and purified using affinity. Using a thioredoxin coupled assay, TrGPx exhibited activity of 28 U and 12.5 U in the presence of the substrates H2O2 and t-BOOH, respectively, and no activity was observed when glutathione was used. These results indicated that TrGPx is a thioredoxin peroxidase and hydrolyses H2O2 better than t-BOOH. TrGPx kinetic parameters using a pyrogallol assay resulted at Kmapp = 11.7 mM, Vmaxapp = 10.9 IU/μg TrGPx, kcat = 19 s-1 and a catalytic efficiency of 1.6 mM-1 s-1 to H2O2 as substrate. Besides that, TrGPx demonstrated an optimum pH ranging from 9.0-12.0 and a half-life of 36 min at 80 °C. TrGPx 3D-structure was obtained in a reduced state and non-catalytic conformation. The overall fold is similar to the other phospholipid-hydroperoxide glutathione peroxidases. These data contribute to understand the antioxidant mechanism in fungi and provide information for using antioxidant enzymes in biotechnological applications.
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