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Zheng ML, Yang ZH, He B, Sun X, Zhan YT, Shao AQ, Hong YC, Yin CX, Wang MZ, Ba YC, Ye P. GFOD1 regulates oxidative stress-induced damage in ADHD via NF-κB signaling pathway. Brain Res 2025; 1858:149605. [PMID: 40210145 DOI: 10.1016/j.brainres.2025.149605] [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: 12/10/2024] [Revised: 03/11/2025] [Accepted: 03/26/2025] [Indexed: 04/12/2025]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a mental behavioral disorder that poses a serious health risk. Oxidative stress, which damages the function of neurons and astrocytes, has been discovered as a key factor contributing to ADHD pathology. A newly identified gene, Glucose-fructose oxidoreductase domain 1 (GFOD1), may be linked to the development of ADHD. It plays a role in regulating oxidative stress in ADHD; however, its exact role is unclear. This manuscript investigates the changes of GFOD1 expression and aim to correlate this with oxidative stress induced by NF-κB signaling pathway in the rat brains with ADHD and in vitro astrocytes. Our results revealed an increase in GFOD1 expression in the prefrontal cortex and cerebellar cortex of rats with ADHD, accompanied by neuronal injury and increased glial fibrillary acidic protein (GFAP) expression in astrocytes, concomitant with activation of the NF-κB p65/NOX2 signaling pathway. Along with this, GFOD1 overexpression in astrocytes resulted in an up-regulation of this signaling pathway similarly. Both ADHD rats and astrocytes in overexpressing GFOD1 showed elevated levels of reactive oxygen species (ROS) and Malondialdehyde (MDA), reduced activity of superoxide dismutase (SOD). Furthermore, treatment with the methylphenidate (MPH) did not affect GFOD1 expression. But it impacted the levels of oxidative stress mediated by the NF-κB p65/NOX2 signaling pathway. Overall, it is suggested that GFOD1 may contribute to increased levels of oxidative stress specifically in the prefrontal cortex and cerebellar cortex regions and astrocytes affected by ADHD via up-regulation of the NF-κB p65/NOX2/oxidative stress axis.
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Affiliation(s)
- Meng-Ling Zheng
- Department of Human Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, Yunnan Province 650500, China.
| | - Zhi-Hong Yang
- Department of Pathology and Pathophysiology, Faculty of Basic Medical Science, Kunming Medical University, Yunnan Province 650500, China.
| | - Bin He
- Department of Radiology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province 650500, China.
| | - Xin Sun
- Department of Human Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, Yunnan Province 650500, China.
| | - Yu-Ting Zhan
- The First School of Clinical Medicine, Kunming Medical University Kunming, Yunnan Province 650500, China.
| | - An-Qi Shao
- Faculty of Basic Medical Science, Kunming Medical University, Yunnan Province 650500, China.
| | - Yu-Chen Hong
- Faculty of Basic Medical Science, Kunming Medical University, Yunnan Province 650500, China.
| | - Cai-Xin Yin
- Faculty of Basic Medical Science, Kunming Medical University, Yunnan Province 650500, China.
| | - Ming-Zheng Wang
- Faculty of Basic Medical Science, Kunming Medical University, Yunnan Province 650500, China.
| | - Ying-Chun Ba
- Department of Human Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, Yunnan Province 650500, China.
| | - Pin Ye
- Department of Human Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, Yunnan Province 650500, China.
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Villegas LD, Mathiesen AV, Rasmussen I, von Broich M, Qvist FL, Skotte N, Bardile CF, Budtz-Jørgensen E, Freude K, Schmid B, Pouladi MA, Nørremølle A, Vilhardt F. A potential role for NADPH oxidase (NOX1/2) in mutant huntingtin-induced anomalous neurite outgrowth. Mol Cell Neurosci 2025:104012. [PMID: 40412581 DOI: 10.1016/j.mcn.2025.104012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 05/09/2025] [Accepted: 05/13/2025] [Indexed: 05/27/2025] Open
Abstract
Neurite growth is regulated by NADPH Oxidase (NOX1 and 2) and in this study, we investigate whether neuritic abnormalities observed in stem cell models of Huntington's disease relates to altered NOX function during NGF-driven differentiation of PC12 neuronal cells. NOX1 and 2 were contained in separate vesicular compartments, and by overexpression inhibited or promoted neurite extension, respectively. Expression of mutant Htt (mHtt; exon 1 fragment) accelerated neuronal induction causing longer neurites in the first phase of differentiation, but fewer and shorter mature neurites. Htt/mHtt increased NOX2 protein levels but did not change global oxidant production; However, Htt/mHtt prominently redistributed NOX activity to neurites. Oxidant production was concentrated in intraluminal vesicles in multivesicular bodies, and mHtt specifically increased secretion of NOX1 in exosomes, which demonstrated oxidant production capacity, while rerouting NOX2 to lysosomal degradation. Knockdown of TSG101, required for intraluminal vesicle formation, increased cellular levels of NOX2/p22phox and neurite growth. Our study provides new insights on the disposition of NOX enzymes in nerve cells, indicating that deficient neurites in HD may be a correlate of altered trafficking, distribution, and activity of NOX.
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Affiliation(s)
- Luisana Duque Villegas
- Department of Cellular and Molecular Medicine, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200N, Denmark
| | - Alberte Vad Mathiesen
- Department of Cellular and Molecular Medicine, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200N, Denmark
| | - Izabela Rasmussen
- Department of Cellular and Molecular Medicine, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200N, Denmark
| | - Maria von Broich
- Department of Cellular and Molecular Medicine, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200N, Denmark
| | - Fillippa Liliendahl Qvist
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niels Skotte
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Costanza Ferrari Bardile
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver V5Z 4H4, Canada
| | - Esben Budtz-Jørgensen
- Section of Biostatistics, Department of Public Health, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200N, Denmark
| | - Kristine Freude
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark
| | | | - Mahmoud A Pouladi
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver V5Z 4H4, Canada
| | - Anne Nørremølle
- Department of Cellular and Molecular Medicine, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200N, Denmark
| | - Frederik Vilhardt
- Department of Cellular and Molecular Medicine, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200N, Denmark.
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Zhang E, Yan X, Shen H, Zhao M, Gao X, Huang Y. Intracranial Aneurysm Biomarkers: A Convergence of Genetics, Inflammation, Oxidative Stress, and the Extracellular Matrix. Int J Mol Sci 2025; 26:3316. [PMID: 40244203 PMCID: PMC11989888 DOI: 10.3390/ijms26073316] [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: 03/13/2025] [Revised: 03/30/2025] [Accepted: 03/30/2025] [Indexed: 04/18/2025] Open
Abstract
Intracranial aneurysm (IA) is a common cerebrovascular disease in which sacral aneurysms occurring in the Wills ring region can lead to devastating subarachnoid hemorrhage. Despite advances in research, the underlying mechanisms of IA formation and rupture remain incompletely understood, hindering early diagnosis and effective treatment. This review comprehensively summarizes the current landscape of IA biomarkers, encompassing genetic markers, DNA, RNA, inflammatory molecules, oxidative stress proteins, and extracellular matrix (ECM) components. Accumulating evidence suggests that various biomarkers are associated with different stages of IA pathogenesis, including initiation, progression, and rupture. Aberrant ECM composition and remodeling have been observed in IA patients, and extracellular matrix-degrading enzymes are implicated in IA growth and rupture. Biomarker research in IA holds great potential for improving clinical outcomes. Future studies should focus on validating the existing biomarkers, identifying novel ones, and investigating their underlying mechanisms to facilitate the development of personalized preventive and therapeutic strategies for IA.
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Affiliation(s)
- Enhao Zhang
- Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China; (E.Z.); (X.Y.); (H.S.); (M.Z.)
| | - Xu Yan
- Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China; (E.Z.); (X.Y.); (H.S.); (M.Z.)
| | - Hangyu Shen
- Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China; (E.Z.); (X.Y.); (H.S.); (M.Z.)
| | - Mingyue Zhao
- Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China; (E.Z.); (X.Y.); (H.S.); (M.Z.)
| | - Xiang Gao
- Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China; (E.Z.); (X.Y.); (H.S.); (M.Z.)
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo 315010, China
| | - Yi Huang
- Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China; (E.Z.); (X.Y.); (H.S.); (M.Z.)
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo 315010, China
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Munteanu C, Galaction AI, Onose G, Turnea M, Rotariu M. The Janus Face of Oxidative Stress and Hydrogen Sulfide: Insights into Neurodegenerative Disease Pathogenesis. Antioxidants (Basel) 2025; 14:360. [PMID: 40227410 PMCID: PMC11939184 DOI: 10.3390/antiox14030360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/09/2025] [Accepted: 03/17/2025] [Indexed: 04/15/2025] Open
Abstract
Oxidative stress plays an essential role in neurodegenerative pathophysiology, acting as both a critical signaling mediator and a driver of neuronal damage. Hydrogen sulfide (H2S), a versatile gasotransmitter, exhibits a similarly "Janus-faced" nature, acting as a potent antioxidant and cytoprotective molecule at physiological concentrations, but becoming detrimental when dysregulated. This review explores the dual roles of oxidative stress and H2S in normal cellular physiology and pathophysiology, focusing on neurodegenerative disease progression. We highlight potential therapeutic opportunities for targeting redox and sulfur-based signaling systems in neurodegenerative diseases by elucidating the intricate balance between these opposing forces.
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Affiliation(s)
- Constantin Munteanu
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania; (A.I.G.); (M.R.)
- Neuromuscular Rehabilitation Clinic Division, Clinical Emergency Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania;
| | - Anca Irina Galaction
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania; (A.I.G.); (M.R.)
| | - Gelu Onose
- Neuromuscular Rehabilitation Clinic Division, Clinical Emergency Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania;
- Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 020022 Bucharest, Romania
| | - Marius Turnea
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania; (A.I.G.); (M.R.)
| | - Mariana Rotariu
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania; (A.I.G.); (M.R.)
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Silva ÁJC, de Lavor MSL. Nitroxidative Stress, Cell-Signaling Pathways, and Manganese Porphyrins: Therapeutic Potential in Neuropathic Pain. Int J Mol Sci 2025; 26:2050. [PMID: 40076672 PMCID: PMC11900433 DOI: 10.3390/ijms26052050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/23/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Neuropathic pain, a debilitating condition arising from somatosensory system damage, significantly impacts quality of life, leading to anxiety, self-mutilation, and depression. Oxidative and nitrosative stress, an imbalance between reactive oxygen and nitrogen species (ROS/RNS) and antioxidant defenses, plays a crucial role in its pathophysiology. While reactive species are essential for physiological functions, excessive levels can cause cellular component damage, leading to neuronal dysfunction and pain. This review highlights the complex interactions between reactive species, antioxidant systems, cell signaling, and neuropathic pain. We discuss the physiological roles of ROS/RNS and the detrimental effects of oxidative and nitrosative stress. Furthermore, we explore the potential of manganese porphyrins, compounds with antioxidant properties, as promising therapeutic agents to mitigate oxidative stress and alleviate neuropathic pain by targeting key cellular pathways involved in pain. Further research is needed to fully understand their therapeutic potential in managing neuropathic pain in human and non-human animals.
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Affiliation(s)
| | - Mário Sérgio Lima de Lavor
- Department of Agricultural and Environmental Sciences, State University of Santa Cruz (UESC), Ilhéus 45662-900, BA, Brazil;
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Chen X, Li P, Wang G. Development of a fluorescent probe for detecting superoxide anions for monitoring the progression and treatment of acute spondylitis. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2025; 17:533-538. [PMID: 39656111 DOI: 10.1039/d4ay01626b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
The superoxide anion (O2˙-) is a vital reactive oxygen species (ROS) and participates in various physiological and pathological processes in organisms. The outbreak of O2˙- in the endoplasmic reticulum (ER) is believed to be closely related to many inflammatory diseases. In this work, a turn-on type ER-targeting fluorescent probe ERO was rationally designed for sensitive and selective detection of O2˙-. The minimum detection limit concentration for O2˙- was about 3.3 × 10-7 M in aqueous solution. More importantly, the probe ERO has minimal biological toxicity and can effectively target the ER and detect O2˙- in macrophage cells. Resveratrol is a natural drug closely related to anti-inflammatory effects. Through fluorescence monitoring of the probe ERO, it was found that there was an outbreak of O2˙- in the ER in acute spondylitis in mice and resveratrol reversed this increase. Thus, the probe ERO has the potential to become a favorable diagnostic tool to visualize the mouse spine during inflammation and the therapeutic effect of resveratrol.
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Affiliation(s)
- Xiaoming Chen
- Department of Spinal Surgery, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China.
| | - Peng Li
- Department of Spinal Surgery, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China.
| | - Guiqing Wang
- Department of Spinal Surgery, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China.
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Yuasa K, Ichikawa T, Ishikawa Y, Jimbo H, Kawai-Yamada M, Shikata T, Nishiyama Y. Production of extracellular superoxide contributes to photosynthesis via elimination of reducing power and regeneration of NADP + in the red-tide-forming raphidophyte Chattonella marina complex. HARMFUL ALGAE 2024; 139:102712. [PMID: 39567064 DOI: 10.1016/j.hal.2024.102712] [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: 06/10/2024] [Revised: 07/29/2024] [Accepted: 08/26/2024] [Indexed: 11/22/2024]
Abstract
The raphidophyte Chattonella marina complex (hereafter Chattonella) consists of noxious red-tide-forming algae that are damaging to fish farms. Chattonella produces and secretes large amounts of the superoxide anion (•O2-), and the production of extracellular •O2- has been associated with fish mortality. We reported previously that photosynthetic electron transport is correlated with the production of •O2- in the genus Chattonella. However, the physiological roles of the production of extracellular •O2- remain to be clarified. In the present study, we examined the effects of the production of extracellular •O2- on photosynthesis and cell proliferation in two strains of Chattonella, namely, Ago03, a highly toxic strain that produces large amounts of •O2- externally, and Ago04, a low-toxicity strain that produces very small amounts of •O2-. Both the growth rate and the net photosynthetic activity of Ago04 were higher than those of Ago03. In Ago04, levels of Rubisco and 3-phosphoglycerate, the product of the reaction catalyzed by Rubisco, were 4-fold higher than those in Ago03, suggesting the higher photosynthetic activity of Ago04. In the presence of glycolaldehyde, a specific inhibitor of the Calvin-Benson cycle, the levels of NADP+ and the photosynthetic parameter qP declined under strong light in Ago04. By contrast, levels of NADP+ and qP in Ago03 changed less significantly than those in Ago04. Given that •O2- is produced by a putative NADPH oxidase that converts O2 to •O2- in Chattonella, it seems likely that the production of •O2- might play a role not only in the elimination of excess reducing power of NADPH from the cell, via •O2-, but also in the regeneration of NADP+, as a result of the action of NADPH oxidase, which oxidizes NADPH, to maintain photosynthetic electron transport.
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Affiliation(s)
- Koki Yuasa
- Fisheries Technology Institute, Japan Fisheries Research and Education Agency, 2-17-5 Maruishi, Hatsukaichi, Hiroshima 738-8635, Japan
| | - Takayoshi Ichikawa
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Yuma Ishikawa
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Haruhiko Jimbo
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Maki Kawai-Yamada
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Tomoyuki Shikata
- Fisheries Technology Institute, Japan Fisheries Research and Education Agency, 122-7 Nunoura, Tamanoura-cho, Goto, Nagasaki 853-0508, Japan
| | - Yoshitaka Nishiyama
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan; Green Bioscience Area, Strategic Research Center, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan.
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Yin Z, Zhang J, Zhao M, Liu J, Xu Y, Peng S, Pan W, Wei C, Zheng Z, Liu S, Qin JJ, Wan J, Wang M. EDIL3/Del-1 prevents aortic dissection through enhancing internalization and degradation of apoptotic vascular smooth muscle cells. Autophagy 2024; 20:2405-2425. [PMID: 38873925 PMCID: PMC11572282 DOI: 10.1080/15548627.2024.2367191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 05/28/2024] [Accepted: 06/08/2024] [Indexed: 06/15/2024] Open
Abstract
Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein involved in macrophage efferocytosis in acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of apoptotic VSMCs during TAD. The levels of EDIL3 were decreased in the serum and aortic tissue from TAD mice. Global edil3 knockout (edil3-/-) mice and edil3-/- bone marrow chimeric mice exhibited a considerable exacerbation in β-aminopropionitrile monofumarate (BAPN)-induced TAD, accompanied with increased apoptotic VSMCs accumulating in the damaged aortic tissue. Two types of phagocytes, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used for in vitro efferocytosis assay. edil3-deficient phagocytes exhibited inefficient internalization and degradation of apoptotic VSMCs. Instead, EDIL3 promoted the internalization phase through interacting with phosphatidylserine (PtdSer) on apoptotic VSMCs and binding to the macrophage ITGAV/αv-ITGB3/β3 integrin. In addition, EDIL3 accelerated the degradation phase through activating LC3-associated phagocytosis (LAP). Mechanically, following the engulfment, EDIL3 enhanced the activity of SMPD1/acid sphingomyelinase in the phagosome through blocking ITGAV-ITGB3 integrin, which facilitates phagosomal reactive oxygen species (ROS) production by NAPDH oxidase CYBB/NOX2. Furthermore, exogenous EDIL3 supplementation alleviated BAPN-induced TAD and promoted apoptotic cell clearance. EDIL3 may be a novel factor for the prevention and treatment of TAD.Abbreviations: BAPN: β-aminopropionitrile monofumarate; BMDM: bone marrow-derived macrophage; C12FDG: 5-dodecanoylaminofluorescein-di-β-D-galactopyranoside; CTRL: control; CYBB/NOX2: cytochrome b-245, beta polypeptide; DCFH-DA: 2',7'-dichlorofluorescin diacetate; EDIL3/Del-1: EGF-like repeats and discoidin I-like domains 3; EdU: 5-ethynyl-2'-deoxyuridine; EVG: elastic van Gieson; H&E: hematoxylin and eosin; IL: interleukin; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAC: N-acetylcysteine; PtdSer: phosphatidylserine; rEDIL3: recombinant EDIL3; ROS: reactive oxygen species; SMPD1: sphingomyelin phosphodiesterase 1; TAD: thoracic aortic dissection; TEM: transmission electron microscopy; VSMC: vascular smooth muscle cell; WT: wild-type.
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Affiliation(s)
- Zheng Yin
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jishou Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Mengmeng Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jianfang Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Yao Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Shanshan Peng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Wei Pan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Cheng Wei
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Zihui Zheng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Siqi Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Juan-Juan Qin
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Center for Healthy Aging, Wuhan University School of Nursing, Wuhan, China
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
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Grobben Y. Targeting amino acid-metabolizing enzymes for cancer immunotherapy. Front Immunol 2024; 15:1440269. [PMID: 39211039 PMCID: PMC11359565 DOI: 10.3389/fimmu.2024.1440269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Despite the immune system's role in the detection and eradication of abnormal cells, cancer cells often evade elimination by exploitation of various immune escape mechanisms. Among these mechanisms is the ability of cancer cells to upregulate amino acid-metabolizing enzymes, or to induce these enzymes in tumor-infiltrating immunosuppressive cells. Amino acids are fundamental cellular nutrients required for a variety of physiological processes, and their inadequacy can severely impact immune cell function. Amino acid-derived metabolites can additionally dampen the anti-tumor immune response by means of their immunosuppressive activities, whilst some can also promote tumor growth directly. Based on their evident role in tumor immune escape, the amino acid-metabolizing enzymes glutaminase 1 (GLS1), arginase 1 (ARG1), inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and interleukin 4 induced 1 (IL4I1) each serve as a promising target for immunotherapeutic intervention. This review summarizes and discusses the involvement of these enzymes in cancer, their effect on the anti-tumor immune response and the recent progress made in the preclinical and clinical evaluation of inhibitors targeting these enzymes.
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Ansari MA, Al-Jarallah A, Rao MS, Babiker A, Bensalamah K. Upregulation of NADPH-oxidase, inducible nitric oxide synthase and apoptosis in the hippocampus following impaired insulin signaling in the rats: Development of sporadic Alzheimer's disease. Brain Res 2024; 1834:148890. [PMID: 38552936 DOI: 10.1016/j.brainres.2024.148890] [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: 12/18/2023] [Revised: 02/21/2024] [Accepted: 03/26/2024] [Indexed: 04/06/2024]
Abstract
NADPH-oxidase (NOX) is a multi-subunit enzyme complex. The upregulation of NOX causes massive production of superoxide (O2¯), which avidly reacts with nitric oxide (NO) and increases cellular reactive oxygen/nitrogen species (ROS/RNS). Increased ROS/RNS plays pivotal role in the sporadic Alzheimer's disease (sAD) development and brain damage following impaired insulin signaling. Hence, this study aimed to examine early-time course of changes in NOX and NOS expression, and apoptotic proteins in the rats hippocampi following insulin signaling impairment [induced by STZ injection; intraperitoneal (IP) or in cerebral ventricles (ICV)]. Early effects (1, 3, or 6 weeks) on the NOX activity, translocation of NOX subunits from cytosol to the membrane, NO-synthases [neuronal-, inducible- and endothelial-NOS; nNOS, iNOS and eNOS], The Rac-1 protein expression, levels of NO and O2¯, cytochrome c release, caspase-3 and 9 activations (cleavage) were studied. STZ injection (in both models) increased NOX activity, O2¯ production, and enhanced cytosolic subunits translocation into membrane. The iNOS but not nNOS and eNOS expression and NO levels were increased in STZ treated rats. Finally, STZ injection increased cytochrome c release, caspase-3 and 9 activations in a manner that was significantly associated with levels of O2¯ and NO in the hippocampus. ICV-STZ administration resulted in significant profound changes over the IP route. In conclusion, impairment in insulin function induces early changes in ROS/RNS contents through NOX and iNOS upregulation and neuronal apoptosis in the hippocampus. Our results could mechanistically explain the role of impaired insulin function in the development of sAD.
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Affiliation(s)
- Mubeen A Ansari
- Department of Pharmacology and Toxicology, Kuwait University, Kuwait City, Safat 13110, Kuwait.
| | - Aishah Al-Jarallah
- Department of Biochemistry, Kuwait University, Kuwait City, Safat 13110, Kuwait
| | - Muddanna S Rao
- Department of Anatomy, Kuwait University, Kuwait City, Safat 13110, Kuwait
| | - Ahmed Babiker
- Faculty of Medicine, Kuwait University, Kuwait City, Safat 13110, Kuwait
| | - Khaled Bensalamah
- Faculty of Medicine, Kuwait University, Kuwait City, Safat 13110, Kuwait
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11
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Valipour J, Taghizadeh F, Esfahani R, Ramesh M, Rastegar T. Role of nuclear factor erythroid 2-related factor 2 (Nrf2) in female and male fertility. Heliyon 2024; 10:e29752. [PMID: 38720768 PMCID: PMC11076650 DOI: 10.1016/j.heliyon.2024.e29752] [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: 09/02/2023] [Revised: 04/14/2024] [Accepted: 04/15/2024] [Indexed: 05/12/2024] Open
Abstract
Oxidative stress refers to a condition where there is an imbalance between the production of reactive oxygen species and their removal by antioxidants. While the function of reactive oxygen species as specific second messengers under physiological conditions is necessary, their overproduction can lead to numerous instances of cell and tissue damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of many cytoprotective genes that respond to redox stresses. Nrf2 is regularly degraded by kelch-like ECH-associated protein 1 through the ubiquitin-proteasome pathway. The kelch-like ECH-associated protein 1 and Nrf2 complex have attracted attention in both basic and clinical infertility research fields. Oxidative stress is implicated in the pathogenesis of female infertility, including primary ovarian insufficiency, polycystic ovarian syndrome, and endometriosis, as well as male infertility, namely varicocele, cryptorchidism, spermatic cord torsion, and orchitis. Most scientists believe that Nrf2 is a potential therapeutic method in female and male infertility disorders due to its antioxidant effect. Here, the potential roles of oxidative stress and Nrf2 in female and male infertility disorders are reviewed. Moreover, the key role of Nrf2 in the inhibition or induction of these diseases is discussed.
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Affiliation(s)
- Jamal Valipour
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Taghizadeh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Roghayeh Esfahani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahya Ramesh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Rastegar
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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12
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Qin L, Yang S, Zhao C, Yang J, Li F, Xu Z, Yang Y, Zhou H, Li K, Xiong C, Huang W, Hu N, Hu X. Prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections. Bone Res 2024; 12:28. [PMID: 38744863 PMCID: PMC11094017 DOI: 10.1038/s41413-024-00332-w] [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: 12/06/2023] [Revised: 03/08/2024] [Accepted: 04/01/2024] [Indexed: 05/16/2024] Open
Abstract
Osteomyelitis is a devastating disease caused by microbial infection in deep bone tissue. Its high recurrence rate and impaired restoration of bone deficiencies are major challenges in treatment. Microbes have evolved numerous mechanisms to effectively evade host intrinsic and adaptive immune attacks to persistently localize in the host, such as drug-resistant bacteria, biofilms, persister cells, intracellular bacteria, and small colony variants (SCVs). Moreover, microbial-mediated dysregulation of the bone immune microenvironment impedes the bone regeneration process, leading to impaired bone defect repair. Despite advances in surgical strategies and drug applications for the treatment of bone infections within the last decade, challenges remain in clinical management. The development and application of tissue engineering materials have provided new strategies for the treatment of bone infections, but a comprehensive review of their research progress is lacking. This review discusses the critical pathogenic mechanisms of microbes in the skeletal system and their immunomodulatory effects on bone regeneration, and highlights the prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections. It will inform the development and translation of antimicrobial and bone repair tissue engineering materials for the management of bone infections.
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Affiliation(s)
- Leilei Qin
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China
| | - Shuhao Yang
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China
| | - Chen Zhao
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China
| | - Jianye Yang
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China
| | - Feilong Li
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China
| | - Zhenghao Xu
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China
| | - Yaji Yang
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China
| | - Haotian Zhou
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China
| | - Kainan Li
- Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, Sichuan, 610081, China
| | - Chengdong Xiong
- University of Chinese Academy of Sciences, Bei Jing, 101408, China
| | - Wei Huang
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China
| | - Ning Hu
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China.
| | - Xulin Hu
- Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, Sichuan, 610081, China.
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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13
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Herb M. NADPH Oxidase 3: Beyond the Inner Ear. Antioxidants (Basel) 2024; 13:219. [PMID: 38397817 PMCID: PMC10886416 DOI: 10.3390/antiox13020219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Reactive oxygen species (ROS) were formerly known as mere byproducts of metabolism with damaging effects on cellular structures. The discovery and description of NADPH oxidases (Nox) as a whole enzyme family that only produce this harmful group of molecules was surprising. After intensive research, seven Nox isoforms were discovered, described and extensively studied. Among them, the NADPH oxidase 3 is the perhaps most underrated Nox isoform, since it was firstly discovered in the inner ear. This stigma of Nox3 as "being only expressed in the inner ear" was also used by me several times. Therefore, the question arose whether this sentence is still valid or even usable. To this end, this review solely focuses on Nox3 and summarizes its discovery, the structural components, the activating and regulating factors, the expression in cells, tissues and organs, as well as the beneficial and detrimental effects of Nox3-mediated ROS production on body functions. Furthermore, the involvement of Nox3-derived ROS in diseases progression and, accordingly, as a potential target for disease treatment, will be discussed.
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Affiliation(s)
- Marc Herb
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50935 Cologne, Germany;
- German Centre for Infection Research, Partner Site Bonn-Cologne, 50931 Cologne, Germany
- Cologne Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50931 Cologne, Germany
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14
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Gleason N, Williams CL, Kowluru A. Novel regulatory roles of small G protein GDP dissociation stimulator (smgGDS) in insulin secretion from pancreatic β-cells. Mol Cell Endocrinol 2024; 580:112104. [PMID: 38013223 PMCID: PMC10842139 DOI: 10.1016/j.mce.2023.112104] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/26/2023] [Accepted: 10/28/2023] [Indexed: 11/29/2023]
Abstract
Emerging evidence implicates novel roles for small G protein GDP dissociation stimulator (smgGDS) in G protein activation and subsequent targeting to relevant subcellular compartments for effector regulation. Given the well-established roles of small G proteins in insulin secretion, we undertook this investigation to determine the putative roles of smgGDS in insulin secretion. Immunoblotting studies revealed that both splice variants of smgGDS are expressed in human islets, rat islets and INS-1 832/13 cells. A significant inhibition (-52%) of glucose-stimulated insulin secretion (GSIS) was observed in INS-1 832/13 cells following siRNA-mediated depletion of smgGDS. In addition, insulin secretion elicited by a membrane depolarizing concentration of KCl (via increased calcium influx), forskolin (via increased cAMP generation) or IBMX (via inhibition of phosphodiesterase) was inhibited by -49%, -27%, and -28%, respectively. Subcellular distribution studies revealed no significant alterations in the abundance of smgGDS in the cytosolic and membrane fractions during the 45-min exposure of INS-1 832/13 cells to an insulinotropic concentration of glucose. Together, we present the first evidence of expression of smgGDS in human islets, rodent islets, and clonal β-cells. We also demonstrate novel regulatory roles of these proteins in insulin secretion derived from glucose metabolic events, including calcium- and cAMP-dependent signaling steps.
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Affiliation(s)
- Noah Gleason
- Research Service, John D. Dingell VA Medical Center, USA; Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
| | - Carol L Williams
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Anjaneyulu Kowluru
- Research Service, John D. Dingell VA Medical Center, USA; Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.
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15
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Yao T, Liu X, Li D, Huang Y, Yang W, Liu R, Wang Q, Li X, Zhou J, Jin C, Liu Y, Yang B, Pang Y. Two-component system RstAB promotes the pathogenicity of adherent-invasive Escherichia coli in response to acidic conditions within macrophages. Gut Microbes 2024; 16:2356642. [PMID: 38769708 PMCID: PMC11135836 DOI: 10.1080/19490976.2024.2356642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/14/2024] [Indexed: 05/22/2024] Open
Abstract
Adherent-invasive Escherichia coli (AIEC) strain LF82, isolated from patients with Crohn's disease, invades gut epithelial cells, and replicates in macrophages contributing to chronic inflammation. In this study, we found that RstAB contributing to the colonization of LF82 in a mouse model of chronic colitis by promoting bacterial replication in macrophages. By comparing the transcriptomes of rstAB mutant- and wild-type when infected macrophages, 83 significant differentially expressed genes in LF82 were identified. And we identified two possible RstA target genes (csgD and asr) among the differentially expressed genes. The electrophoretic mobility shift assay and quantitative real-time PCR confirmed that RstA binds to the promoters of csgD and asr and activates their expression. csgD deletion attenuated LF82 intracellular biofilm formation, and asr deletion reduced acid tolerance compared with the wild-type. Acidic pH was shown by quantitative real-time PCR to be the signal sensed by RstAB to activate the expression of csgD and asr. We uncovered a signal transduction pathway whereby LF82, in response to the acidic environment within macrophages, activates transcription of the csgD to promote biofilm formation, and activates transcription of the asr to promote acid tolerance, promoting its replication within macrophages and colonization of the intestine. This finding deepens our understanding of the LF82 replication regulation mechanism in macrophages and offers new perspectives for further studies on AIEC virulence mechanisms.
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Affiliation(s)
- Ting Yao
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Xingmei Liu
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Dan Li
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Yu Huang
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Wen Yang
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Ruiying Liu
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Qian Wang
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Xueping Li
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Jiarui Zhou
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Chen Jin
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Yutao Liu
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Bin Yang
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
| | - Yu Pang
- TEDA (Tianjin Economic-Technological Development Area) Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China
- The Key Laboratory of Molecular Microbiology and Technology, TEDA Institute of Biological Sciences and Biotechnology, Ministry of Education, Nankai University, Tianjin, China
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16
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He Z, Li Q, Xu Y, Zhang D, Pan X. Production of extracellular superoxide radical in microorganisms and its environmental implications: A review. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 338:122563. [PMID: 37717891 DOI: 10.1016/j.envpol.2023.122563] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/24/2023] [Accepted: 09/14/2023] [Indexed: 09/19/2023]
Abstract
Extracellular superoxide radical (O2•-) is ubiquitous in microbial environments and has significant implications for pollutant transformation. Microbial extracellular O2•- can be produced through multiple pathways, including electron leakage from the respiratory electron transport chain (ETC), NADPH oxidation by the transmembrane NADPH oxidase (NOX), and extracellular reactions. Extracellular O2•- significantly influences the geochemical processes of various substances, including toxic metals and refractory organic pollutants. On one hand, extracellular O2•- can react with variable-valence metals and detoxify certain highly toxic metals, such as As(III), Cr(VI), and Hg(II). On the other hand, extracellular O2•- can directly or indirectly (via Bio-Fenton) degrade many organic pollutants, including a variety of emerging contaminants. In this work, we summarize the production mechanisms of microbial extracellular O2•-, review its roles in the transformation of environmental pollutants, and discuss the potential applications, limiting factors, and future research directions in this field.
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Affiliation(s)
- Zhanfei He
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, China
| | - Qunqun Li
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, China
| | - Yao Xu
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, China
| | - Daoyong Zhang
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, China
| | - Xiangliang Pan
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, China.
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17
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Khan F, Chen Y, Hartwell HJ, Yan J, Lin YH, Freedman A, Zhang Z, Zhang Y, Lambe AT, Turpin BJ, Gold A, Ault AP, Szmigielski R, Fry RC, Surratt JD. Heterogeneous Oxidation Products of Fine Particulate Isoprene Epoxydiol-Derived Methyltetrol Sulfates Increase Oxidative Stress and Inflammatory Gene Responses in Human Lung Cells. Chem Res Toxicol 2023; 36:1814-1825. [PMID: 37906555 DOI: 10.1021/acs.chemrestox.3c00278] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Hydroxyl radical (·OH)-initiated oxidation of isoprene, the most abundant nonmethane hydrocarbon in the atmosphere, is responsible for substantial amounts of secondary organic aerosol (SOA) within ambient fine particles. Fine particulate 2-methyltetrol sulfate diastereoisomers (2-MTSs) are abundant SOA products formed via acid-catalyzed multiphase chemistry of isoprene-derived epoxydiols with inorganic sulfate aerosols under low-nitric oxide conditions. We recently demonstrated that heterogeneous ·OH oxidation of particulate 2-MTSs leads to the particle-phase formation of multifunctional organosulfates (OSs). However, it remains uncertain if atmospheric chemical aging of particulate 2-MTSs induces toxic effects within human lung cells. We show that inhibitory concentration-50 (IC50) values decreased from exposure to fine particulate 2-MTSs that were heterogeneously aged for 0 to 22 days by ·OH, indicating increased particulate toxicity in BEAS-2B lung cells. Lung cells further exhibited concentration-dependent modulation of oxidative stress- and inflammatory-related gene expression. Principal component analysis was carried out on the chemical mixtures and revealed positive correlations between exposure to aged multifunctional OSs and altered expression of targeted genes. Exposure to particulate 2-MTSs alone was associated with an altered expression of antireactive oxygen species (ROS)-related genes (NQO-1, SOD-2, and CAT) indicative of a response to ROS in the cells. Increased aging of particulate 2-MTSs by ·OH exposure was associated with an increased expression of glutathione pathway-related genes (GCLM and GCLC) and an anti-inflammatory gene (IL-10).
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Affiliation(s)
- Faria Khan
- Institute of Physical Chemistry,Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Yuzhi Chen
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Hadley J Hartwell
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Jin Yan
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Ying-Hsuan Lin
- Department of Environmental Sciences, University of California, Riverside, California 92521, United States
| | - Anastasia Freedman
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Zhenfa Zhang
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Yue Zhang
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Department of Atmospheric Sciences, Texas A&M University, College Station Texas 77843, United States
| | - Andrew T Lambe
- Aerodyne Research Inc, Billerica, Massachusetts 01821, United States
| | - Barbara J Turpin
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Avram Gold
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Andrew P Ault
- Department of Chemistry, College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Rafal Szmigielski
- Institute of Physical Chemistry,Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
| | - Rebecca C Fry
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Jason D Surratt
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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18
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Hamza A, Cho JY, Cap KC, Hossain AJ, Kim JG, Park JB. Extracellular pyruvate kinase M2 induces cell migration through p-Tyr42 RhoA-mediated superoxide generation and epithelial-mesenchymal transition. Free Radic Biol Med 2023; 208:614-629. [PMID: 37722568 DOI: 10.1016/j.freeradbiomed.2023.09.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 09/12/2023] [Accepted: 09/15/2023] [Indexed: 09/20/2023]
Abstract
In the tumor microenvironment (TME), communication between cancer cells and tumor-associated macrophages (TAMs) through secreted extracellular proteins promotes cancer progression. Here, we observed that co-culturing cancer cells (4T1) and macrophage cells (Raw264.7) significantly enhanced superoxide production in both cell types. Using MALDI-TOF, we identified PKM2 as a highly secreted protein by Raw264.7 cells and bone marrow-derived monocytes. The extracellular recombinant PKM2 protein not only enhanced cancer cell migration and invasion but also increased superoxide production. Additionally, PKM2 was found to associate with the cell surface, and its binding to integrin α5/β1 receptor was inhibited by antibodies specifically targeting it. Furthermore, we investigated downstream signaling pathways involved in PKM2-induced superoxide production. We found that knock-down of RhoA and p47phox using siRNAs effectively abolished superoxide generation in response to extracellular PKM2. Notably, extracellular PKM2 triggered the phosphorylation of p47phox at Ser345 residue and RhoA at Tyr42 residue (p-Tyr42 RhoA). Moreover, extracellular PKM2 exerted regulatory control over the expression of key epithelial-mesenchymal transition (EMT) markers, including ZEB1, Snail1, vimentin, and E-cadherin. Interestingly, p-Tyr42 RhoA translocated to the nucleus, where it bound to the ZEB1 promoter region. In light of these findings, we propose that extracellular PKM2 within the TME plays a critical role in tumorigenesis by promoting cancer cell migration and invasion through RhoA/p47phox signaling pathway.
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Affiliation(s)
- Amir Hamza
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea
| | - Jung Yoon Cho
- Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea
| | - Kim Cuong Cap
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea; Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea
| | - Abu Jubayer Hossain
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea; Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea
| | - Jae-Gyu Kim
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea; Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea
| | - Jae-Bong Park
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea; Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea.
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19
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Cipriano A, Viviano M, Feoli A, Milite C, Sarno G, Castellano S, Sbardella G. NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors. J Med Chem 2023; 66:11632-11655. [PMID: 37650225 PMCID: PMC10510401 DOI: 10.1021/acs.jmedchem.3c00770] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Indexed: 09/01/2023]
Abstract
NADPH oxidases (NOXs) form a family of electron-transporting membrane enzymes whose main function is reactive oxygen species (ROS) generation. Strong evidence suggests that ROS produced by NOX enzymes are major contributors to oxidative damage under pathologic conditions. Therefore, blocking the undesirable actions of these enzymes is a therapeutic strategy for treating various pathological disorders, such as cardiovascular diseases, inflammation, and cancer. To date, identification of selective NOX inhibitors is quite challenging, precluding a pharmacologic demonstration of NOX as therapeutic targets in vivo. The aim of this Perspective is to furnish an updated outlook about the small-molecule NOX inhibitors described over the last two decades. Structures, activities, and in vitro/in vivo specificity are discussed, as well as the main biological assays used.
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Affiliation(s)
- Alessandra Cipriano
- Department
of Pharmacy, Epigenetic Med Chem Lab, and PhD Program in Drug Discovery and
Development, University of Salerno, via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy
| | - Monica Viviano
- Department
of Pharmacy, Epigenetic Med Chem Lab, and PhD Program in Drug Discovery and
Development, University of Salerno, via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy
| | - Alessandra Feoli
- Department
of Pharmacy, Epigenetic Med Chem Lab, and PhD Program in Drug Discovery and
Development, University of Salerno, via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy
| | - Ciro Milite
- Department
of Pharmacy, Epigenetic Med Chem Lab, and PhD Program in Drug Discovery and
Development, University of Salerno, via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy
| | - Giuliana Sarno
- Department
of Pharmacy, Epigenetic Med Chem Lab, and PhD Program in Drug Discovery and
Development, University of Salerno, via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy
| | - Sabrina Castellano
- Department
of Pharmacy, Epigenetic Med Chem Lab, and PhD Program in Drug Discovery and
Development, University of Salerno, via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy
| | - Gianluca Sbardella
- Department
of Pharmacy, Epigenetic Med Chem Lab, and PhD Program in Drug Discovery and
Development, University of Salerno, via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy
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20
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Hiramoto K, Kubo S, Tsuji K, Sugiyama D, Hamano H. Induction of Skin Cancer by Long-Term Blue Light Irradiation. Biomedicines 2023; 11:2321. [PMID: 37626816 PMCID: PMC10452187 DOI: 10.3390/biomedicines11082321] [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: 07/04/2023] [Revised: 07/19/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Presently, people are not only exposed to sunlight but also to a large amount of blue light from personal computers and smartphones. This blue light has various effects on the living body. However, its effect on the induction of skin cancer is unknown. In this study, we investigated the induction of skin cancer by long-term blue light irradiation. Hairless mice were irradiated with blue light (LED; peak emission 479 nm) every day for one year, and a control was irradiated with white light (LED), green light (LED; peak emission 538 nm), and red light (LED; peak emission 629 nm) for one year, respectively. Skin cancer was induced only in the mice exposed to blue light. Long-term blue light irradiation also increased the migration of neutrophils and macrophages involved in carcinogenesis in the skin. In neutrophils, an increased expression of citH3 and PAD4 was observed, suggesting the possibility of NETosis. Conversely, in macrophages, inflammatory macrophages (type 1 macrophages) increased and anti-inflammatory macrophages (type 2 macrophages) decreased due to continuous blue light irradiation. These findings suggest that long-term continuous irradiation with blue light induces neutrophil NETosis and an increase in type 1 macrophages, resulting in skin cancer.
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Affiliation(s)
- Keiichi Hiramoto
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Japan
| | - Sayaka Kubo
- Research Department, Daiichi Sankyo Healthcare Co., Ltd., Chuo-ku, Tokyo 140-8170, Japan; (S.K.); (K.T.); (D.S.); (H.H.)
| | - Keiko Tsuji
- Research Department, Daiichi Sankyo Healthcare Co., Ltd., Chuo-ku, Tokyo 140-8170, Japan; (S.K.); (K.T.); (D.S.); (H.H.)
| | - Daijiro Sugiyama
- Research Department, Daiichi Sankyo Healthcare Co., Ltd., Chuo-ku, Tokyo 140-8170, Japan; (S.K.); (K.T.); (D.S.); (H.H.)
| | - Hideo Hamano
- Research Department, Daiichi Sankyo Healthcare Co., Ltd., Chuo-ku, Tokyo 140-8170, Japan; (S.K.); (K.T.); (D.S.); (H.H.)
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21
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Li X, Sun C, Zhang J, Hu L, Yu Z, Zhang X, Wang Z, Chen J, Wu M, Liu L. Protective effects of paeoniflorin on cardiovascular diseases: A pharmacological and mechanistic overview. Front Pharmacol 2023; 14:1122969. [PMID: 37324475 PMCID: PMC10267833 DOI: 10.3389/fphar.2023.1122969] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/10/2023] [Indexed: 06/17/2023] Open
Abstract
Background and ethnopharmacological relevance: The morbidity and mortality of cardiovascular diseases (CVDs) are among the highest of all diseases, necessitating the search for effective drugs and the improvement of prognosis for CVD patients. Paeoniflorin (5beta-[(Benzoyloxy)methyl] tetrahydro-5-hydroxy-2-methyl-2,5-methano-1H-3,4-dioxacyclobuta [cd] pentalen-1alpha (2H)-yl-beta-D-glucopyranoside, C23H28O11) is mostly derived from the plants of the family Paeoniaceae (a single genus family) and is known to possess multiple pharmacological properties in the treatment of CVDs, making it a promising agent for the protection of the cardiovascular system. Aim of the study: This review evaluates the pharmacological effects and potential mechanisms of paeoniflorin in the treatment of CVDs, with the aim of advancing its further development and application. Methods: Various relevant literatures were searched in PubMed, ScienceDirect, Google Scholar and Web of Science. All eligible studies were analyzed and summarized in this review. Results: Paeoniflorin is a natural drug with great potential for development, which can protect the cardiovascular system by regulating glucose and lipid metabolism, exerting anti-inflammatory, anti-oxidative stress, and anti-arteriosclerotic activities, improving cardiac function, and inhibiting cardiac remodeling. However, paeoniflorin was found to have low bioavailability, and its toxicology and safety must be further studied and analyzed, and clinical studies related to it must be carried out. Conclusion: Before paeoniflorin can be used as an effective therapeutic drug for CVDs, further in-depth experimental research, clinical trials, and structural modifications or development of new preparations are required.
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Affiliation(s)
- Xiaoya Li
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Changxin Sun
- Beijing University of Chinese Medicine, Beijing, China
| | - Jingyi Zhang
- Beijing University of Chinese Medicine, Beijing, China
| | - Lanqing Hu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zongliang Yu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaonan Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zeping Wang
- Beijing University of Chinese Medicine, Beijing, China
| | - Jiye Chen
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Min Wu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Longtao Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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22
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Shu P, Liang H, Zhang J, Lin Y, Chen W, Zhang D. Reactive oxygen species formation and its effect on CD4 + T cell-mediated inflammation. Front Immunol 2023; 14:1199233. [PMID: 37304262 PMCID: PMC10249013 DOI: 10.3389/fimmu.2023.1199233] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/16/2023] [Indexed: 06/13/2023] Open
Abstract
Reactive oxygen species (ROS) are produced both enzymatically and non-enzymatically in vivo. Physiological concentrations of ROS act as signaling molecules that participate in various physiological and pathophysiological activities and play an important role in basic metabolic functions. Diseases related to metabolic disorders may be affected by changes in redox balance. This review details the common generation pathways of intracellular ROS and discusses the damage to physiological functions when the ROS concentration is too high to reach an oxidative stress state. We also summarize the main features and energy metabolism of CD4+ T-cell activation and differentiation and the effects of ROS produced during the oxidative metabolism of CD4+ T cells. Because the current treatment for autoimmune diseases damages other immune responses and functional cells in the body, inhibiting the activation and differentiation of autoreactive T cells by targeting oxidative metabolism or ROS production without damaging systemic immune function is a promising treatment option. Therefore, exploring the relationship between T-cell energy metabolism and ROS and the T-cell differentiation process provides theoretical support for discovering effective treatments for T cell-mediated autoimmune diseases.
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Affiliation(s)
| | | | | | | | | | - Dunfang Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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23
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Ahmadi Y, Fard JK, Ghafoor D, Eid AH, Sahebkar A. Paradoxical effects of statins on endothelial and cancer cells: the impact of concentrations. Cancer Cell Int 2023; 23:43. [PMID: 36899388 PMCID: PMC9999585 DOI: 10.1186/s12935-023-02890-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 03/04/2023] [Indexed: 03/12/2023] Open
Abstract
In addition to their lipid-lowering functions, statins elicit additional pleiotropic effects on apoptosis, angiogenesis, inflammation, senescence, and oxidative stress. Many of these effects have been reported in cancerous and noncancerous cells like endothelial cells (ECs), endothelial progenitor cells (EPCs) and human umbilical vein cells (HUVCs). Not surprisingly, statins' effects appear to vary largely depending on the cell context, especially as pertains to modulation of cell cycle, senescence, and apoptotic processes. Perhaps the most critical reason for this discordance is the bias in selecting the applied doses in various cells. While lower (nanomolar) concentrations of statins impose anti-senescence, and antiapoptotic effects, higher concentrations (micromolar) appear to precipitate opposite effects. Indeed, most studies performed in cancer cells utilized high concentrations, where statin-induced cytotoxic and cytostatic effects were noted. Some studies report that even at low concentrations, statins induce senescence or cytostatic impacts but not cytotoxic effects. However, the literature appears to be relatively consistent that in cancer cells, statins, in both low or higher concentrations, induce apoptosis or cell cycle arrest, anti-proliferative effects, and cause senescence. However, statins' effects on ECs depend on the concentrations; at micromolar concentrations statins cause cell senescence and apoptosis, while at nonomolar concentrations statins act reversely.
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Affiliation(s)
- Yasin Ahmadi
- College of Science, Department of Medical Laboratory Sciences, Komar University of Science and Technology, 46001, Sulaymania, Iraq.
| | - Javad Khalili Fard
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dlzar Ghafoor
- College of Science, Department of Medical Laboratory Sciences, Komar University of Science and Technology, 46001, Sulaymania, Iraq
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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24
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Azarova I, Polonikov A, Klyosova E. Molecular Genetics of Abnormal Redox Homeostasis in Type 2 Diabetes Mellitus. Int J Mol Sci 2023; 24:4738. [PMID: 36902173 PMCID: PMC10003739 DOI: 10.3390/ijms24054738] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023] Open
Abstract
Numerous studies have shown that oxidative stress resulting from an imbalance between the production of free radicals and their neutralization by antioxidant enzymes is one of the major pathological disorders underlying the development and progression of type 2 diabetes (T2D). The present review summarizes the current state of the art advances in understanding the role of abnormal redox homeostasis in the molecular mechanisms of T2D and provides comprehensive information on the characteristics and biological functions of antioxidant and oxidative enzymes, as well as discusses genetic studies conducted so far in order to investigate the contribution of polymorphisms in genes encoding redox state-regulating enzymes to the disease pathogenesis.
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Affiliation(s)
- Iuliia Azarova
- Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
| | - Alexey Polonikov
- Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
| | - Elena Klyosova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
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25
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Structure, Activation, and Regulation of NOX2: At the Crossroad between the Innate Immunity and Oxidative Stress-Mediated Pathologies. Antioxidants (Basel) 2023; 12:antiox12020429. [PMID: 36829988 PMCID: PMC9952346 DOI: 10.3390/antiox12020429] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/04/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is a multisubunit enzyme complex that participates in the generation of superoxide or hydrogen peroxide (H2O2) and plays a key role in several biological functions. Among seven known NOX isoforms, NOX2 was the first identified in phagocytes but is also expressed in several other cell types including endothelial cells, platelets, microglia, neurons, and muscle cells. NOX2 has been assigned multiple roles in regulating many aspects of innate and adaptive immunity, and human and mouse models of NOX2 genetic deletion highlighted this key role. On the other side, NOX2 hyperactivation is involved in the pathogenesis of several diseases with different etiologies but all are characterized by an increase in oxidative stress and inflammatory process. From this point of view, the modulation of NOX2 represents an important therapeutic strategy aimed at reducing the damage associated with its hyperactivation. Although pharmacological strategies to selectively modulate NOX2 are implemented thanks to new biotechnologies, this field of research remains to be explored. Therefore, in this review, we analyzed the role of NOX2 at the crossroads between immunity and pathologies mediated by its hyperactivation. We described (1) the mechanisms of activation and regulation, (2) human, mouse, and cellular models studied to understand the role of NOX2 as an enzyme of innate immunity, (3) some of the pathologies associated with its hyperactivation, and (4) the inhibitory strategies, with reference to the most recent discoveries.
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26
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Abstract
NOX2 is the prototypical member of the NADPH oxidase NOX superfamily and produces superoxide (O2•-), a key reactive oxygen species (ROS) that is essential in innate and adaptive immunity. Mutations that lead to deficiency in NOX2 activity correlate with increased susceptibility to bacterial and fungal infections, resulting in chronic granulomatous disease. The core of NOX2 is formed by a heterodimeric transmembrane complex composed of NOX2 (formerly gp91) and p22, but a detailed description of its structural architecture is lacking. Here, we present the structure of the human NOX2 core complex bound to a selective anti-NOX2 antibody fragment. The core complex reveals an intricate extracellular topology of NOX2, a four-transmembrane fold of the p22 subunit, and an extensive transmembrane interface which provides insights into NOX2 assembly and activation. Functional assays uncover an inhibitory activity of the 7G5 antibody mediated by internalization-dependent and internalization-independent mechanisms. Overall, our results provide insights into the NOX2 core complex architecture, disease-causing mutations, and potential avenues for selective NOX2 pharmacological modulation.
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27
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Abou-Hamdan A, Mahler R, Grossenbacher P, Biner O, Sjöstrand D, Lochner M, Högbom M, von Ballmoos C. Functional design of bacterial superoxide:quinone oxidoreductase. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2022; 1863:148583. [PMID: 35671795 DOI: 10.1016/j.bbabio.2022.148583] [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: 01/30/2022] [Revised: 05/10/2022] [Accepted: 05/31/2022] [Indexed: 06/15/2023]
Abstract
The superoxide anion - molecular oxygen reduced by a single electron - is produced in large amounts by enzymatic and adventitious reactions. It can perform a range of cellular functions, including bacterial warfare and iron uptake, signalling and host immune response in eukaryotes. However, it also serves as precursor for more deleterious species such as the hydroxyl anion or peroxynitrite and defense mechanisms to neutralize superoxide are important for cellular health. In addition to the soluble proteins superoxide dismutase and superoxide reductase, recently the membrane embedded diheme cytochrome b561 (CybB) from E. coli has been proposed to act as a superoxide:quinone oxidoreductase. Here, we confirm superoxide and cellular ubiquinones or menaquinones as natural substrates and show that quinone binding to the enzyme accelerates the reaction with superoxide. The reactivity of the substrates is in accordance with the here determined midpoint potentials of the two b hemes (+48 and -23 mV / NHE). Our data suggest that the enzyme can work near the diffusion limit in the forward direction and can also catalyse the reverse reaction efficiently under physiological conditions. The data is discussed in the context of described cytochrome b561 proteins and potential physiological roles of CybB.
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Affiliation(s)
- Abbas Abou-Hamdan
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Roman Mahler
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Philipp Grossenbacher
- Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland
| | - Olivier Biner
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland; Department of Plant and Microbial Biology, University of Zürich, 8008 Zürich, Switzerland
| | - Dan Sjöstrand
- Stockholm center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden
| | - Martin Lochner
- Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland
| | - Martin Högbom
- Stockholm center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden
| | - Christoph von Ballmoos
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland.
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28
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Nyssen P, Franck T, Serteyn D, Mouithys-Mickalad A, Hoebeke M. Propofol metabolites and derivatives inhibit the oxidant activities of neutrophils and myeloperoxidase. Free Radic Biol Med 2022; 191:164-175. [PMID: 36064069 DOI: 10.1016/j.freeradbiomed.2022.08.039] [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: 05/24/2022] [Revised: 08/10/2022] [Accepted: 08/29/2022] [Indexed: 10/14/2022]
Abstract
In previous studies, propofol has shown immunomodulatory abilities on various in vitro models. As this anesthetic molecule is extensively used in intensive care units, its anti-inflammatory properties present a great interest for the treatment of inflammatory disorders like the systemic inflammatory response syndrome. In addition to its inhibition abilities on important neutrophils mechanisms (chemotaxis, reactive oxygen species (ROS) production, Neutrophil Extracellular Traps (NETs) formation, …), our group has shown that propofol is also a reversible inhibitor of the oxidant myeloperoxidase (MPO) activity. Propofol being subject to rapid metabolism, its derivatives could contribute to its anti-inflammatory action. First, propofol-β-glucuronide (PPFG), 2,6-diisopropyl-1,4-p-benzoquinone (PPFQ) and 3,5,3',5'-tetraisopropyl-(4,4')-diphenoquinone (PPFDQ) were compared on their superoxide (O2.-) scavenging properties and more importantly on their inhibitory action on the O2.- release by activated neutrophils using EPR spectroscopy and chemiluminescence assays. PPFQ and PPFDQ are potent superoxide scavengers and also inhibit the release of ROS by neutrophils. An Enzyme-Linked Immunosorbent Assay (ELISA) has also highlighted the ability of both molecules to significantly decrease the MPO degranulation process of neutrophils. Fluorescence enzymatic assays helped to investigate the action of the propofol derivatives on the peroxidase and chlorination activities of MPO. In addition, using SIEFED (Specific Immunological Extraction Followed by Enzyme Detection) assays and docking, we demonstrated the concentration-dependent inhibitory action of PPFQ and its ability to bind to the enzyme active site while PPFG presented a much weaker inhibitory action. Overall, the oxidation derivatives and metabolites PPFQ and PPFDQ can, at physiological concentrations, perpetuate the immunomodulatory action of propofol by acting on the oxidant response of PMN and MPO.
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Affiliation(s)
- Pauline Nyssen
- Biomedical Spectroscopy Laboratory, Department of Physics, CESAM, University of Liège, Building B5a, Quartier Agora, Allée Du 6 Août, 19, 4000 Liège (Sart-Tilman), Belgium.
| | - Thierry Franck
- CORD, Department of Chemistry, CIRM, University of Liège, Building B6a, Quartier Agora, Allée Du 6 Août, 13, 4000 Liège (Sart-Tilman), Belgium
| | - Didier Serteyn
- CORD, Department of Chemistry, CIRM, University of Liège, Building B6a, Quartier Agora, Allée Du 6 Août, 13, 4000 Liège (Sart-Tilman), Belgium; Department of Clinical Sciences, Anesthesiology and Equine Surgery, Faculty of Veterinary Medicine, University of Liège, Building B41, Quartier Vallée 2, Avenue de Cureghem 5, 4000 Liège (Sart-Tilman), Belgium
| | - Ange Mouithys-Mickalad
- CORD, Department of Chemistry, CIRM, University of Liège, Building B6a, Quartier Agora, Allée Du 6 Août, 13, 4000 Liège (Sart-Tilman), Belgium
| | - Maryse Hoebeke
- Biomedical Spectroscopy Laboratory, Department of Physics, CESAM, University of Liège, Building B5a, Quartier Agora, Allée Du 6 Août, 19, 4000 Liège (Sart-Tilman), Belgium
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29
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NADPH Oxidases in Aortic Aneurysms. Antioxidants (Basel) 2022; 11:antiox11091830. [PMID: 36139902 PMCID: PMC9495752 DOI: 10.3390/antiox11091830] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/08/2022] [Accepted: 09/12/2022] [Indexed: 12/02/2022] Open
Abstract
Abdominal aortic aneurysms (AAAs) are a progressive dilation of the infrarenal aorta and are characterized by inflammatory cell infiltration, smooth muscle cell migration and proliferation, and degradation of the extracellular matrix. Oxidative stress and the production of reactive oxygen species (ROS) have been shown to play roles in inflammatory cell infiltration, and smooth muscle cell migration and apoptosis in AAAs. In this review, we discuss the principles of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase/NOX) signaling and activation. We also discuss the effects of some of the major mediators of NOX signaling in AAAs. Separately, we also discuss the influence of genetic or pharmacologic inhibitors of NADPH oxidases on experimental pre-clinical AAAs. Experimental evidence suggests that NADPH oxidases may be a promising future therapeutic target for developing pharmacologic treatment strategies for halting AAA progression or rupture prevention in the management of clinical AAAs.
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30
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Piccirillo S, Magi S, Preziuso A, Serfilippi T, Cerqueni G, Orciani M, Amoroso S, Lariccia V. The Hidden Notes of Redox Balance in Neurodegenerative Diseases. Antioxidants (Basel) 2022; 11:1456. [PMID: 35892658 PMCID: PMC9331713 DOI: 10.3390/antiox11081456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/15/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Reactive oxygen species (ROS) are versatile molecules that, even if produced in the background of many biological processes and responses, possess pleiotropic roles categorized in two interactive yet opposite domains. In particular, ROS can either function as signaling molecules that shape physiological cell functions, or act as deleterious end products of unbalanced redox reactions. Indeed, cellular redox status needs to be tightly regulated to ensure proper cellular functioning, and either excessive ROS accumulation or the dysfunction of antioxidant systems can perturb the redox homeostasis, leading to supraphysiological concentrations of ROS and potentially harmful outcomes. Therefore, whether ROS would act as signaling molecules or as detrimental factors strictly relies on a dynamic equilibrium between free radical production and scavenging resources. Of notice, the mammalian brain is particularly vulnerable to ROS-mediated toxicity, because it possesses relatively poor antioxidant defenses to cope with the redox burden imposed by the elevated oxygen consumption rate and metabolic activity. Many features of neurodegenerative diseases can in fact be traced back to causes of oxidative stress, which may influence both the onset and progression of brain demise. This review focuses on the description of the dual roles of ROS as double-edge sword in both physiological and pathological settings, with reference to Alzheimer's and Parkinson's diseases.
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Affiliation(s)
- Silvia Piccirillo
- Department of Biomedical Sciences and Public Health, School of Medicine, University Politecnica delle Marche, Via Tronto 10/A, 60126 Ancona, Italy; (S.P.); (A.P.); (T.S.); (G.C.); (S.A.); (V.L.)
| | - Simona Magi
- Department of Biomedical Sciences and Public Health, School of Medicine, University Politecnica delle Marche, Via Tronto 10/A, 60126 Ancona, Italy; (S.P.); (A.P.); (T.S.); (G.C.); (S.A.); (V.L.)
| | - Alessandra Preziuso
- Department of Biomedical Sciences and Public Health, School of Medicine, University Politecnica delle Marche, Via Tronto 10/A, 60126 Ancona, Italy; (S.P.); (A.P.); (T.S.); (G.C.); (S.A.); (V.L.)
| | - Tiziano Serfilippi
- Department of Biomedical Sciences and Public Health, School of Medicine, University Politecnica delle Marche, Via Tronto 10/A, 60126 Ancona, Italy; (S.P.); (A.P.); (T.S.); (G.C.); (S.A.); (V.L.)
| | - Giorgia Cerqueni
- Department of Biomedical Sciences and Public Health, School of Medicine, University Politecnica delle Marche, Via Tronto 10/A, 60126 Ancona, Italy; (S.P.); (A.P.); (T.S.); (G.C.); (S.A.); (V.L.)
| | - Monia Orciani
- Department of Clinical and Molecular Sciences-Histology, School of Medicine, University Politecnica delle Marche, Via Tronto 10/A, 60126 Ancona, Italy;
| | - Salvatore Amoroso
- Department of Biomedical Sciences and Public Health, School of Medicine, University Politecnica delle Marche, Via Tronto 10/A, 60126 Ancona, Italy; (S.P.); (A.P.); (T.S.); (G.C.); (S.A.); (V.L.)
| | - Vincenzo Lariccia
- Department of Biomedical Sciences and Public Health, School of Medicine, University Politecnica delle Marche, Via Tronto 10/A, 60126 Ancona, Italy; (S.P.); (A.P.); (T.S.); (G.C.); (S.A.); (V.L.)
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Lee SH, Won GW, Choi SH, Kim MY, Oh CH, Park JT, Park JI. Antiaging effect of inotodiol on oxidative stress in human dermal fibroblasts. Biomed Pharmacother 2022; 153:113311. [PMID: 35759867 DOI: 10.1016/j.biopha.2022.113311] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/06/2022] [Accepted: 06/15/2022] [Indexed: 11/24/2022] Open
Abstract
Oxidative damage is one of the major causes of human skin aging. Inotodiol is a lanostane triterpenoid that demonstrates antiviral, anticancer, and anti-inflammatory activities. Previous studies have reported that inotodiol also has antiallergic effects. However, whether inotodiol inhibits oxidative stress-induced human skin aging is not known. Stimulation of human dermal fibroblast cells with hydrogen peroxide is related to skin aging. Inotodiol inhibited the expression of mitogen-activated protein kinase (MAPK) and NADPH Oxidase 5 (NOX5). Moreover, inotodiol effectively decreased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), as well as nitric oxide (NO), reactive oxygen species (ROS), cyclooxygenase-2 (COX-2), and cytokines such as IL-1β, IL-6, and TNF-α. Based on our results, inotodiol protects human dermal fibroblast by preventing MAPK-NOX5 and NF-κB activation and attenuates the expression of aging genes. Inotodiol may therefore be considered a potential candidate for developing natural antiaging products, because it protects the human skin from oxidative stress-induced skin aging by inhibiting the MAPK-NOX5 and NF-κB signaling pathways.
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Affiliation(s)
- Seung Hoon Lee
- Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; Translational Immunology Institute, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Gun-Woo Won
- Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, Daejeon, Republic of Korea
| | - Seung-Hyeon Choi
- Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; Translational Immunology Institute, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Mi-Yoon Kim
- Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Cheong-Hae Oh
- Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Jong-Tae Park
- Department of Food Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea; CARBOEXPERT Inc., Daejeon 34134, Republic of Korea.
| | - Jong-Il Park
- Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; Translational Immunology Institute, Chungnam National University College of Medicine, Daejeon, Republic of Korea; Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, Daejeon, Republic of Korea.
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Eaton L, Pamenter ME. What to do with low O 2: Redox adaptations in vertebrates native to hypoxic environments. Comp Biochem Physiol A Mol Integr Physiol 2022; 271:111259. [PMID: 35724954 DOI: 10.1016/j.cbpa.2022.111259] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 06/11/2022] [Accepted: 06/14/2022] [Indexed: 01/05/2023]
Abstract
Reactive oxygen species (ROS) are important cellular signalling molecules but sudden changes in redox balance can be deleterious to cells and lethal to the whole organism. ROS production is inherently linked to environmental oxygen availability and many species live in variable oxygen environments that can range in both severity and duration of hypoxic exposure. Given the importance of redox homeostasis to cell and animal viability, it is not surprising that early studies in species adapted to various hypoxic niches have revealed diverse strategies to limit or mitigate deleterious ROS changes. Although research in this area is in its infancy, patterns are beginning to emerge in the suites of adaptations to different hypoxic environments. This review focuses on redox adaptations (i.e., modifications of ROS production and scavenging, and mitigation of oxidative damage) in hypoxia-tolerant vertebrates across a range of hypoxic environments. In general, evidence suggests that animals adapted to chronic lifelong hypoxia are in homeostasis, and do not encounter major oxidative challenges in their homeostatic environment, whereas animals exposed to seasonal chronic anoxia or hypoxia rapidly downregulate redox balance to match a hypometabolic state and employ robust scavenging pathways during seasonal reoxygenation. Conversely, animals adapted to intermittent hypoxia exposure face the greatest degree of ROS imbalance and likely exhibit enhanced ROS-mitigation strategies. Although some progress has been made, research in this field is patchy and further elucidation of mechanisms that are protective against environmental redox challenges is imperative for a more holistic understanding of how animals survive hypoxic environments.
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Affiliation(s)
- Liam Eaton
- Department of Biology, University of Ottawa, Ottawa, ON, Canada
| | - Matthew E Pamenter
- Department of Biology, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada.
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Garsi JB, Komjáti B, Cullia G, Fejes I, Sipos M, Sipos Z, Fördős E, Markacz P, Balázs B, Lancelot N, Berger S, Raimbaud E, Brown D, Vuillard LM, Haberkorn L, Cukier C, Szlávik Z, Hanessian S. Targeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics. ACS Med Chem Lett 2022; 13:949-954. [DOI: 10.1021/acsmedchemlett.2c00094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/26/2022] [Indexed: 11/28/2022] Open
Affiliation(s)
- Jean-Baptiste Garsi
- Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-Ville, Montréal, QC H2V 0B3, Canada
| | - Balázs Komjáti
- Servier Research Institute of Medicinal Chemistry, 1031 Záhony utca 7 Mb, Budapest 1031, Hungary
| | - Gregorio Cullia
- Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-Ville, Montréal, QC H2V 0B3, Canada
| | - Imre Fejes
- Servier Research Institute of Medicinal Chemistry, 1031 Záhony utca 7 Mb, Budapest 1031, Hungary
| | - Melinda Sipos
- Servier Research Institute of Medicinal Chemistry, 1031 Záhony utca 7 Mb, Budapest 1031, Hungary
| | - Zoltán Sipos
- Servier Research Institute of Medicinal Chemistry, 1031 Záhony utca 7 Mb, Budapest 1031, Hungary
| | - Eszter Fördős
- Servier Research Institute of Medicinal Chemistry, 1031 Záhony utca 7 Mb, Budapest 1031, Hungary
| | - Piroska Markacz
- Servier Research Institute of Medicinal Chemistry, 1031 Záhony utca 7 Mb, Budapest 1031, Hungary
| | - Barbara Balázs
- Servier Research Institute of Medicinal Chemistry, 1031 Záhony utca 7 Mb, Budapest 1031, Hungary
| | - Nathalie Lancelot
- Institut de Recherche Servier, 125 Chemin de la Ronde, 78290 Croissy, France
| | - Sylvie Berger
- Institut de Recherche Servier, 125 Chemin de la Ronde, 78290 Croissy, France
| | - Eric Raimbaud
- Institut de Recherche Servier, 125 Chemin de la Ronde, 78290 Croissy, France
| | - David Brown
- Institut de Recherche Servier, 125 Chemin de la Ronde, 78290 Croissy, France
| | | | - Laure Haberkorn
- Institut de Recherche Servier, 125 Chemin de la Ronde, 78290 Croissy, France
| | - Cyprian Cukier
- Selvita S.A., ul. Bobrzyńskiego 14, 30-348 Kraków, Poland
| | - Zoltán Szlávik
- Servier Research Institute of Medicinal Chemistry, 1031 Záhony utca 7 Mb, Budapest 1031, Hungary
| | - Stephen Hanessian
- Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-Ville, Montréal, QC H2V 0B3, Canada
- Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92617, USA
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Azarova IE, Klyosova EY, Kolomoets II, Polonikov AV. Polymorphic Variants of the Neutrophil Cytosolic Factor 2 Gene: Associations with Susceptibility to Type 2 Diabetes Mellitus and Cardiovascular Autonomic Neuropathy. RUSS J GENET+ 2022; 58:593-602. [DOI: 10.1134/s1022795422050039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/08/2021] [Accepted: 12/14/2021] [Indexed: 07/28/2024]
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Zhang J, Fan M, Chen M, Wang H, Miao N, Yu H, Zhang L, Deng Q, Yi C. Identification of a novel mutation in CYBB gene in a Chinese neonate with X-linked chronic granulomatous disease: A case report. Medicine (Baltimore) 2022; 101:e28875. [PMID: 35451380 PMCID: PMC8913083 DOI: 10.1097/md.0000000000028875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/01/2022] [Indexed: 01/04/2023] Open
Abstract
RATIONALE X-linked chronic granulomatous disease (X-CGD) is an X-linked recessive disorder of the Nicotinamide adenine dinucleotide phosphate oxidase system that can cause primary immunodeficiency. Mutations in the CYBB gene located in Xp21.1 were accounting for X-CGD disease. More than 600 mutations have been identified as the cause of X-CGD in various populations worldwide. PATIENT CONCERNS AND DIAGNOSIS In this study, the proband suffered from elevated white blood cells (WBC, 23.65 × 109/L), mainly in neutral (16.4 × 109/L). The neutrophil oxidative index of the patient was 2.13, which was extremely low, whereas his mother was 69.0 (Ref >100). Next, next-generation sequencing of the primary immunodeficiency diseases -related gene panel was performed. One novel mutation was identified in the CYBB gene in the CGD case: c.55C>G in exon 2. The mutation was verified by Sanger sequencing. The mother of the patient was heterozygous for the c.55C>G mutation, and the father was normal. These mutations were not present in the 100 unrelated normal controls. INTERVENTIONS AND OUTCOMES The patient died from severe and uncontrollable pulmonary infection at 3 months of age. LESSONS The identification of these mutations in this study further expands the spectrum of known CYBB gene mutations and contributes to the genetic counseling and prenatal molecular diagnosis of X-CGD.
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Affiliation(s)
- Jie Zhang
- Organization and Personnel Section, Jinan Children's Hospital (Children's Hospital of Shandong University), Jinan 250022, China
| | - Meili Fan
- Enuresis Clinic of Tuina Department, Jinan Children's Hospital (Children's Hospital of Shandong University), Jinan 250022, China
| | - Mengmeng Chen
- Clinical Laboratory, Jinan Children's Hospital (Children's Hospital of Shandong University), Jinan 250022, China
| | - Huihui Wang
- Trauma Center, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan 250021, China
| | - Na Miao
- Department of Obstetrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Haihua Yu
- Neonatal Intensive Care Unit, Jinan Children's Hospital (Children's Hospital of Shandong University), Jinan 250022, China
| | - Lehai Zhang
- Clinical Laboratory, Jinan Children's Hospital (Children's Hospital of Shandong University), Jinan 250022, China
| | - Qianqian Deng
- Obstetrics and Gynecology Department, Lingcheng District's Traditional Chinese Medicine Hospital, Dezhou 253500, China
| | - Changying Yi
- Clinical Laboratory, Jinan Children's Hospital (Children's Hospital of Shandong University), Jinan 250022, China
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Ellson CD, Goretti Riça I, Kim JS, Huang YMM, Lim D, Mitra T, Hsu A, Wei EX, Barrett CD, Wahl M, Delbrück H, Heinemann U, Oschkinat H, Chang CEA, Yaffe MB. An integrated pharmacological, structural, and genetic analysis of extracellular versus intracellular ROS production in neutrophils. J Mol Biol 2022; 434:167533. [DOI: 10.1016/j.jmb.2022.167533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/03/2022] [Indexed: 11/28/2022]
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Diabetes, heart damage, and angiotensin II. What is the relationship link between them? A minireview. Endocr Regul 2022; 56:55-65. [PMID: 35180818 DOI: 10.2478/enr-2022-0007] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Cardiovascular complications are the main cause of mortality and morbidity in the diabetic patients, in whom changes in myocardial structure and function have been described. Numerous molecular mechanisms have been proposed that could contribute to the development of a cardiac damage. In this regard, angiotensin II (Ang II), a proinflammatory peptide that constitutes the main effector of the renin-angiotensin system (RAS) has taken a relevant role. The aim of this review was to analyze the role of Ang II in the different biochemical pathways that could be involved in the development of cardiovascular damage during diabetes. We performed an exhaustive review in the main databases, using the following terms: angiotensin II, cardiovascular damage, renin angiotensin system, inflammation, and diabetes mellitus. Classically, the RAS has been defined as a complex system of enzymes, receptors, and peptides that help control the blood pressure and the fluid homeostasis. However, in recent years, this concept has undergone substantial changes. Although this system has been known for decades, recent discoveries in cellular and molecular biology, as well as cardiovascular physiology, have introduced a better understanding of its function and relationship to the development of the diabetic cardiomyopathy.
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38
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de Obeso Fernandez del Valle A, Scheckhuber CQ. Superoxide Dismutases in Eukaryotic Microorganisms: Four Case Studies. Antioxidants (Basel) 2022; 11:antiox11020188. [PMID: 35204070 PMCID: PMC8868140 DOI: 10.3390/antiox11020188] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/12/2022] [Accepted: 01/16/2022] [Indexed: 01/08/2023] Open
Abstract
Various components in the cell are responsible for maintaining physiological levels of reactive oxygen species (ROS). Several different enzymes exist that can convert or degrade ROS; among them are the superoxide dismutases (SODs). If left unchecked, ROS can cause damage that leads to pathology, can contribute to aging, and may, ultimately, cause death. SODs are responsible for converting superoxide anions to hydrogen peroxide by dismutation. Here we review the role of different SODs on the development and pathogenicity of various eukaryotic microorganisms relevant to human health. These include the fungal aging model, Podospora anserina; various members of the genus Aspergillus that can potentially cause aspergillosis; the agents of diseases such as Chagas and sleeping disease, Trypanosoma cruzi and Trypanosoma brucei, respectively; and, finally, pathogenic amoebae, such as Acanthamoeba spp. In these organisms, SODs fulfill essential and often regulatory functions that come into play during processes such as the development, host infection, propagation, and control of gene expression. We explore the contribution of SODs and their related factors in these microorganisms, which have an established role in health and disease.
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Pretreatment with 6-Gingerol Ameliorates Sepsis-Induced Immune Dysfunction by Regulating the Cytokine Balance and Reducing Lymphocyte Apoptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2021:5427153. [PMID: 35003518 PMCID: PMC8731291 DOI: 10.1155/2021/5427153] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 10/04/2021] [Accepted: 11/26/2021] [Indexed: 11/19/2022]
Abstract
Sepsis is characterized by an initial net hyperinflammatory response, followed by a period of immunosuppression, termed immunoparalysis. During this immunosuppressive phase, patients may have difficulty eradicating invading pathogens and are susceptible to life-threatening secondary hospital-acquired infections. Due to progress in antimicrobial treatment and supportive care, most patients survive early sepsis. Mortality is more frequently attributed to subsequent secondary nosocomial infections and multiorgan system failure. 6-Gingerol is the major pharmacologically active component of ginger. Although it is known to exhibit a variety of biological activities, including anti-inflammation and antioxidation, the role of 6-gingerol in sepsis-induced immune dysfunction remains elusive. Thus, we investigated whether 6-gingerol improves septic host response to infections during sepsis. 6-Gingerol-treated mice showed significantly lower mortality in polymicrobial sepsis induced by cecal ligation and puncture LPS via enhanced bacterial clearance in the peritoneum, blood, and organs (liver, spleen, and kidney) and inhibited the production of TNF-α and IL-6 in TLR2 and/or TLR4-stimulated macrophages. In addition, we demonstrated that survival improvement of secondary infection following septic insult was associated with an initial response of enhanced neutrophil numbers and function at the infection site, reduced apoptosis of immune cells, and a shift from a T helper cell type 2 (Th2) to a T helper cell type 1 (Th1) cytokine balance in the hypoinflammation phase. Our overall findings suggest that 6-gingerol potentially restores sepsis-induced immune dysfunction by shifting the balance of Th1/Th2 and by regulating apoptosis of immune cells.
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40
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Romero-Pinedo S, Barros DIR, Ruiz-Magaña MJ, Maganto-García E, Moreno de Lara L, Abadía-Molina F, Terhorst C, Abadía-Molina AC. SLAMF8 Downregulates Mouse Macrophage Microbicidal Mechanisms via PI3K Pathways. Front Immunol 2022; 13:910112. [PMID: 35837407 PMCID: PMC9273976 DOI: 10.3389/fimmu.2022.910112] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/11/2022] [Indexed: 11/13/2022] Open
Abstract
Signaling lymphocytic activation molecule family 8 (SLAMF8) is involved in the negative modulation of NADPH oxidase activation. However, the impact of SLAMF8 downregulation on macrophage functionality and the microbicide mechanism remains elusive. To study this in depth, we first analyzed NADPH oxidase activation pathways in wild-type and SLAMF8-deficient macrophages upon different stimulus. Herein, we describe increased phosphorylation of the Erk1/2 and p38 MAP kinases, as well as increased phosphorylation of NADPH oxidase subunits in SLAMF8-deficient macrophages. Furthermore, using specific inhibitors, we observed that specific PI3K inhibition decreased the differences observed between wild-type and SLAMF8-deficient macrophages, stimulated with either PMA, LPS, or Salmonella typhimurium infection. Consequently, SLAMF8-deficient macrophages also showed increased recruitment of small GTPases such as Rab5 and Rab7, and the p47phox subunit to cytoplasmic Salmonella, suggesting an impairment of Salmonella-containing vacuole (SCV) progression in SLAMF8-deficient macrophages. Enhanced iNOS activation, NO production, and IL-6 expression were also observed in the absence of SLAMF8 upon Salmonella infection, either in vivo or in vitro, while overexpression of SLAMF8 in RAW264.7 macrophages showed the opposite phenotype. In addition, SLAMF8-deficient macrophages showed increased activation of Src kinases and reduced SHP-1 phosphate levels upon IFNγ and Salmonella stimuli in comparison to wild-type macrophages. In agreement with in vitro results, Salmonella clearance was augmented in SLAMF8-deficient mice compared to that in wild-type mice. Therefore, in conclusion, SLAMF8 intervention upon bacterial infection downregulates mouse macrophage activation, and confirmed that SLAMF8 receptor could be a potential therapeutic target for the treatment of severe or unresolved inflammatory conditions.
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Affiliation(s)
- Salvador Romero-Pinedo
- Unidad de Inmunología, Instituto de Biopatología y Medicina Regenerativa (IBIMER), Centro de Investigación Biomédica (CIBM), Universidad de Granada, Granada, Spain
| | - Domingo I Rojas Barros
- Unidad de Inmunología, Instituto de Biopatología y Medicina Regenerativa (IBIMER), Centro de Investigación Biomédica (CIBM), Universidad de Granada, Granada, Spain
| | - María José Ruiz-Magaña
- Unidad de Inmunología, Instituto de Biopatología y Medicina Regenerativa (IBIMER), Centro de Investigación Biomédica (CIBM), Universidad de Granada, Granada, Spain
| | - Elena Maganto-García
- Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
| | - Laura Moreno de Lara
- Unidad de Inmunología, Instituto de Biopatología y Medicina Regenerativa (IBIMER), Centro de Investigación Biomédica (CIBM), Universidad de Granada, Granada, Spain
| | - Francisco Abadía-Molina
- Departamento de Biología Celular, Facultad de Ciencias, Universidad de Granada, Granada, Spain.,Instituto de Nutrición Y Tecnología de los Alimentos "José Mataix", (INYTIA), Centro de Investigación Biomédica (CIBM), Universidad de Granada, Granada, Spain
| | - Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Ana C Abadía-Molina
- Unidad de Inmunología, Instituto de Biopatología y Medicina Regenerativa (IBIMER), Centro de Investigación Biomédica (CIBM), Universidad de Granada, Granada, Spain.,Departamento de Bioqu´ımica y Biolog´ıa Molecular III e Inmunolog´ıa, Facultad de Medicina, Universidad de Granada, Granada, Spain
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Berman R, Rose CS, Downey GP, Day BJ, Chu HW. Role of Particulate Matter from Afghanistan and Iraq in Deployment-Related Lung Disease. Chem Res Toxicol 2021; 34:2408-2423. [PMID: 34808040 DOI: 10.1021/acs.chemrestox.1c00090] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Approximately 3 million United States military personnel and contractors were deployed to Southwest Asia and Afghanistan over the past two decades. After returning to the United States, many developed persistent respiratory symptoms, including those due to asthma, rhinosinusitis, bronchiolitis, and others, which we collectively refer to as deployment-related lung diseases (DRLD). The mechanisms of different DRLD have not been well defined. Limited studies from us and others suggest that multiple factors and biological signaling pathways contribute to the onset of DRLD. These include, but are not limited to, exposures to high levels of particulate matter (PM) from sandstorms, burn pit combustion products, improvised explosive devices, and diesel exhaust particles. Once inhaled, these hazardous substances can activate lung immune and structural cells to initiate numerous cell-signaling pathways such as oxidative stress, Toll-like receptors, and cytokine-driven cell injury (e.g., interleukin-33). These biological events may lead to a pro-inflammatory response and airway hyperresponsiveness. Additionally, exposures to PM and other environmental hazards may predispose military personnel and contractors to more severe disease due to the interactions of those hazardous materials with subsequent exposures to allergens and cigarette smoke. Understanding how airborne exposures during deployment contribute to DRLD may identify effective targets to alleviate respiratory diseases and improve quality of life in veterans and active duty military personnel.
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Affiliation(s)
- Reena Berman
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
| | - Cecile S Rose
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
| | - Gregory P Downey
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
| | - Brian J Day
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
| | - Hong Wei Chu
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
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42
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Hawkins P, McEnery T, Gabillard-Lefort C, Bergin DA, Alfawaz B, Shutchaidat V, Meleady P, Henry M, Coleman O, Murphy M, McElvaney NG, Reeves EP. In vitro and in vivo modulation of NADPH oxidase activity and reactive oxygen species production in human neutrophils by α 1-antitrypsin. ERJ Open Res 2021; 7:00234-2021. [PMID: 34881324 PMCID: PMC8645872 DOI: 10.1183/23120541.00234-2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 08/29/2021] [Indexed: 12/17/2022] Open
Abstract
Oxidative stress from innate immune cells is a driving mechanism that underlies COPD pathogenesis. Individuals with α-1 antitrypsin (AAT) deficiency (AATD) have a dramatically increased risk of developing COPD. To understand this further, the aim of this study was to investigate whether AATD presents with altered neutrophil NADPH oxidase activation, due to the specific lack of plasma AAT. Experiments were performed using circulating neutrophils isolated from healthy controls and individuals with AATD. Superoxide anion (O2−) production was determined from the rate of reduction of cytochrome c. Quantification of membrane NADPH oxidase subunits was performed by mass spectrometry and Western blot analysis. The clinical significance of our in vitro findings was assessed in patients with AATD and severe COPD receiving intravenous AAT replacement therapy. In vitro, AAT significantly inhibited O2− production by stimulated neutrophils and suppressed receptor stimulation of cyclic adenosine monophosphate and extracellular signal-regulated kinase (ERK)1/2 phosphorylation. In addition, AAT reduced plasma membrane translocation of cytosolic phox components of the NADPH oxidase. Ex vivo, AATD neutrophils demonstrated increased plasma membrane-associated p67phox and p47phox and significantly increased O2− production. The described variance in phox protein membrane assembly was resolved post-AAT augmentation therapy in vivo, the effects of which significantly reduced AATD neutrophil O2− production to that of healthy control cells. These results expand our knowledge on the mechanism of neutrophil-driven airways disease associated with AATD. Therapeutic AAT augmentation modified neutrophil NADPH oxidase assembly and reactive oxygen species production, with implications for clinical use in conditions in which oxidative stress plays a pathogenic role. Circulating neutrophils in COPD due to α1-antitrypsin deficiency illustrate increased NADPH oxidase assembly and reactive oxygen species production, a defect corrected by α1-antitrypsin augmentation therapyhttps://bit.ly/38NNTzM
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Affiliation(s)
- Padraig Hawkins
- Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Thomas McEnery
- Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Claudie Gabillard-Lefort
- Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - David A Bergin
- Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Bader Alfawaz
- Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Vipatsorn Shutchaidat
- Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Paula Meleady
- National Institute for Cellular Biology, Dublin City University, Glasnevin, Dublin, Ireland
| | - Michael Henry
- National Institute for Cellular Biology, Dublin City University, Glasnevin, Dublin, Ireland
| | - Orla Coleman
- National Institute for Cellular Biology, Dublin City University, Glasnevin, Dublin, Ireland
| | - Mark Murphy
- Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Noel G McElvaney
- Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.,These authors contributed equally
| | - Emer P Reeves
- Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.,These authors contributed equally
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Villegas L, Nørremølle A, Freude K, Vilhardt F. Nicotinamide Adenine Dinucleotide Phosphate Oxidases Are Everywhere in Brain Disease, but Not in Huntington's Disease? Front Aging Neurosci 2021; 13:736734. [PMID: 34803655 PMCID: PMC8602359 DOI: 10.3389/fnagi.2021.736734] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 10/08/2021] [Indexed: 11/13/2022] Open
Abstract
Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by neuronal loss and tissue atrophy mainly in the striatum and cortex. In the early stages of the disease, impairment of neuronal function, synaptic dysfunction and white matter loss precedes neuronal death itself. Relative to other neurodegenerative diseases such as Alzheimer's and Parkinson's disease and Amyotrophic Lateral Sclerosis, where the effects of either microglia or NADPH oxidases (NOXs) are recognized as important contributors to disease pathogenesis and progression, there is a pronounced lack of information in HD. This information void contrasts with evidence from human HD patients where blood monocytes and microglia are activated well before HD clinical symptoms (PET scans), and the clear signs of oxidative stress and inflammation in post mortem HD brain. Habitually, NOX activity and oxidative stress in the central nervous system (CNS) are equated with microglia, but research of the last two decades has carved out important roles for NOX enzyme function in neurons. Here, we will convey recent information about the function of NOX enzymes in neurons, and contemplate on putative roles of neuronal NOX in HD. We will focus on NOX-produced reactive oxygen species (ROS) as redox signaling molecules in/among neurons, and the specific roles of NOXs in important processes such as neurogenesis and lineage specification, neurite outgrowth and growth cone dynamics, and synaptic plasticity where NMDAR-dependent signaling, and long-term depression/potentiation are redox-regulated phenomena. HD animal models and induced pluripotent stem cell (iPSC) studies have made it clear that the very same physiological processes are also affected in HD, and we will speculate on possible roles for NOX in the pathogenesis and development of disease. Finally, we also take into account the limited information on microglia in HD and relate this to any contribution of NOX enzymes.
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Affiliation(s)
- Luisana Villegas
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Anne Nørremølle
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Kristine Freude
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Frederik Vilhardt
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Epigenetically-regulated RPN2 gene influences lymphocyte activation and is involved in pathogenesis of rheumatoid arthritis. Gene 2021; 810:146059. [PMID: 34740730 DOI: 10.1016/j.gene.2021.146059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/22/2021] [Accepted: 10/29/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND To identify RA-associated genes and to ascertain epigenetic factors and functional mechanisms underlying RA pathogenesis. METHODS Peripheral blood mononuclear cells (PBMC) transcriptome- and proteome- wide gene expressions were profiled in a case-control study sample. Differentially expressed genes (DEGs) were discovered and validated independently. In-house PBMC genome-wide SNP genotyping data, miRNA expression data and DNA methylation data in the same sample were utilized to identify SNPs [expression quantitative trait locus (eQTLs) and protein quantitative trait locus (pQTLs)], miRNAs, and DNA methylation positions (DMPs) regulating key DEG of interest. Lentivirus transfection was conducted to study the effects of RPN2 on T lymphocyte activation, proliferation, apoptosis, and inflammatory cytokine expression. Rpn2 protein level in plasma was quantitated by ELISA to assess its performance in discriminating RA cases and controls. RESULTS Twenty-two DEGs were discovered in PBMCs. The most significant DEG, i.e., RPN2, was validated to be up-regulated with RA in PBMCs. A complex regulatory network for RPN2 gene expression in PBMCs was constructed, which consists of 38 eQTL and 53 pQTL SNPs, 3 miRNAs and 2 DMPs. Besides, RPN2 expression was significantly up-regulated with RA in primary T lymphocytes, as well as in PHA-activated T lymphocytes. RPN2 over-expression in T lymphocytes significantly inhibited apoptosis and IL-4 expression and promoted proliferation and activation. PBMCs-expressed RPN2 mRNA and plasma Rpn2 protein demonstrated superior and modest performances in discriminating RA cases and controls, respectively. CONCLUSIONS RPN2 gene influences T lymphocyte growth and activation and is involved in the pathogenesis of RA. Rpn2 may serve as a novel protein biomarker for RA diagnosis.
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Lushchak VI, Duszenko M, Gospodaryov DV, Garaschuk O. Oxidative Stress and Energy Metabolism in the Brain: Midlife as a Turning Point. Antioxidants (Basel) 2021; 10:1715. [PMID: 34829586 PMCID: PMC8614699 DOI: 10.3390/antiox10111715] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 01/10/2023] Open
Abstract
Neural tissue is one of the main oxygen consumers in the mammalian body, and a plentitude of metabolic as well as signaling processes within the brain is accompanied by the generation of reactive oxygen (ROS) and nitrogen (RNS) species. Besides the important signaling roles, both ROS and RNS can damage/modify the self-derived cellular components thus promoting neuroinflammation and oxidative stress. While previously, the latter processes were thought to progress linearly with age, newer data point to midlife as a critical turning point. Here, we describe (i) the main pathways leading to ROS/RNS generation within the brain, (ii) the main defense systems for their neutralization and (iii) summarize the recent literature about considerable changes in the energy/ROS homeostasis as well as activation state of the brain's immune system at midlife. Finally, we discuss the role of calorie restriction as a readily available and cost-efficient antiaging and antioxidant lifestyle intervention.
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Affiliation(s)
- Volodymyr I. Lushchak
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., 76018 Ivano-Frankivsk, Ukraine; (V.I.L.); (D.V.G.)
- Department of Medical Biochemistry, I. Horbachevsky Ternopil National Medical University, 46002 Ternopil, Ukraine
- Research and Development University, 13a Shota Rustaveli Str., 76018 Ivano-Frankivsk, Ukraine
| | - Michael Duszenko
- Department of Neurophysiology, Institute of Physiology, University of Tübingen, 72074 Tübingen, Germany;
| | - Dmytro V. Gospodaryov
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., 76018 Ivano-Frankivsk, Ukraine; (V.I.L.); (D.V.G.)
| | - Olga Garaschuk
- Department of Neurophysiology, Institute of Physiology, University of Tübingen, 72074 Tübingen, Germany;
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Yassin NYS, AbouZid SF, El-Kalaawy AM, Ali TM, Elesawy BH, Ahmed OM. Tackling of Renal Carcinogenesis in Wistar Rats by Silybum marianum Total Extract, Silymarin, and Silibinin via Modulation of Oxidative Stress, Apoptosis, Nrf2, PPAR γ, NF- κB, and PI3K/Akt Signaling Pathways. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:7665169. [PMID: 34630852 PMCID: PMC8497111 DOI: 10.1155/2021/7665169] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/18/2021] [Accepted: 08/27/2021] [Indexed: 12/20/2022]
Abstract
The present work was designed to assess the efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally induced renal carcinogenesis in male Wistar rats and their roles in regulating oxidative stress, inflammation, apoptosis, and carcinogenesis. The diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4)-administered rats were orally treated with STE (200 mg/kg b.w.), Sm (150 mg/kg b.w.), and Sb (5 mg/kg b.w.) every other day either from the 1st week or from the 16th week of carcinogen administration to the end of 25th week. The treatments with STE, Sm, and Sb attenuated markers of toxicity in serum, decreased kidney lipid peroxidation (LPO), and significantly reinforced the renal antioxidant armory. The biochemical results were further confirmed by the histopathological alterations. The treatments also led to suppression of proinflammatory mediators such as NF-κβ, p65, Iκβα, and IL-6 in association with inhibition of the PI3K/Akt pathway. Furthermore, they activated the expressions of PPARs, Nrf2, and IL-4 in addition to downregulation of apoptotic proteins p53 and caspase-3 and upregulation of antiapoptotic mediator Bcl-2. The obtained data supply potent proof for the efficacy of STE, Sm, and Sb to counteract renal carcinogenesis via alteration of varied molecular pathways.
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Affiliation(s)
- Nour Y. S. Yassin
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Sameh F. AbouZid
- Department of Pharmacognosy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Asmaa M. El-Kalaawy
- Department of Pharmacology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Tarek M. Ali
- Department of Physiology, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Basem H. Elesawy
- Department of Pathology, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
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Evaluating of Red Blood Cell Distribution Width, Comorbidities and Electrocardiographic Ratios as Predictors of Prognosis in Patients with Pulmonary Hypertension. Diagnostics (Basel) 2021; 11:diagnostics11071297. [PMID: 34359380 PMCID: PMC8305029 DOI: 10.3390/diagnostics11071297] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/01/2021] [Accepted: 07/08/2021] [Indexed: 11/16/2022] Open
Abstract
Pulmonary hypertension is a rare condition that impairs patients' quality of life and life expectancy. The development of noninvasive instruments may help elucidate the prognosis of this cardiorespiratory disease. We aimed to evaluate the utility of routinely performed noninvasive test results as prognostic markers in patients with pulmonary hypertension. We enrolled 198 patients with mean pulmonary artery pressure >25 mmHg measured at cardiac catheterisation or echocardiographic pulmonary artery systolic pressure > 40 mmHg and tricuspid regurgitation Vmax >2.9 m/s, and clinical information regarding management and follow-up studies from the date of diagnosis. Multivariate analysis revealed that female sex [HR: 0.21, (95% CI: 0.07-0.64); p = 0.006], the presence of collagenopathies [HR: 8.63, (95% CI: 2.38-31.32); p = 0.001], an increased red blood cell distribution width [HR: 1.25, (95% CI: 1.04-1.49); p = 0.017] and an increased electrocardiographic P axis (P°)/T axis (T°) ratio [HR: 0.93, (95% CI: 0.88-0.98); p = 0.009] were severity-associated factors, while older age [HR: 1.57, (95% CI: 1.04-1.28); p = 0.006], an increased QRS axis (QRS°)/T° ratio [HR: 1.21, (95% CI: 1.09-1.34); p < 0.001], forced expiratory volume in 1 s [HR: 0.94, (95% CI: 0.91-0.98); p = 0.01] and haematocrit [HR: 0.93, (95% CI: 0.87-0.99); p = 0.04] were mortality-associated factors. Our results support the importance of red blood cell distribution width, electrocardiographic ratios and collagenopathies for assessing pulmonary hypertension prognosis.
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Vermot A, Petit-Härtlein I, Smith SME, Fieschi F. NADPH Oxidases (NOX): An Overview from Discovery, Molecular Mechanisms to Physiology and Pathology. Antioxidants (Basel) 2021; 10:890. [PMID: 34205998 PMCID: PMC8228183 DOI: 10.3390/antiox10060890] [Citation(s) in RCA: 368] [Impact Index Per Article: 92.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 01/17/2023] Open
Abstract
The reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX) was first identified in the membrane of phagocytic cells. For many years, its only known role was in immune defense, where its ROS production leads to the destruction of pathogens by the immune cells. NOX from phagocytes catalyzes, via one-electron trans-membrane transfer to molecular oxygen, the production of the superoxide anion. Over the years, six human homologs of the catalytic subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the NOX2/gp91phox component present in the phagocyte NADPH oxidase assembly itself, the homologs are now referred to as the NOX family of NADPH oxidases. NOX are complex multidomain proteins with varying requirements for assembly with combinations of other proteins for activity. The recent structural insights acquired on both prokaryotic and eukaryotic NOX open new perspectives for the understanding of the molecular mechanisms inherent to NOX regulation and ROS production (superoxide or hydrogen peroxide). This new structural information will certainly inform new investigations of human disease. As specialized ROS producers, NOX enzymes participate in numerous crucial physiological processes, including host defense, the post-translational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. These diversities of physiological context will be discussed in this review. We also discuss NOX misregulation, which can contribute to a wide range of severe pathologies, such as atherosclerosis, hypertension, diabetic nephropathy, lung fibrosis, cancer, or neurodegenerative diseases, giving this family of membrane proteins a strong therapeutic interest.
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Affiliation(s)
- Annelise Vermot
- Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 38000 Grenoble, France; (A.V.); (I.P.-H.)
| | - Isabelle Petit-Härtlein
- Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 38000 Grenoble, France; (A.V.); (I.P.-H.)
| | - Susan M. E. Smith
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA 30144, USA;
| | - Franck Fieschi
- Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 38000 Grenoble, France; (A.V.); (I.P.-H.)
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Tavassolifar MJ, Changaei M, Salehi Z, Ghasemi F, Javidan M, Nicknam MH, Pourmand MR. Redox imbalance in Crohn's disease patients is modulated by Azathioprine. Redox Rep 2021; 26:80-84. [PMID: 33882797 PMCID: PMC8079067 DOI: 10.1080/13510002.2021.1915665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Crohn's disease (CD) is a chronic inflammatory disease without a specific cause. Inflammation in these patients can disturb the oxidants/antioxidants balance and results in oxidative stress that plays a destructive role. This study aimed to evaluate the gene expression of sod1, sod2, cat, nrf2 and gp91phox in CD patients before and after Azathioprine (Aza) consumption. Method Peripheral bloodmononuclear cells (PBMCs) were separated from CD patients (n= 15, mean age = 33.6 ± 1.8) before and after treatment with Aza and healthy controls (n= 15, mean age = 31.5 ± 1.2). The expression levels of sod1, sod2, cat, nrf2 and gp91phox were measured in byusing real-time qRT-PCR technique. Result The expression levels of gp91phox (P-value < 0.001), cat (P-value < 0.05), sod1 (P-value < 0.001), nrf2 (P-value < 0.001) were significantly increased compared to control group. Following treatment with Aza, the decreased expression levels of gp91phox (P-value < 0.05), cat (P-value < 0.05), sod1(P-value < 0.001) and nrf2 (P-value < 0.001) were observed in CD patients. Conclusion Overall, our results showed that prescription of Azathioprine can lead to the altered expression of redox system-related genes in patients with CD.
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Affiliation(s)
| | - Mostafa Changaei
- Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Salehi
- Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ghasemi
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Moslem Javidan
- Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammad Reza Pourmand
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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