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Rojas-Solé C, Pinilla-González V, Lillo-Moya J, González-Fernández T, Saso L, Rodrigo R. Integrated approach to reducing polypharmacy in older people: exploring the role of oxidative stress and antioxidant potential therapy. Redox Rep 2024; 29:2289740. [PMID: 38108325 PMCID: PMC10732214 DOI: 10.1080/13510002.2023.2289740] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2023] Open
Abstract
Increased life expectancy, attributed to improved access to healthcare and drug development, has led to an increase in multimorbidity, a key contributor to polypharmacy. Polypharmacy is characterised by its association with a variety of adverse events in the older persons. The mechanisms involved in the development of age-related chronic diseases are largely unknown; however, altered redox homeostasis due to ageing is one of the main theories. In this context, the present review explores the development and interaction between different age-related diseases, mainly linked by oxidative stress. In addition, drug interactions in the treatment of various diseases are described, emphasising that the holistic management of older people and their pathologies should prevail over the individual treatment of each condition.
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Affiliation(s)
- Catalina Rojas-Solé
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Víctor Pinilla-González
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - José Lillo-Moya
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Tommy González-Fernández
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Faculty of Pharmacy and Medicine, Sapienza University, Rome, Italy
| | - Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
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2
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Liu Z, Li H, Huang X, Liu Q. Animal Models of Helicobacter pylori Infection and Vaccines: Current Status and Future Prospects. Helicobacter 2024; 29:e13119. [PMID: 39108210 DOI: 10.1111/hel.13119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/10/2024] [Accepted: 07/23/2024] [Indexed: 01/02/2025]
Abstract
Helicobacter pylori infection causes chronic gastritis, ulcers, and gastric cancer, making it a threat to human health. Despite the use of antibiotic therapy, the global prevalence of H. pylori infection remains high, necessitating early eradication measures. Immunotherapy, especially vaccine development, is a promising solution in this direction, albeit the selection of an appropriate animal model is critical in efficient vaccine production. Accordingly, we conducted a literature, search and summarized the commonly used H. pylori strains, H. pylori infection-related animal models, and models for evaluating H. pylori vaccines. Based on factors such as the ability to replicate human diseases, strain compatibility, vaccine types, and eliciting of immune responses, we systematically compared the advantages and disadvantages of different animal models, to obtain the informed recommendations. In addition, we have proposed novel perspectives on H. pylori-related animal models to advance research and vaccine evaluation for the prevention and treatment of diseases such as gastric cancer.
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Affiliation(s)
- Zhili Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- HuanKui Academy, Nanchang University, Nanchang, China
| | - He Li
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xiaotian Huang
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Qiong Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
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Li B, Lv X, Xu Z, He J, Liu S, Zhang X, Tong X, Li J, Zhang Y. Helicobacter pylori infection induces autophagy via ILK regulation of NOXs-ROS-Nrf2/HO-1-ROS loop. World J Microbiol Biotechnol 2023; 39:284. [PMID: 37599292 DOI: 10.1007/s11274-023-03710-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 07/21/2023] [Indexed: 08/22/2023]
Abstract
Reactive oxygen species (ROS) can regulate the occurrence of autophagy, and effective control of the balance between ROS and autophagy may be an important strategy for Helicobacter pylori induced gastric-related diseases. In this study, infection with H. pylori led to a lower level of ILK phosphorylation and increased ROS generation. Knockdown of ILK enhanced total ROS generation, and upregulated NADPH oxidase (NOX) subunit p22-phox levels. Inhibition of NOXs affected total ROS generation. The inhibition of NOX and ROS generation reduced Nrf2 and HO-1 levels, and knockdown of ILK significantly enhanced Nrf2 levels in H. pylori-infected GES-1 cells. Activation of Nrf2 by DMF decreased ROS levels. Therefore, NOX-dependent ROS production regulated by ILK was essential for activation of Nrf2/HO-1 signaling pathways in H. pylori-infected GES-1 cells. Beclin1, ATG5 and LC3B-II levels were higher both in H. pylori-infected and ILK-knockdown GES-1 cells. In NAC-pretreated GES-1 cells infected with H. pylori, the LC3B-II level was decreased compared to that in cells after H. pylori infection alone. Stable low expression of ILK with further knockdown of Beclin1 or ATG5 significantly reduced LC3B-II levels in GES-1 cells, while with the addition of the autophagy inhibitor chloroquine (CQ), LC3B-II and p62 protein levels were both remarkably upregulated. H. pylori accelerated the accumulation of ROS and further led to the induction of ROS-mediated autophagy by inhibiting ILK levels. Together, these results indicate that H. pylori infection manipulates the NOX-ROS-Nrf2/HO-1-ROS loop to control intracellular oxygen stress and further induced ROS-mediated autophagy by inhibiting ILK levels.
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Affiliation(s)
- Boqing Li
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Xin Lv
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Zheng Xu
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Jing He
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - SiSi Liu
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Xiaolin Zhang
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Xiaohan Tong
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Jing Li
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Ying Zhang
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China.
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Campylobacter jejuni Modulates Reactive Oxygen Species Production and NADPH Oxidase 1 Expression in Human Intestinal Epithelial Cells. Cell Microbiol 2023. [DOI: 10.1155/2023/3286330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Campylobacter jejuni is the major bacterial cause of foodborne gastroenteritis worldwide. Mechanistically, how this pathogen interacts with intrinsic defence machinery of human intestinal epithelial cells (IECs) remains elusive. To address this, we investigated how C. jejuni counteracts the intracellular and extracellular reactive oxygen species (ROS) in IECs. Our work shows that C. jejuni differentially regulates intracellular and extracellular ROS production in human T84 and Caco-2 cells. C. jejuni downregulates the transcription and translation of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX1), a key ROS-generating enzyme in IECs and antioxidant defence genes CAT and SOD1. Furthermore, inhibition of NOX1 by diphenylene iodonium (DPI) and siRNA reduced C. jejuni ability to interact, invade, and intracellularly survive within T84 and Caco-2 cells. Collectively, these findings provide mechanistic insight into how C. jejuni modulates the IEC defence machinery.
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Kang JH, Park S, Rho J, Hong EJ, Cho YE, Won YS, Kwon HJ. IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC. Gastric Cancer 2023; 26:82-94. [PMID: 36125689 PMCID: PMC9813207 DOI: 10.1007/s10120-022-01342-5] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 09/11/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer (GC) is a common malignancy worldwide, with a major attribution to Helicobacter pylori. Interleukin (IL)-17A has been reported to be up-regulated in serum and tumor of GC patients, but the precise mechanisms underlying its involvement in gastric tumorigenesis are yet to be established. Here, we investigated the roles of IL-17A in the pathogenesis of H. pylori-induced GC. METHODS GC was induced in IL-17A knockout (KO) and wild-type (WT) mice via N-methyl-N-nitrosourea (MNU) treatment and H. pylori infection. At 50 weeks after treatment, gastric tissues were examined by histopathology, immunohistochemistry, and immunoblot analyses. In vitro experiments on the human GC cell lines were additionally performed to elucidate the underlying mechanisms. RESULTS Deletion of IL-17A suppressed MNU and H. pylori-induced gastric tumor development accompanied by a decrease in gastric epithelial cell growth, oxidative stress, and expression of gastric epithelial stem cells markers. In AGS cells, recombinant human IL-17A (rhIL-17A) inhibited apoptosis and G1/S phase transition arrest while promoting reactive oxygen species production, sphere formation ability of cancer stem cells (CSC), and expression of stemness-related genes. In addition, rhIL-17A induced expression of IL-17RC, leading to NF-κB activation and increased NADPH oxidase 1 (NOX1) levels. Inhibition of NOX1 with GKT136901 attenuated rhIL-17A-mediated elevation of GC cell growth, ROS generation, and CSC stemness. Clinically, IL-17RC expressions were significantly upregulated in human GC compared with normal gastric tissues. CONCLUSION Our results suggest that IL-17A promotes gastric carcinogenesis, in part, by regulating IL-17RC/NF-κB/NOX1 pathway, supporting its potential as a target in human GC therapy.
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Affiliation(s)
- Jee Hyun Kang
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Korea
| | - Suyoung Park
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Korea
| | - Jinhyung Rho
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Korea
| | - Eun-Ju Hong
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Korea
| | - Young-Eun Cho
- Department of Food and Nutrition, Andong National University, Andong, Korea
| | - Young-Suk Won
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Korea
| | - Hyo-Jung Kwon
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Korea.
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Host Cell Antimicrobial Responses against Helicobacter pylori Infection: From Biological Aspects to Therapeutic Strategies. Int J Mol Sci 2022; 23:ijms231810941. [PMID: 36142852 PMCID: PMC9504325 DOI: 10.3390/ijms231810941] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/13/2022] [Accepted: 09/16/2022] [Indexed: 02/07/2023] Open
Abstract
The colonization of Helicobacter pylori (H. pylori) in human gastric mucosa is highly associated with the occurrence of gastritis, peptic ulcer, and gastric cancer. Antibiotics, including amoxicillin, clarithromycin, furazolidone, levofloxacin, metronidazole, and tetracycline, are commonly used and considered the major treatment regimens for H. pylori eradication, which is, however, becoming less effective by the increasing prevalence of H pylori resistance. Thus, it is urgent to understand the molecular mechanisms of H. pylori pathogenesis and develop alternative therapeutic strategies. In this review, we focus on the virulence factors for H. pylori colonization and survival within host gastric mucosa and the host antimicrobial responses against H. pylori infection. Moreover, we describe the current treatments for H. pylori eradication and provide some insights into new therapeutic strategies for H. pylori infection.
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7
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Jain U, Saxena K, Chauhan N. Helicobacter pylori induced reactive oxygen Species: A new and developing platform for detection. Helicobacter 2021; 26:e12796. [PMID: 33666321 DOI: 10.1111/hel.12796] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/11/2021] [Accepted: 02/10/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastric cancer is the third leading cause of cancer-related deaths worldwide. Approximately 70% of cases are caused by a microaerophilic gram-negative bacteria, Helicobacter pylori (H. pylori), which potentially infect almost 50% of world's population. H. pylori is mainly responsible for persistent oxidative stress in stomach and induction of chronic immune responses which ultimately result into DNA damage that eventually can lead to gastric cancer. Oxidative stress is the result of excessive release of ROS/RNS by activated neutrophils whereas bacteria itself also produce ROS in host cells. Therefore, ROS detection is an important factor for development of new strategies related to identification of H. pylori infection. METHODS The review summarizes the various available techniques for ROS detection with their advantages, disadvantages, and limitations. All of the information included in this review have been retrieved from published studies on ROS generation and its detection methods. RESULTS Precisely, 71 articles have been incorporated and evaluated for this review. The studied articles were divided into two major categories including articles on H. pylori-related pathogenesis and various ROS detection methods for example probe-based methods, immunoassays, gene expression profiling, and other techniques. The major part of probe activity is based on fluorescence, chemiluminescence, or bioluminescence and detected by complementary techniques such as LC-MS, HPLC, EPR, and redox blotting. CONCLUSION The review describes the methods for ROS detection but due to some limitations in conventional methods, there is a need of cost-effective, early and fast detection methods like biosensors to diagnose the infection at its initial stage.
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Affiliation(s)
- Utkarsh Jain
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh, Noida, India
| | - Kirti Saxena
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh, Noida, India
| | - Nidhi Chauhan
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh, Noida, India
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8
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Vona R, Pallotta L, Cappelletti M, Severi C, Matarrese P. The Impact of Oxidative Stress in Human Pathology: Focus on Gastrointestinal Disorders. Antioxidants (Basel) 2021; 10:201. [PMID: 33573222 PMCID: PMC7910878 DOI: 10.3390/antiox10020201] [Citation(s) in RCA: 176] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/15/2022] Open
Abstract
Accumulating evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of many diseases. The imbalance between the production of reactive oxygen species (ROS) and the antioxidant systems has been extensively studied in pulmonary, neurodegenerative cardiovascular disorders; however, its contribution is still debated in gastrointestinal disorders. Evidence suggests that oxidative stress affects gastrointestinal motility in obesity, and post-infectious disorders by favoring the smooth muscle phenotypic switch toward a synthetic phenotype. The aim of this review is to gain insight into the role played by oxidative stress in gastrointestinal pathologies (GIT), and the involvement of ROS in the signaling underlying the muscular alterations of the gastrointestinal tract (GIT). In addition, potential therapeutic strategies based on the use of antioxidants for the treatment of inflammatory gastrointestinal diseases are reviewed and discussed. Although substantial progress has been made in identifying new techniques capable of assessing the presence of oxidative stress in humans, the biochemical-molecular mechanisms underlying GIT mucosal disorders are not yet well defined. Therefore, further studies are needed to clarify the mechanisms through which oxidative stress-related signaling can contribute to the alteration of the GIT mucosa in order to devise effective preventive and curative therapeutic strategies.
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Affiliation(s)
- Rosa Vona
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;
| | - Lucia Pallotta
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy; (L.P.); (M.C.); (C.S.)
| | - Martina Cappelletti
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy; (L.P.); (M.C.); (C.S.)
| | - Carola Severi
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy; (L.P.); (M.C.); (C.S.)
| | - Paola Matarrese
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;
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Basak D, Uddin MN, Hancock J. The Role of Oxidative Stress and Its Counteractive Utility in Colorectal Cancer (CRC). Cancers (Basel) 2020; 12:E3336. [PMID: 33187272 PMCID: PMC7698080 DOI: 10.3390/cancers12113336] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/06/2020] [Accepted: 11/08/2020] [Indexed: 12/12/2022] Open
Abstract
An altered redox status accompanied by an elevated generation of reactive oxygen/nitrogen species (ROS/RNS) has been implicated in a number of diseases including colorectal cancer (CRC). CRC, being one of the most common cancers worldwide, has been reported to be associated with multiple environmental and lifestyle factors (e.g., dietary habits, obesity, and physical inactivity) and harboring heightened oxidative stress that results in genomic instability. Although under normal condition ROS regulate many signal transduction pathways including cell proliferation and survival, overwhelming of the antioxidant capacity due to metabolic abnormalities and oncogenic signaling leads to a redox adaptation response that imparts drug resistance. Nevertheless, excessive reliance on elevated production of ROS makes the tumor cells increasingly vulnerable to further ROS insults, and the abolition of such drug resistance through redox perturbation could be instrumental to preferentially eliminate them. The goal of this review is to demonstrate the evidence that links redox stress to the development of CRC and assimilate the most up-to-date information that would facilitate future investigation on CRC-associated redox biology. Concomitantly, we argue that the exploitation of this distinct biochemical property of CRC cells might offer a fresh avenue to effectively eradicate these cells.
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Affiliation(s)
- Debasish Basak
- College of Pharmacy, Larkin University, Miami, FL 33169, USA;
| | | | - Jake Hancock
- College of Pharmacy, Larkin University, Miami, FL 33169, USA;
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10
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Dang PMC, Rolas L, El-Benna J. The Dual Role of Reactive Oxygen Species-Generating Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Gastrointestinal Inflammation and Therapeutic Perspectives. Antioxid Redox Signal 2020; 33:354-373. [PMID: 31968991 DOI: 10.1089/ars.2020.8018] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Despite their intrinsic cytotoxic properties, mounting evidence indicates that reactive oxygen species (ROS) physiologically produced by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) of epithelial cells (NOX1, dual oxidase [DUOX]2) and phagocytes (NOX2) are critical for innate immune response and homeostasis of the intestinal mucosa. However, dysregulated ROS production could be a driving factor in inflammatory bowel diseases (IBDs). Recent Advances: In addition to NOX2, recent studies have demonstrated that NOX1- and DUOX2-derived ROS can regulate intestinal innate immune defense and homeostasis by impacting many processes, including bacterial virulence, expression of bacteriostatic proteins, epithelial renewal and restitution, and microbiota composition. Moreover, the antibacterial role of DUOX2 is a function conserved in evolution as it has been described in invertebrates, and lower and higher vertebrates. In humans, variants of the NOX2, NOX1, and DUOX2 genes, which are associated with impaired ROS production, have been identified in very early onset IBD, but overexpression of NOX/DUOX, especially DUOX2, has also been described in IBD, suggesting that loss-of-function or excessive activity of the ROS-generating enzymes could contribute to disease progression. Critical Issues: Therapeutic perspectives aiming at targeting NOX/DUOX in IBD should take into account the two sides of NOX/DUOX-derived ROS in intestinal inflammation. Hence, NOX/DUOX inhibitors or ROS inducers should be considered as a function of the disease context. Future Directions: A thorough understanding of the physiological and pathological regulation of NOX/DUOX in the gastrointestinal tract is an absolute pre-requisite for the development of therapeutic strategies that can modulate ROS levels in space and time.
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Affiliation(s)
- Pham My-Chan Dang
- INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France.,Faculté de Médecine, Laboratoire d'Excellence Inflamex, DHU FIRE, Université de Paris, Paris, France
| | - Loïc Rolas
- INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France
| | - Jamel El-Benna
- INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation, Paris, France.,Faculté de Médecine, Laboratoire d'Excellence Inflamex, DHU FIRE, Université de Paris, Paris, France
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11
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Role of Superoxide Reductase FA796 in Oxidative Stress Resistance in Filifactor alocis. Sci Rep 2020; 10:9178. [PMID: 32513978 PMCID: PMC7280497 DOI: 10.1038/s41598-020-65806-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 05/07/2020] [Indexed: 12/20/2022] Open
Abstract
Filifactor alocis, a Gram-positive anaerobic bacterium, is now a proposed diagnostic indicator of periodontal disease. Because the stress response of this bacterium to the oxidative environment of the periodontal pocket may impact its pathogenicity, an understanding of its oxidative stress resistance strategy is vital. Interrogation of the F. alocis genome identified the HMPREF0389_00796 gene that encodes for a putative superoxide reductase (SOR) enzyme. SORs are non-heme, iron-containing enzymes that can catalyze the reduction of superoxide radicals to hydrogen peroxide and are important in the protection against oxidative stress. In this study, we have functionally characterized the putative SOR (FA796) from F. alocis ATCC 35896. The recombinant FA796 protein, which is predicted to be a homotetramer of the 1Fe-SOR class, can reduce superoxide radicals. F. alocis FLL141 (∆FA796::ermF) was significantly more sensitive to oxygen/air exposure compared to the parent strain. Sensitivity correlated with the level of intracellular superoxide radicals. Additionally, the FA796-defective mutant had increased sensitivity to hydrogen peroxide-induced stress, was inhibited in its ability to form biofilm and had reduced survival in epithelial cells. Collectively, these results suggest that the F. alocis SOR protein is a key enzymatic scavenger of superoxide radicals and protects the bacterium from oxidative stress conditions.
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12
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Chen J, Xu Q, Zhang Y, Zhang H. RNA Profiling Analysis of the Serum Exosomes Derived from Patients with Chronic Hepatitis and Acute-on-chronic Liver Failure Caused By HBV. Sci Rep 2020; 10:1528. [PMID: 32001731 PMCID: PMC6992791 DOI: 10.1038/s41598-020-58233-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 01/13/2020] [Indexed: 11/25/2022] Open
Abstract
Hepatitis B virus (HBV) is the main causative viral agent for liver diseases in China. In liver injury, exosomes may impede the interaction with chromatin in the target cell and transmit inflammatory, apoptosis, or regeneration signals through RNAs. Therefore, we attempted to determine the potential functions of exosomal RNAs using bioinformatics technology. We performed RNA sequencing analysis in exosomes derived from clinical specimens of healthy control (HC) individuals and patients with chronic hepatitis B (CHB) and acute-on-chronic liver failure caused by HBV (HBV-ACLF). This analysis resulted in the identification of different types and proportions of RNAs in exosomes from the HC individuals and patients. Exosomes from the CHB and HBV-ACLF patients showed distinct upregulation and downregulation patterns of differentially expressed genes compared with those from the HC subjects. Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway analysis further confirmed different patterns of biological functions and signalling pathways in CHB and HBV-ACLF. Then we chose two upregulated RNAs both in CHB and HBV-ACLF for further qPCR validation. It confirmed the significantly different expression levels in CHB and HBV-ACLF compared with HC. Our findings indicate selective packaging of the RNA cargo into exosomes under different HBV attacks; these may represent potential targets for the diagnosis and treatment of HBV-caused liver injury.
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Affiliation(s)
- Jiajia Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China. .,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 310003, China.
| | - Qingsheng Xu
- Department of Neurosurgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Yan Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 310003, China
| | - Huafen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 310003, China
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13
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Zhang F, Chen C, Hu J, Su R, Zhang J, Han Z, Chen H, Li Y. Molecular mechanism of Helicobacter pylori-induced autophagy in gastric cancer. Oncol Lett 2019; 18:6221-6227. [PMID: 31788098 DOI: 10.3892/ol.2019.10976] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 07/26/2019] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a gram-negative pathogen that colonizes gastric epithelial cells. The drug resistance rates of H. pylori have dramatically increased, causing persistent infections. Chronic infection by H. pylori is a critical cause of gastritis, peptic ulcers and even gastric cancer. In host cells, autophagy is stimulated to maintain cellular homeostasis following intracellular pathogen recognition by the innate immune defense system. However, H. pylori-induced autophagy is not consistent during acute and chronic infection. Therefore, a deeper understanding of the association between H. pylori infection and autophagy in gastric epithelial cells could aid the understanding of the mechanisms of persistent infection and the identification of autophagy-associated therapeutic targets for H. pylori infection. The present review describes the role of H. pylori and associated virulence factors in the induction of autophagy by different signaling pathways during acute infection. Additionally, the inhibition of autophagy in gastric epithelial cells during chronic infection was discussed. The present review summarized H. pylori-mediated autophagy and provided insights into its mechanism of action, suggesting the induction of autophagy as a novel therapeutic target for persistent H. pylori infection.
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Affiliation(s)
- Fan Zhang
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Cong Chen
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Jike Hu
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Ruiliang Su
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Junqiang Zhang
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Zhijian Han
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Hao Chen
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Yumin Li
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
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14
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Wal P, Saraswat N, Pal RS, Wal A, Chaubey M. A Detailed Insight of the Anti-inflammatory Effects of Curcumin with the Assessment of Parameters, Sources of ROS and Associated Mechanisms. ACTA ACUST UNITED AC 2019. [DOI: 10.2174/1874220301906010064] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background:Curcumin is an active constituent ofCurcuma longa,which belongs to Zingiberaceae family. It is derived from the Rhizome of a perennial plant having molecular formula C21H20O6and chemically it is (1, 7- bis (4- hydroxy - 3 methoxyphenyl) -1, 6 - heptadine - 3, 5 - diene), also known as diferuloylmethane. Curcumin has been extensively used as a herbal constituent for curing several diseases and is scientifically proven to show major effects as an anti-inflammatory agent.Objective:Inflammation is an important factor for numerous diseases including diabetes neuropathy, cancer, asthma, arthritis, and other diseases. Prophylaxis of inflammatory diseases through synthetic medications tends to have major toxicity and side effects on a large number of population. The foremost aim of this review paper is to assess the natural anti-inflammatory effect of curcumin, source, and mechanism of action, potential therapeutic effect and models associated. Additionally, this paper aims to scrutinize inflammation, sources of reactive oxygen species, and pathways of reactive oxygen species generation and potential side effects of curcumin.Methods:Selection of data has been done by studying the combination of research and review papers from different databases like PubMed, Medline and Web of science from the year 1985- 2018 by using search keywords like “curcumin”, “anti-inflammatory”, “ROS”, “Curcuma longa”, “medicinal uses of curcumin”, “assessing parameters”, “inflammation”, “anti-oxidant”Results:On the basis of our interpretation, we have concluded that curcumin has potential therapeutic effects in different inflammatory diseases, it inhibits the inflammatory mediators, oxidation processes, and oxidative stress and has no severe toxicity on animals and humans.Conclusion:Oxidative stress is a major cause of inflammation and curcumin has a good potential for blocking it. Curcumin is also easily accessible herbal source and should be consumed in the form of food, antioxidant, anti-inflammatory agents and further observation should be done on its therapeutic parameters, risk factors, and toxicity studies and oral viability.
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15
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Huang C, Niethammer P. Tissue Damage Signaling Is a Prerequisite for Protective Neutrophil Recruitment to Microbial Infection in Zebrafish. Immunity 2019; 48:1006-1013.e6. [PMID: 29768163 DOI: 10.1016/j.immuni.2018.04.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 04/04/2018] [Accepted: 04/17/2018] [Indexed: 12/28/2022]
Abstract
Tissue damage and infection are deemed likewise triggers of innate immune responses. But whereas neutrophil responses to microbes are generally protective, neutrophil recruitment into damaged tissues without infection is deleterious. Why neutrophils respond to tissue damage and not just to microbes is unknown. Is it a flaw of the innate immune system that persists because evolution did not select against it, or does it provide a selective advantage? Here we dissect the contribution of tissue damage signaling to antimicrobial immune responses in a live vertebrate. By intravital imaging of zebrafish larvae, a powerful model for innate immunity, we show that prevention of tissue damage signaling upon microbial ear infection abrogates leukocyte chemotaxis and reduces animal survival, at least in part, through suppression of cytosolic phospholipase A2 (cPla2), which integrates tissue damage- and microbe-derived cues. Thus, microbial cues are insufficient, and damage signaling is essential for antimicrobial neutrophil responses in zebrafish.
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Affiliation(s)
- Cong Huang
- Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; BCMB Allied Program, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA
| | - Philipp Niethammer
- Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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16
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You X, Ma M, Hou G, Hu Y, Shi X. Gene expression and prognosis of NOX family members in gastric cancer. Onco Targets Ther 2018; 11:3065-3074. [PMID: 29872318 PMCID: PMC5975617 DOI: 10.2147/ott.s161287] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
INTRODUCTION Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) are frequently deregulated in several human malignancies, including gastric cancer (GC). NOX-derived reactive oxygen species have been reported to contribute to gastric carcinogenesis and cancer progression. However, the expression and prognostic role of individual NOX in GC patients remain elusive. METHODS AND MATERIALS We investigated genetic alteration and mRNA expression of NOX family in GC patients via the cBioPortal, Human Protein Atlas, and Oncomine databases. Furthermore, we evaluated prognostic value of distinct NOX in GC patients through "The Kaplan-Meier plotter" database. RESULTS Our analysis demonstrated that mRNA deregulation of NOX genes was common alteration in GC patients. Compared with normal tissues, NOX1/2/4 mRNA expression levels in GC tissues were higher, while NOX5 and DUOX1/2 expression levels were lower. Importantly, our results indicated that high mRNA expression of NOX2 was associated with better overall survival whereas NOX4 and DUOX1 were correlated with worse overall survival in all GC patients, particularly in intestinal-type GC patients. In addition, our data also shed light on the diverse roles of individual NOX members in GC patients with different clinicopathological features, including human epidermal growth factor receptor 2 status, clinical stages, pathological grades, and different choices of treatments of GC patients. CONCLUSION These findings suggest that individual NOX family genes, especially NOX2/4, and DUOX1, are potential prognostic markers in GC and implicate that the use of NOX inhibitor targeting NOX4 and DUOX1 may be an effective strategy for GC therapy.
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Affiliation(s)
- Xin You
- The First Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Mingzhe Ma
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Gastric Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Guoxin Hou
- Department of Oncology, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Yumin Hu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xi Shi
- The First Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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17
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Vaziri F, Tarashi S, Fateh A, Siadat SD. New insights of Helicobacter pylori host-pathogen interactions: The triangle of virulence factors, epigenetic modifications and non-coding RNAs. World J Clin Cases 2018; 6:64-73. [PMID: 29774218 PMCID: PMC5955730 DOI: 10.12998/wjcc.v6.i5.64] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 02/09/2018] [Accepted: 03/07/2018] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a model organism for understanding host-pathogen interactions and infection-mediated carcinogenesis. Gastric cancer and H. pylori colonization indicates the strong correlation. The progression and exacerbation of H. pylori infection are influenced by some factors of pathogen and host. Several virulence factors involved in the proper adherence and attenuation of immune defense to contribute the risk of emerging gastric cancer, therefore analysis of them is very important. H. pylori also modulates inflammatory and autophagy process to intensify its pathogenicity. From the host regard, different genetic factors particularly affect the development of gastric cancer. Indeed, epigenetic modifications, MicroRNA and long non-coding RNA received more attention. Generally, various factors related to pathogen and host that modulate gastric cancer development in response to H. pylori need more attention due to develop an efficacious therapeutic intervention. Therefore, this paper will present a brief overview of host-pathogen interaction especially emphases on bacterial virulence factors, interruption of host cellular signaling, the role of epigenetic modifications and non-coding RNAs.
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Affiliation(s)
- Farzam Vaziri
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Samira Tarashi
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Abolfazl Fateh
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
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18
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Mommersteeg MC, Yu J, Peppelenbosch MP, Fuhler GM. Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms. Biochim Biophys Acta Rev Cancer 2017; 1869:42-52. [PMID: 29154808 DOI: 10.1016/j.bbcan.2017.11.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/13/2017] [Accepted: 11/13/2017] [Indexed: 02/09/2023]
Abstract
Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori.
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Affiliation(s)
- Michiel C Mommersteeg
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
| | - Jun Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences and CUHK-Shenzhen Research Institute, Rm 707A, 7/F., Li Ka Shing Medical Science Building, The Chinese University of Hong Kong, Hong Kong.
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
| | - Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical center Rotterdam, Office NA-619, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
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19
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Singh A, Koduru B, Carlisle C, Akhter H, Liu RM, Schroder K, Brandes RP, Ojcius DM. NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4. Sci Rep 2017; 7:14346. [PMID: 29085012 PMCID: PMC5662726 DOI: 10.1038/s41598-017-14574-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/12/2017] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammation plays a key role in development of many liver diseases. Stimulation of Toll-like receptor 4 (TLR4) by bacterial lipopolysaccharide (LPS) initiates inflammation and promotes development of hepatocellular carcinoma and other liver diseases. NADPH oxidases contribute to LPS-induced reactive oxygen species (ROS) production and modulate TLR responses, but whether these enzymes function in TLR4 responses of hepatocytes is unknown. In the present work, we examined the role of NADPH oxidase 4 (Nox4) in LPS-induced TLR4 responses in human hepatoma cells and wildtype and Nox4-deficient mice. We found that LPS increased expression of Nox4, TNF-α, and proliferating cell nuclear antigen (PCNA). Nox4 silencing suppressed LPS-induced TNF-α and PCNA increases in human cells. The LPS-induced TNF-α increases were MyD88-dependent, and were attenuated in primary hepatocytes isolated from Nox4-deficient mice. We found that Nox4 mediated LPS-TLR4 signaling in hepatocytes via NF-ĸB and AP-1 pathways. Moreover, the effect of Nox4 depletion was time-dependent; following six weeks of repeated LPS stimulation in vivo, hepatic TNF-α and PCNA responses subsided in Nox4-deficient mice compared with wildtype mice. Therefore, our data suggest that Nox4 mediates LPS-TLR4 signaling in human hepatoma cells and murine hepatocytes and may contribute to the ability of LPS to stimulate liver pathology.
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Affiliation(s)
- Anand Singh
- Health Sciences Research Institute, University of California, Merced, CA, USA
| | - Bhargav Koduru
- Health Sciences Research Institute, University of California, Merced, CA, USA
| | - Cameron Carlisle
- Health Sciences Research Institute, University of California, Merced, CA, USA
| | - Hasina Akhter
- School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rui-Ming Liu
- School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Katrin Schroder
- Institute for Cardiovascular Physiology, Goethe Universität, Frankfurt am Main, Germany
| | - Ralf P Brandes
- Institute for Cardiovascular Physiology, Goethe Universität, Frankfurt am Main, Germany
| | - David M Ojcius
- Health Sciences Research Institute, University of California, Merced, CA, USA. .,University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, USA.
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20
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Mejías-Luque R, Gerhard M. Immune Evasion Strategies and Persistence of Helicobacter pylori. Curr Top Microbiol Immunol 2017; 400:53-71. [PMID: 28124149 DOI: 10.1007/978-3-319-50520-6_3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori infection is commonly acquired during childhood, can persist lifelong if not treated, and can cause different gastric pathologies, including chronic gastritis, peptic ulcer disease, and eventually gastric cancer. H. pylori has developed a number of strategies in order to cope with the hostile conditions found in the human stomach as well as successful mechanisms to evade the strong innate and adaptive immune responses elicited upon infection. Thus, by manipulating innate immune receptors and related signaling pathways, inducing tolerogenic dendritic cells and inhibiting effector T cell responses, H. pylori ensures low recognition by the host immune system as well as its persistence in the gastric epithelium. Bacterial virulence factors such as cytotoxin-associated gene A, vacuolating cytotoxin A, or gamma-glutamyltranspeptidase have been extensively studied in the context of bacterial immune escape and persistence. Further, the bacterium possesses other factors that contribute to immune evasion. In this chapter, we discuss in detail the main evasion and persistence strategies evolved by the bacterium as well as the specific bacterial virulence factors involved.
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Affiliation(s)
- Raquel Mejías-Luque
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany. .,German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
| | - Markus Gerhard
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany.,German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany
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21
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Liu HM, Liao JF, Lee TY. Farnesoid X receptor agonist GW4064 ameliorates lipopolysaccharide-induced ileocolitis through TLR4/MyD88 pathway related mitochondrial dysfunction in mice. Biochem Biophys Res Commun 2017. [PMID: 28647362 DOI: 10.1016/j.bbrc.2017.06.129] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory condition of the gastro intestinal tract characterized by diarrhoea and abdominal pain. Farnesoid X receptor (FXR) plays an important role in enteroprotection and mucosal injury by regulating inflammatory responses and barrier function in the intestinal tract. Here we show the mechanisms of FXR agonist, GW4064, inhibits mucosal injury in ileum caused by lipopolysaccharides (LPS). Ileum injury was induced by intraperitoneal injection of LPS in Wild-type (WT) and FXR knockout (KO) mice. GW4064 alleviates LPS-mediated tight junction dysfunction as well as macrophage infiltration in WT mice, but not in FXR KO mice. Interesting, GW4064 suppresses NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome mediates tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-1β, as well as mitochondrial respiratory complexes mRNA expression in WT and FXR KO mice treated with LPS. This results demonstrated that central roles of FXR in coordinating regulation of both inflammation and mitochondrial dysfunction. We propose that GW4064 is promising therapeutic agent for treatment of ileocolitis.
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Affiliation(s)
- Hsuan-Miao Liu
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Jyh-Fei Liao
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
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22
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Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Semin Cell Dev Biol 2017; 80:50-64. [PMID: 28587975 DOI: 10.1016/j.semcdb.2017.05.023] [Citation(s) in RCA: 1292] [Impact Index Per Article: 161.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 05/17/2017] [Accepted: 05/29/2017] [Indexed: 12/19/2022]
Abstract
Increased reactive oxygen species (ROS) production has been detected in various cancers and has been shown to have several roles, for example, they can activate pro-tumourigenic signalling, enhance cell survival and proliferation, and drive DNA damage and genetic instability. Counterintuitively ROS can also promote anti-tumourigenic signalling, initiating oxidative stress-induced tumour cell death. Tumour cells express elevated levels of antioxidant proteins to detoxify elevated ROS levels, establish a redox balance, while maintaining pro-tumourigenic signalling and resistance to apoptosis. Tumour cells have an altered redox balance to that of their normal counterparts and this identifies ROS manipulation as a potential target for cancer therapies. This review discusses the generation and sources of ROS within tumour cells, the regulation of ROS by antioxidant defence systems, as well as the effect of elevated ROS production on their signalling targets in cancer. It also provides an insight into how pro- and anti-tumourigenic ROS signalling pathways could be manipulated in the treatment of cancer.
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Affiliation(s)
- Jennifer N Moloney
- Tumour Biology Laboratory, School of Biochemistry and Cell Biology, Bioscience Research Institute, University College Cork, Cork, Ireland
| | - Thomas G Cotter
- Tumour Biology Laboratory, School of Biochemistry and Cell Biology, Bioscience Research Institute, University College Cork, Cork, Ireland.
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23
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Aviello G, Knaus UG. ROS in gastrointestinal inflammation: Rescue Or Sabotage? Br J Pharmacol 2017; 174:1704-1718. [PMID: 26758851 PMCID: PMC5446568 DOI: 10.1111/bph.13428] [Citation(s) in RCA: 196] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 12/09/2015] [Accepted: 01/07/2016] [Indexed: 12/15/2022] Open
Abstract
The intestine is composed of many distinct cell types that respond to commensal microbiota or pathogens with immune tolerance and proinflammatory signals respectively. ROS produced by mucosa-resident cells or by newly recruited innate immune cells are essential for antimicrobial responses and regulation of signalling pathways including processes involved in wound healing. Impaired ROS production due to inactivating patient variants in genes encoding NADPH oxidases as ROS source has been associated with Crohn's disease and pancolitis, whereas overproduction of ROS due to up-regulation of oxidases or altered mitochondrial function was linked to ileitis and ulcerative colitis. Here, we discuss recent advances in our understanding of how maintaining a redox balance is crucial to preserve gut homeostasis. LINKED ARTICLES This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
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Affiliation(s)
- G Aviello
- National Children's Research CentreOur Lady's Children's HospitalDublinIreland
| | - UG Knaus
- National Children's Research CentreOur Lady's Children's HospitalDublinIreland
- Conway Institute, School of MedicineUniversity College DublinDublinIreland
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24
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Teixeira G, Szyndralewiez C, Molango S, Carnesecchi S, Heitz F, Wiesel P, Wood JM. Therapeutic potential of NADPH oxidase 1/4 inhibitors. Br J Pharmacol 2017; 174:1647-1669. [PMID: 27273790 PMCID: PMC5446584 DOI: 10.1111/bph.13532] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 05/23/2016] [Accepted: 05/23/2016] [Indexed: 12/16/2022] Open
Abstract
The NADPH oxidase (NOX) family of enzymes produces ROS as their sole function and is becoming recognized as key modulators of signal transduction pathways with a physiological role under acute stress and a pathological role after excessive activation under chronic stress. The seven isoforms differ in their regulation, tissue and subcellular localization and ROS products. The most studied are NOX1, 2 and 4. Genetic deletion of NOX1 and 4, in contrast to NOX2, has revealed no significant spontaneous pathologies and a pathogenic relevance of both NOX1 and 4 across multiple organs in a wide range of diseases and in particular inflammatory and fibrotic diseases. This has stimulated interest in NOX inhibitors for therapeutic application. GKT136901 and GKT137831 are two structurally related compounds demonstrating a preferential inhibition of NOX1 and 4 that have suitable properties for in vivo studies and have consequently been evaluated across a range of disease models and compared with gene deletion. In contrast to gene deletion, these inhibitors do not completely suppress ROS production, maintaining some basal level of ROS. Despite this and consistent with most gene deletion studies, these inhibitors are well tolerated and slow or prevent disease progression in a range of models of chronic inflammatory and fibrotic diseases by modulating common signal transduction pathways. Clinical trials in patients with GKT137831 have demonstrated excellent tolerability and reduction of various markers of chronic inflammation. NOX1/4 inhibition may provide a safe and effective therapeutic strategy for a range of inflammatory and fibrotic diseases. LINKED ARTICLES This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
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Affiliation(s)
- G Teixeira
- Evotec International GmbHGoettingenGermany
| | | | - S Molango
- Genkyotex SAPlan les OuatesSwitzerland
| | | | - F Heitz
- Genkyotex SAPlan les OuatesSwitzerland
| | - P Wiesel
- Genkyotex SAPlan les OuatesSwitzerland
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25
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Gobert AP, Wilson KT. Polyamine- and NADPH-dependent generation of ROS during Helicobacter pylori infection: A blessing in disguise. Free Radic Biol Med 2017; 105:16-27. [PMID: 27682363 PMCID: PMC5366100 DOI: 10.1016/j.freeradbiomed.2016.09.024] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 09/16/2016] [Accepted: 09/23/2016] [Indexed: 12/20/2022]
Abstract
Helicobacter pylori is a Gram-negative bacterium that specifically colonizes the gastric ecological niche. During the infectious process, which results in diseases ranging from chronic gastritis to gastric cancer, the host response is characterized by the activation of the innate immunity of gastric epithelial cells and macrophages. These cells thus produce effector molecules such as reactive oxygen species (ROS) to counteract the infection. The generation of ROS in response to H. pylori involves two canonical pathways: 1) the NADPH-dependent reduction of molecular oxygen to generate O2•-, which can dismute to generate ROS; and 2) the back-conversion of the polyamine spermine into spermidine through the enzyme spermine oxidase, leading to H2O2 production. Although these products have the potential to affect the survival of bacteria, H. pylori has acquired numerous strategies to counteract their deleterious effects. Nonetheless, ROS-mediated oxidative DNA damage and mutations may participate in the adaptation of H. pylori to its ecological niche. Lastly, ROS have been shown to play a major role in the development of the inflammation and carcinogenesis. It is the purpose of this review to summarize the literature about the production of ROS during H. pylori infection and their role in this infectious gastric disease.
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Affiliation(s)
- Alain P Gobert
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, United States; Center for Mucosal Inflammation and Cancer, United States
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, United States; Department of Pathology, Microbiology, and Immunology, United States; Department of Cancer Biology, United States; Center for Mucosal Inflammation and Cancer, United States; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, United States.
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26
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Pérez S, Taléns-Visconti R, Rius-Pérez S, Finamor I, Sastre J. Redox signaling in the gastrointestinal tract. Free Radic Biol Med 2017; 104:75-103. [PMID: 28062361 DOI: 10.1016/j.freeradbiomed.2016.12.048] [Citation(s) in RCA: 196] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 12/20/2016] [Accepted: 12/31/2016] [Indexed: 12/16/2022]
Abstract
Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett's esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett's esophagus and its transformation to adenocarcinoma. In Helicobacter pylori-induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract.
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Affiliation(s)
- Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Raquel Taléns-Visconti
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Isabela Finamor
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
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STAT5A-mediated NOX5-L expression promotes the proliferation and metastasis of breast cancer cells. Exp Cell Res 2017; 351:51-58. [DOI: 10.1016/j.yexcr.2016.12.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 12/21/2016] [Accepted: 12/25/2016] [Indexed: 11/22/2022]
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Lactobacilli enhance reactive oxygen species-dependent apoptosis-inducing signaling. Redox Biol 2017; 11:715-724. [PMID: 28193594 PMCID: PMC5310163 DOI: 10.1016/j.redox.2017.01.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 01/23/2017] [Indexed: 12/18/2022] Open
Abstract
H2O2-producing lactobacilli in the vaginal fluid have been suggested to play a potential tumor-preventive role in addition to the control of undesirable microorganisms. As the vaginal fluid also contains a significant concentration of peroxidase that might utilize lactobacilli-derived H2O2 as substrate for HOCl synthesis, a dominant biological role of HOCl in both natural defence systems has been postulated. Our study shows that lactobacillus-derived H2O2 per se is not likely to be beneficial for the vaginal epithelium, as it causes apoptosis nonselectively in nontransformed as well as transformed cells. However, the combination of lactobacilli and peroxidase, i.e. the situation that is actually found in vivo, leads to the conversion of H2O2 to HOCl which does not affect non-malignant cells, as these do not generate extracellular superoxide anions. In contrast, malignant cells, due to their abundant extracellular superoxide anion generation allow the generation of apoptosis-inducing hydroxyl radicals through HOCl/superoxide anion interaction. In total, our data show that the combination of H2O2 -generating lactobacilli and peroxidase causes the selective elimination of malignant cells and thus might contribute to the tumorpreventive potential of lactobacilli. These findings are in good agreement with epidemiological data. The contribution of lactobacilli in this system can be completely mimicked by H2O2-generating glucose oxidase, indicating that it is fully explained by bacterial generation of H2O2.
Lactobacillus-derived H2O2 induces apoptosis in nontransformed and transformed cells. MPO converts H2O2 into HOCl that exerts a selective apoptosis-inducing effect on malignant cells. Extracellular superoxide anions of malignant cells are crucial for selective apoptosis induction. A model for the tumor protective role of lactobacilli in the presence of peroxidase is presented.
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Flint A, Stintzi A, Saraiva LM. Oxidative and nitrosative stress defences of Helicobacter and Campylobacter species that counteract mammalian immunity. FEMS Microbiol Rev 2016; 40:938-960. [PMID: 28201757 PMCID: PMC5091033 DOI: 10.1093/femsre/fuw025] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/29/2016] [Accepted: 07/02/2016] [Indexed: 12/18/2022] Open
Abstract
Helicobacter and Campylobacter species are Gram-negative microaerophilic host-associated heterotrophic bacteria that invade the digestive tract of humans and animals. Campylobacter jejuni is the major worldwide cause of foodborne gastroenteritis in humans, while Helicobacter pylori is ubiquitous in over half of the world's population causing gastric and duodenal ulcers. The colonisation of the gastrointestinal system by Helicobacter and Campylobacter relies on numerous cellular defences to sense the host environment and respond to adverse conditions, including those imposed by the host immunity. An important antimicrobial tool of the mammalian innate immune system is the generation of harmful oxidative and nitrosative stresses to which pathogens are exposed during phagocytosis. This review summarises the regulators, detoxifying enzymes and subversion mechanisms of Helicobacter and Campylobacter that ultimately promote the successful infection of humans.
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Affiliation(s)
- Annika Flint
- Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Alain Stintzi
- Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Lígia M. Saraiva
- Instituto de Tecnologia Química e Biológica, NOVA, Av. da República, 2780-157 Oeiras, Portugal
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30
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Habib SL, Abboud HE. Tuberin regulates reactive oxygen species in renal proximal cells, kidney from rodents, and kidney from patients with tuberous sclerosis complex. Cancer Sci 2016; 107:1092-100. [PMID: 27278252 PMCID: PMC4982584 DOI: 10.1111/cas.12984] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 05/30/2016] [Accepted: 06/07/2016] [Indexed: 12/20/2022] Open
Abstract
Reactive oxygen species (ROS) are an important endogenous source of DNA damage and oxidative stress in all cell types. Deficiency in tuberin resulted in increased oxidative DNA damage in renal cells. In this study, the role of tuberin in the regulating of ROS and NADPH oxidases was investigated. Formation of ROS and activity of NADPH oxidases were significantly higher in mouse embryonic fibroblasts and in primary culture of rat renal proximal tubular epithelial tuberin‐deficient cells compared to wild‐type cells. In addition, expression of NADPH oxidase (Nox)1, Nox2, and Nox4 (Nox isoforms) was higher in mouse embryonic fibroblasts and renal proximal tubular epithelial tuberin‐deficient cells compared to wild‐type cells. Furthermore, activity levels of NADPH oxidases and protein expression of all Nox isoforms were higher in the renal cortex of rat deficient in tuberin. However, treatment of tuberin‐deficient cells with rapamycin showed significant decrease in protein expression of all Nox. Significant increase in protein kinase C βII expression was detected in tuberin‐deficient cells, whereas inhibition of protein kinase C βII by bisindolylmaleimide I resulted in decreased protein expression of all Nox isoforms. In addition, treatment of mice deficient in tuberin with rapamycin resulted in significant decrease in all Nox protein expression. Moreover, protein and mRNA expression of all Nox were highly expressed in tumor kidney tissue of patients with tuberous sclerosis complex compared to control kidney tissue of normal subjects. These data provide the first evidence that tuberin plays a novel role in regulating ROS generation, NADPH oxidase activity, and Nox expression that may potentially be involved in development of kidney tumor in patients with tuberous sclerosis complex.
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Affiliation(s)
- Samy L Habib
- Geriatric Research, Education and Clinical Department, South Texas Veterans Health Care System, San Antonio, Texas, USA.,Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Hanna E Abboud
- Geriatric Research, Education and Clinical Department, South Texas Veterans Health Care System, San Antonio, Texas, USA.,Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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31
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den Hartog G, Chattopadhyay R, Ablack A, Hall EH, Butcher LD, Bhattacharyya A, Eckmann L, Harris PR, Das S, Ernst PB, Crowe SE. Regulation of Rac1 and Reactive Oxygen Species Production in Response to Infection of Gastrointestinal Epithelia. PLoS Pathog 2016; 12:e1005382. [PMID: 26761793 PMCID: PMC4711900 DOI: 10.1371/journal.ppat.1005382] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 12/12/2015] [Indexed: 12/15/2022] Open
Abstract
Generation of reactive oxygen species (ROS) during infection is an immediate host defense leading to microbial killing. APE1 is a multifunctional protein induced by ROS and after induction, protects against ROS-mediated DNA damage. Rac1 and NAPDH oxidase (Nox1) are important contributors of ROS generation following infection and associated with gastrointestinal epithelial injury. The purpose of this study was to determine if APE1 regulates the function of Rac1 and Nox1 during oxidative stress. Gastric or colonic epithelial cells (wild-type or with suppressed APE1) were infected with Helicobacter pylori or Salmonella enterica and assessed for Rac1 and NADPH oxidase-dependent superoxide production. Rac1 and APE1 interactions were measured by co-immunoprecipitation, confocal microscopy and proximity ligation assay (PLA) in cell lines or in biopsy specimens. Significantly greater levels of ROS were produced by APE1-deficient human gastric and colonic cell lines and primary gastric epithelial cells compared to control cells after infection with either gastric or enteric pathogens. H. pylori activated Rac1 and Nox1 in all cell types, but activation was higher in APE1 suppressed cells. APE1 overexpression decreased H. pylori-induced ROS generation, Rac1 activation, and Nox1 expression. We determined that the effects of APE1 were mediated through its N-terminal lysine residues interacting with Rac1, leading to inhibition of Nox1 expression and ROS generation. APE1 is a negative regulator of oxidative stress in the gastrointestinal epithelium during bacterial infection by modulating Rac1 and Nox1. Our results implicate APE1 in novel molecular interactions that regulate early stress responses elicited by microbial infections. Helicobacter pylori infection of the gastric mucosa is largely lifelong leading to continued stimulation of immune cells. This results in the generation of reactive oxygen species (ROS) which are produced to kill bacteria, but at the same time ROS regulate cellular events in the host. However, prolonged generation of ROS has been implicated in damage of DNA, which ultimately could lead to the development of cancer. We studied a molecule known as APE-1 in gastric and intestinal cells, which is activated upon encounter of ROS. Our results show that APE1 limits the production of ROS in cells that form the lining of the gastrointestinal tract. APE1 regulates ROS production by inhibiting activation of the molecule Rac1. Inhibition of ROS production by APE1 occurred after infection of gastric cells with Helicobacter pylori and after Salmonella infection of intestinal cells. These data demonstrate that APE1 inhibits production of ROS in cells that line the inside of the digestive tract.
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Affiliation(s)
- Gerco den Hartog
- Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
| | - Ranajoy Chattopadhyay
- Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
| | - Amber Ablack
- Department of Pathology, University of California, San Diego, La Jolla, California, United States of America
| | - Emily H. Hall
- Department of Surgery, University of Virginia, Charlottesville, Virginia, United States of America
| | - Lindsay D. Butcher
- Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
| | - Asima Bhattacharyya
- National Institute of Science Education and Research (NISER), Bhubaneswar, India
| | - Lars Eckmann
- Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
| | - Paul R. Harris
- Division of Pediatrics, Unit of Gastroenterology and Nutrition, School of Medicine, Pontifical Catholic University, Santiago, Chile
| | - Soumita Das
- Department of Pathology, University of California, San Diego, La Jolla, California, United States of America
| | - Peter B. Ernst
- Department of Pathology, University of California, San Diego, La Jolla, California, United States of America
| | - Sheila E. Crowe
- Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
- * E-mail:
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Violi F, Pignatelli P. Clinical Application of NOX Activity and Other Oxidative Biomarkers in Cardiovascular Disease: A Critical Review. Antioxid Redox Signal 2015; 23:514-32. [PMID: 24382131 DOI: 10.1089/ars.2013.5790] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
SIGNIFICANCE The oxidative stress theory of atherosclerosis is based on the assumption that the production of reactive oxidant species (ROS) by blood, as well as resident cells of the artery wall, elicits the formation of oxidized low-density lipoproteins (ox-LDL), which, in turn, promotes a series of inflammatory responses, ultimately leading to atherosclerotic plaque. This theory prompted the development of new laboratory methodologies that aimed at assessing the relationship between oxidative stress and clinical progression of human atherosclerosis. CRITICAL ISSUES Markers assessing the oxidation of phospholipid and protein components of LDL were among the first to be developed. Clinical trials included cross-sectional as well as retrospective and prospective studies that, however, provided equivocal results. Thus, clear evidence that oxidative biomarkers add more to the risk stratification by common atherosclerotic risk factors is still lacking. RECENT ADVANCES More recently, the analysis of oxidative stress focused on enzymatic pathways generating ROS, such as NADPH oxidase and myeloperoxidase (MPO). Experimental and clinical studies suggest that both enzymes may be implicated in promoting atherosclerotic disease. Novel laboratory methodologies have been, therefore, developed to study NADPH oxidase and MPO in patients with stable atherosclerosis as well as in patients with acute coronary and cerebro-vascular syndromes. FUTURE DIRECTIONS This review will analyze the strengths and weaknesses of the current methodology to study these enzymes in human atherosclerosis with particular regard to their clinical application in several settings of cardiovascular disease. Clinical methodology and results of previous studies with regard to markers of LDL oxidation have also been reviewed as a useful background for the future development of clinical trials.
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Affiliation(s)
- Francesco Violi
- I Clinica Medica , Department of Internal Medicine and Medical Specialties, Rome, Italy
| | - Pasquale Pignatelli
- I Clinica Medica , Department of Internal Medicine and Medical Specialties, Rome, Italy
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Cho SO, Lim JW, Kim H. Diphenyleneiodonium Inhibits Apoptotic Cell Death of Gastric Epithelial Cells Infected with Helicobacter pylori in a Korean Isolate. Yonsei Med J 2015; 56:1150-4. [PMID: 26069142 PMCID: PMC4479847 DOI: 10.3349/ymj.2015.56.4.1150] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
NADPH oxidase produces a large amount of reactive oxygen species (ROS) in Helicobacter pylori (H. pylori)-induced gastric epithelial cells. Even though ROS mediate apoptotic cell death, direct involvement of NADPH oxidase on H. pylori-induced apoptosis remains unclear. Besides, H. pylori isolates show a high degree of genetic variability. The predominant genotype of H. pylori in Korea has been reported as cagA⁺, vacA s1b, m2, iceA genotype. Present study aims to investigate whether NADPH oxidase-generated ROS mediate apoptosis in human gastric epithelial AGS cells infected with H. pylori in a Korean isolate. AGS cells were pretreated with or without an NADPH oxidase inhibitor diphenyleneiodonium (DPI) and cultured in the presence of H. pylori at a bacterium/cell ratio of 300:1. Cell viability, hydrogen peroxide level, DNA fragmentation, and protein levels of p53, Bcl-2, and Bax were determined. Results showed that H. pylori inhibited cell viability with the density of H. pylori added to the cells. Inhibition of NADPH oxidase by DPI suppressed H. pylori-induced cell death, increased hydrogen peroxide, DNA fragmentation, and the ratio of Bax/Bcl-2, and p53 induction in AGS cells dose-dependently. The results suggest that targeting NADPH oxidase may prevent the development of gastric inflammation associated with H. pylori infection by suppressing abnormal apoptotic cell death of gastric epithelial cells.
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Affiliation(s)
- Soon Ok Cho
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
| | - Joo Weon Lim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea.
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Pastori D, Pignatelli P, Carnevale R, Violi F. Nox-2 up-regulation and platelet activation: Novel insights. Prostaglandins Other Lipid Mediat 2015; 120:50-5. [DOI: 10.1016/j.prostaglandins.2015.03.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Revised: 03/24/2015] [Accepted: 03/27/2015] [Indexed: 12/26/2022]
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Escherichia coli LF82 differentially regulates ROS production and mucin expression in intestinal epithelial T84 cells: implication of NOX1. Inflamm Bowel Dis 2015; 21:1018-26. [PMID: 25822013 DOI: 10.1097/mib.0000000000000365] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Increased reactive oxygen species (ROS) production is associated with inflamed ileal lesions in Crohn's disease colonized by pathogenic adherent-invasive Escherichia coli LF82. We investigated whether such ileal bacteria can modulate ROS production by epithelial cells, thus impacting on inflammation and mucin expression. METHODS Ileal bacteria from patients with Crohn's disease were incubated with cultured epithelial T84 cells, and ROS production was assayed using the luminol-amplified chemiluminescence method. The gentamicin protection assay was used for bacterial invasion of T84 cell. The expression of NADPH oxidase (NOX) subunits, mucin, and IL-8 was analyzed by quantitative real-time PCR and Western blots. Involvement of NOX and ROS was analyzed using diphenyleneiodonium (DPI) and N-acetylcysteine (NAC). RESULTS Among different bacteria tested, only LF82 induced an increase of ROS production by T84 cells in a dose-dependent manner. This response was inhibited by DPI and NAC. Heat- or ethanol-attenuated LF82 bacteria and the mutant LF82ΔFimA, which does not express pili type 1 and poorly adheres to epithelial cells, did not induce the oxidative response. The LF82-induced oxidative response coincides with its invasion in T84 cells, and both processes were inhibited by DPI. Also, we observed an increased expression of NOX1 and NOXO1 in response to LF82 bacteria versus the mutant LF82ΔFimA. Furthermore, LF82 inhibited mucin gene expression (MUC2 and MUC5AC) in T84 cells while increasing the chemotactic IL-8 expression, both in a DPI-sensitive manner. CONCLUSIONS Adherent-invasive E. coli LF82 induced ROS production by intestinal NADPH oxidase and altered mucin and IL-8 expression, leading to perpetuation of inflammatory lesions in Crohn's disease.
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Abstract
The mechanism by which reactive oxygen species (ROS) are produced by tumour cells remained incompletely understood until the discovery over the last 15 years of the family of NADPH oxidases (NOXs 1–5 and dual oxidases DUOX1/2) which are structural homologues of gp91phox, the major membrane-bound component of the respiratory burst oxidase of leucocytes. Knowledge of the roles of the NOX isoforms in cancer is rapidly expanding. Recent evidence suggests that both NOX1 and DUOX2 species produce ROS in the gastrointestinal tract as a result of chronic inflammatory stress; cytokine induction (by interferon-γ, tumour necrosis factor α, and interleukins IL-4 and IL-13) of NOX1 and DUOX2 may contribute to the development of colorectal and pancreatic carcinomas in patients with inflammatory bowel disease and chronic pancreatitis, respectively. NOX4 expression is increased in pre-malignant fibrotic states which may lead to carcinomas of the lung and liver. NOX5 is highly expressed in malignant melanomas, prostate cancer and Barrett's oesophagus-associated adenocarcinomas, and in the last it is related to chronic gastro-oesophageal reflux and inflammation. Over-expression of functional NOX proteins in many tissues helps to explain tissue injury and DNA damage from ROS that accompany pre-malignant conditions, as well as elucidating the potential mechanisms of NOX-related damage that contribute to both the initiation and the progression of a wide range of solid and haematopoietic malignancies.
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37
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Lugrin J, Rosenblatt-Velin N, Parapanov R, Liaudet L. The role of oxidative stress during inflammatory processes. Biol Chem 2014; 395:203-30. [PMID: 24127541 DOI: 10.1515/hsz-2013-0241] [Citation(s) in RCA: 495] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 10/09/2013] [Indexed: 12/22/2022]
Abstract
Abstract The production of various reactive oxidant species in excess of endogenous antioxidant defense mechanisms promotes the development of a state of oxidative stress, with significant biological consequences. In recent years, evidence has emerged that oxidative stress plays a crucial role in the development and perpetuation of inflammation, and thus contributes to the pathophysiology of a number of debilitating illnesses, such as cardiovascular diseases, diabetes, cancer, or neurodegenerative processes. Oxidants affect all stages of the inflammatory response, including the release by damaged tissues of molecules acting as endogenous danger signals, their sensing by innate immune receptors from the Toll-like (TLRs) and the NOD-like (NLRs) families, and the activation of signaling pathways initiating the adaptive cellular response to such signals. In this article, after summarizing the basic aspects of redox biology and inflammation, we review in detail the current knowledge on the fundamental connections between oxidative stress and inflammatory processes, with a special emphasis on the danger molecule high-mobility group box-1, the TLRs, the NLRP-3 receptor, and the inflammasome, as well as the transcription factor nuclear factor-κB.
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Elfvin A, Edebo A, Hallersund P, Casselbrant A, Fändriks L. Oxidative and nitrosative stress enzymes in relation to nitrotyrosine in Helicobacter pylori-infected humans. World J Gastrointest Pathophysiol 2014; 5:373-379. [PMID: 25133038 PMCID: PMC4133535 DOI: 10.4291/wjgp.v5.i3.373] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 04/25/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare a possible relation between Helicobacter pylori (H. pylori) and the oxygen- and nitrogen radical system in humans.
METHODS: Mechanisms for H. pylori to interfere with the oxygen and nitrogen radical system is of great importance for understanding of the H. pylori persistence and pathogenesis. Biopsies were obtained from the gastric wall of 21 individuals. Ongoing infection with H. pylori was detected using direct analyze from the biopsies using campylobacter-like organism test (CLO-test) and/or by using 14C-urea breath test. The individuals were divided in a negative H. pylori and a positive H. pylori group. Expression in the gastric mucosa of inducible nitric oxide syntase (iNOS), nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-oxidase) myeloperoxidase (MPO), and nitrotyrosine were assessed by Western blotting.
RESULTS: The individuals who undervent gastroscopy were divided in a H. pylori neg. [n = 13, m/f = 7/6, age (mean) = 39] and a H. pylori pos. group [n= 8, m/f = 5/3, age (mean) = 53]. Using western blot analysis iNOS was detected as a 130 kDa band. The iNOS expression was upregulated in the antrum of H. pylori infected individuals in comparison to the controls, mean ± SD being 12.6 ± 2.4 vs 8.3 ± 3.1, P < 0.01. There was a markedly upregulated expression of MPO in the antrum of H. pylori infected individuals in comparison to the control group without infection. In several of non-infected controls it was not possible to detect any MPO expression at all, whereas the expression was high in all the infected subjects, mean ± SD being 5.1 ± 3.4 vs 2.1 ± 1.9, P < 0.05. The NADPH-oxidase expression was analysed by detecting the NADPH-oxidase subunit p47-phox expression. P47-phox was detected as a 47 kDa band using Western blot, and showed a significantly higher expression of p47-phox in the antrum of the H. pylori infected individuals compared to the controls, mean ± SD being 3.1 ± 2.2 vs 0.3 ± 0.2, P < 0.01. Regarding nitrotyrosine formation, Western blot did not show any significant increase or decrease compared to controls, 7.0 ± 0.9 vs 6.9 ± 1.1, not significant.
CONCLUSION: iNOS, MPO and NADPH-oxidase was up-regulated among H. pylori infected. Regarding nitrotyrosine no difference was found. This support an H. pylori related inhibition of radical formation.
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Bauer G, Bereswill S, Aichele P, Glocker E. Helicobacter pylori protects oncogenically transformed cells from reactive oxygen species-mediated intercellular induction of apoptosis. Carcinogenesis 2014; 35:1582-91. [PMID: 24662971 DOI: 10.1093/carcin/bgu074] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Malignant transformation of gastric epithelial cells by chronic Helicobacter pylori infection is caused by several mechanisms including attraction of reactive oxygen species (ROS)-producing neutrophils and cytotoxin-associated antigen A-mediated dysplastic alterations. Here we show that H.pylori protects transformed cells from ROS-mediated intercellular induction of apoptosis. This potential control step in oncogenesis depends on the HOCl and NO/peroxynitrite (PON) signaling pathways. Helicobacter pylori-associated catalase and superoxide dismutase (SOD) efficiently cooperate in the inhibition of HOCl and the NO/PON signaling pathways. Helicobacter pylori catalase prevents HOCl synthesis through decomposition of hydrogen peroxide. Helicobacter pylori-associated SOD interferes with the crucial interactions between superoxide anions and HOCl, as well as superoxide anions and NO. The ratio of bacteria to malignant cells is critical for sufficient protection of transformed cells. Low concentrations of H.pylori more efficiently inhibited ROS-mediated destruction of transformed cells when compared with high concentrations of bacteria. Our data demonstrate the critical role of H.pylori antioxidant enzymes in the survival of transformed cells, modulating an early step of oncogenesis that is distinct from the transformation process per se.
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Affiliation(s)
- Georg Bauer
- Institute of Virology, Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg D-79104, Germany, Institute of Medical Microbiology, Charité, Berlin D-12203, Germany and Institute of Immunology and Institute of Microbiology, Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg D-79104, Germany
| | - Stefan Bereswill
- Institute of Medical Microbiology, Charité, Berlin D-12203, Germany and
| | | | - Erik Glocker
- Institute of Microbiology, Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg D-79104, Germany
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40
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Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 2014; 20:1126-67. [PMID: 23991888 PMCID: PMC3929010 DOI: 10.1089/ars.2012.5149] [Citation(s) in RCA: 3145] [Impact Index Per Article: 285.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Abstract Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury.
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Affiliation(s)
- Manish Mittal
- 1 Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois
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Violi F, Pignatelli P. Platelet NOX, a novel target for anti-thrombotic treatment. Thromb Haemost 2014; 111:817-23. [PMID: 24402688 DOI: 10.1160/th13-10-0818] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 12/05/2013] [Indexed: 12/17/2022]
Abstract
There is a growing body of evidence to suggest that reactive oxidant species (ROS) including O2-, OH- or H2O2 act as second messengers to activate platelets via 1) calcium mobilisation, 2) nitric oxide (NO) inactivation, and 3) interaction with arachidonic to give formation of isoprostanes. Among the enzymes generating ROS formation NOX2, the catalytic core of NADPH oxidase (NOX), plays a prominent role as shown by the almost absent ROS production by platelets taken from patients with hereditary deficiency of NOX2. Experimental and clinical studies provided evidence that NOX2 is implicated in platelet activation. Thus, impaired platelet activation has been detected in patients with NOX2 hereditary deficiency. Similarly, normal platelets added with NOX2 specific inhibitors disclosed impaired platelet activation along with ROS down-regulation. Accordingly, animals prone to atherosclerosis treated with apocynin, a NOX inhibitor, showed reduced platelet adhesion and atherosclerotic plaque. Furthermore, a significant association between NOX2 up-regulation and platelet activation has been detected in patients at athero-thrombotic risk, but a cause-effect relationship needs to be established. These findings may represent a rationale to plan interventional trials with NOX inhibitors to establish if blocking NOX2 or other NOX isoforms may represent a novel anti-platelet approach.
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Affiliation(s)
- Francesco Violi
- Prof. Francesco Violi, I Clinica Medica, Viale del Policlinico 155, Roma, 00161, Italy, Tel.: +39 064461933, Fax: +39 0649970103, E-mail:
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Katsuyama M. [Superoxide-generating enzymes NADPH oxidases, potential targets of drug therapy: various mechanisms for regulation of their expression]. Nihon Yakurigaku Zasshi 2013; 142:285-90. [PMID: 24334927 DOI: 10.1254/fpj.142.285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Wu Y, Antony S, Meitzler JL, Doroshow JH. Molecular mechanisms underlying chronic inflammation-associated cancers. Cancer Lett 2013; 345:164-73. [PMID: 23988267 DOI: 10.1016/j.canlet.2013.08.014] [Citation(s) in RCA: 205] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 08/08/2013] [Accepted: 08/13/2013] [Indexed: 12/17/2022]
Abstract
Although it is now accepted that chronic inflammation plays an essential role in tumorigenesis, the underlying molecular mechanisms linking inflammation and cancer remain to be fully explored. Inflammatory mediators present in the tumor microenvironment, including cytokines and growth factors, as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS), have been implicated in the etiology of inflammation-associated cancers. Epithelial NADPH oxidase (Nox) family proteins, which generate ROS regulated by cytokines, are upregulated during chronic inflammation and cancer. ROS serve as effector molecules participating in host defense or as chemo-attractants recruiting leukocytes to wounds, thereby influencing the inflammatory reaction in damaged tissues. ROS can alter chromosomal DNA, leading to genomic instability, and may serve as signaling molecules that affect tumor cell proliferation, survival, metabolism, angiogenesis, and metastasis. Targeting Noxs and their downstream signaling components may be a promising approach to pre-empting inflammation-related malignancies.
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Affiliation(s)
- Yongzhong Wu
- Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Smitha Antony
- Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jennifer L Meitzler
- Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - James H Doroshow
- Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Contribution of NADPH oxidase to membrane CD38 internalization and activation in coronary arterial myocytes. PLoS One 2013; 8:e71212. [PMID: 23940720 PMCID: PMC3737089 DOI: 10.1371/journal.pone.0071212] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 06/27/2013] [Indexed: 12/22/2022] Open
Abstract
The CD38-ADP-ribosylcyclase-mediated Ca2+ signaling pathway importantly contributes to the vasomotor response in different arteries. Although there is evidence indicating that the activation of CD38-ADP-ribosylcyclase is associated with CD38 internalization, the molecular mechanism mediating CD38 internalization and consequent activation in response to a variety of physiological and pathological stimuli remains poorly understood. Recent studies have shown that CD38 may sense redox signals and is thereby activated to produce cellular response and that the NADPH oxidase isoform, NOX1, is a major resource to produce superoxide (O2·−) in coronary arterial myocytes (CAMs) in response to muscarinic receptor agonist, which uses CD38-ADP-ribosylcyclase signaling pathway to exert its action in these CAMs. These findings led us hypothesize that NOX1-derived O2·− serves in an autocrine fashion to enhance CD38 internalization, leading to redox activation of CD38-ADP-ribosylcyclase activity in mouse CAMs. To test this hypothesis, confocal microscopy, flow cytometry and a membrane protein biotinylation assay were used in the present study. We first demonstrated that CD38 internalization induced by endothelin-1 (ET-1) was inhibited by silencing of NOX1 gene, but not NOX4 gene. Correspondingly, NOX1 gene silencing abolished ET-1-induced O2·− production and increased CD38-ADP-ribosylcyclase activity in CAMs, while activation of NOX1 by overexpression of Rac1 or Vav2 or administration of exogenous O2·− significantly increased CD38 internalization in CAMs. Lastly, ET-1 was found to markedly increase membrane raft clustering as shown by increased colocalization of cholera toxin-B with CD38 and NOX1. Taken together, these results provide direct evidence that Rac1-NOX1-dependent O2·− production mediates CD38 internalization in CAMs, which may represent an important mechanism linking receptor activation with CD38 activity in these cells.
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Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy. Clin Sci (Lond) 2013; 124:597-615. [PMID: 23379642 DOI: 10.1042/cs20120212] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pathological angiogenesis is a key feature of many diseases including retinopathies such as ROP (retinopathy of prematurity) and DR (diabetic retinopathy). There is considerable evidence that increased production of ROS (reactive oxygen species) in the retina participates in retinal angiogenesis, although the mechanisms by which this occurs are not fully understood. ROS is produced by a number of pathways, including the mitochondrial electron transport chain, cytochrome P450, xanthine oxidase and uncoupled nitric oxide synthase. The family of NADPH oxidase (Nox) enzymes are likely to be important given that their primary function is to produce ROS. Seven isoforms of Nox have been identified named Nox1-5, Duox (dual oxidase) 1 and Duox2. Nox1, Nox2 and Nox4 have been most extensively studied and are implicated in the development of conditions such as hypertension, cardiovascular disease and diabetic nephropathy. In recent years, evidence has accumulated to suggest that Nox1, Nox2 and Nox4 participate in pathological angiogenesis; however, there is no clear consensus about which Nox isoform is primarily responsible. In terms of retinopathy, there is growing evidence that Nox contribute to vascular injury. The RAAS (renin-angiotensin-aldosterone system), and particularly AngII (angiotensin II), is a key stimulator of Nox. It is known that a local RAAS exists in the retina and that blockade of AngII and aldosterone attenuate pathological angiogenesis in the retina. Whether the RAAS influences the production of ROS derived from Nox in retinopathy is yet to be fully determined. These topics will be reviewed with a particular emphasis on ROP and DR.
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Kotsias F, Hoffmann E, Amigorena S, Savina A. Reactive oxygen species production in the phagosome: impact on antigen presentation in dendritic cells. Antioxid Redox Signal 2013; 18:714-29. [PMID: 22827577 DOI: 10.1089/ars.2012.4557] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SIGNIFICANCE The NADPH oxidase 2 (NOX2) is known to play a major role in innate immunity for several decades. Phagocytic cells provide host defense by ingesting microbes and destroy them by different mechanisms, including the generation of reactive oxygen species (ROS) by NOX2, a process known as oxidative burst. The phagocytic pathway of dendritic cells (DCs), highly adapted to antigen processing, has been shown to display remarkable differences compared to other phagocytes. Contrary to macrophages and neutrophils, the main function of DC phagosomes is antigen presentation rather than pathogen killing or clearance of cell debris. RECENT ADVANCES In the last few years, it became clear that NOX2 is also involved in the establishment of adaptive immunity. Several studies support the idea of a relationship between antigen presentation and the level of antigen degradation, the latter one being regulated by the pH and ROS within phagosomes. CRITICAL ISSUES The regulation of phagosomal pH exerted by NOX2, and thereby of the efficacy of antigen cross-presentation in DCs, represents a clear illustration of how NOX2 can influence CD8(+) T lymphocyte responses. In this review, we want to put emphasis on the relationship between ROS generation and antigen processing and presentation, since there is growing evidence that the low levels of ROS generated by DCs play an important role in these processes. FUTURE DIRECTIONS In the next years, it will be interesting to unravel possible mechanisms involved and to find other possible connections between NOX family members and adaptive immune responses.
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Shi F, Zhu X. NOX-mediated MAPK and PI3K/Akt signaling pathways and liver fibrosis. Shijie Huaren Xiaohua Zazhi 2012; 20:2685-2690. [DOI: 10.11569/wcjd.v20.i28.2685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic satellite cells (HSCs) are the main cell type involved in the development of liver fibrosis and have been recognized as the important cellular source of extracellular matrix (ECM). NADPH oxidase (NOX) catalyzes the generation of reactive oxygen species (ROS), regulates signal transduction in HSCs, and thereby plays a key role in the pathogenesis of hepatic fibrosis. ROS generated by NOX promotes proliferation and inhibits apoptosis of HSCs by activation of mitogen-activated protein kinase and phosphatidylinositol-3 kinase/Akt signaling pathways, thus contributing to the development of liver fibrosis. Inhibition of NOX activation to generate ROS and NOX-mediated signal transduction induces HSC apoptosis. Therefore, drugs that target specific NOX can be expected to be useful in arresting the progression of liver fibrosis.
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Choi DH, Cristóvão AC, Guhathakurta S, Lee J, Joh TH, Beal MF, Kim YS. NADPH oxidase 1-mediated oxidative stress leads to dopamine neuron death in Parkinson's disease. Antioxid Redox Signal 2012; 16:1033-45. [PMID: 22098189 PMCID: PMC3315177 DOI: 10.1089/ars.2011.3960] [Citation(s) in RCA: 140] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
AIM Oxidative stress has long been considered as a major contributing factor in the pathogenesis of Parkinson's disease. However, molecular sources for reactive oxygen species in Parkinson's disease have not been clearly elucidated. Herein, we sought to investigate whether a superoxide-producing NADPH oxidases (NOXs) are implicated in oxidative stress-mediated dopaminergic neuronal degeneration. RESULTS Expression of various Nox isoforms and cytoplasmic components were investigated in N27, rat dopaminergic cells. While most of Nox isoforms were constitutively expressed, Nox1 expression was significantly increased after treatment with 6-hydroxydopamine. Rac1, a key regulator in the Nox1 system, was also activated. Striatal injection of 6-hydroxydopamine increased Nox1 expression in dopaminergic neurons in the rat substantia nigra. Interestingly, it was localized into the nucleus, and immunostaining for DNA oxidative stress marker, 8-oxo-dG, was increased. Nox1 expression was also found in the nucleus of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Adeno-associated virus-mediated Nox1 knockdown or Rac1 inhibition reduced 6-hydroxydopamine-induced oxidative DNA damage and dopaminergic neuronal degeneration significantly. INNOVATION Nox1/Rac1 could serve as a potential therapeutic target for Parkinson's disease. CONCLUSION We provide evidence that dopaminergic neurons are equipped with the Nox1/Rac1 superoxide-generating system. Stress-induced Nox1/Rac1 activation causes oxidative DNA damage and neurodegeneration. Reduced dopaminergic neuronal death achieved by targeting Nox1/Rac1, emphasizes the impact of oxidative stress caused by this system on the pathogenesis and therapy in Parkinson's disease.
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Affiliation(s)
- Dong-Hee Choi
- Neurology/Neuroscience Department, Weill Medical College of Cornell University, New York, New York, USA
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Carnesecchi S, Pache JC, Barazzone-Argiroffo C. NOX enzymes: potential target for the treatment of acute lung injury. Cell Mol Life Sci 2012; 69:2373-85. [PMID: 22581364 PMCID: PMC7095984 DOI: 10.1007/s00018-012-1013-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 04/18/2012] [Accepted: 04/20/2012] [Indexed: 12/19/2022]
Abstract
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), is characterized by acute inflammation, disruption of the alveolar-capillary barrier, and in the organizing stage by alveolar pneumocytes hyperplasia and extensive lung fibrosis. The cellular and molecular mechanisms leading to the development of ALI/ARDS are not completely understood, but there is evidence that reactive oxygen species (ROS) generated by inflammatory cells as well as epithelial and endothelial cells are responsible for inflammatory response, lung damage, and abnormal repair. Among all ROS-producing enzymes, the members of NADPH oxidases (NOXs), which are widely expressed in different lung cell types, have been shown to participate in cellular processes involved in the maintenance of lung integrity. It is not surprising that change in NOXs’ expression and function is involved in the development of ALI/ARDS. In this context, the use of NOX inhibitors could be a possible therapeutic perspective in the management of this syndrome. In this article, we summarize the current knowledge concerning some cellular aspects of NOXs localization and function in the lungs, consider their contribution in the development of ALI/ARDS and discuss the place of NOX inhibitors as potential therapeutical target.
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Affiliation(s)
- Stéphanie Carnesecchi
- Department of Pediatrics/Pathology and Immunology, Centre Médical Universitaire, Geneva, Switzerland.
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Necchi V, Minelli A, Sommi P, Vitali A, Caruso R, Longoni D, Frau MR, Nasi C, De Gregorio F, Zecca M, Ricci V, Danesino C, Solcia E. Ubiquitin-proteasome-rich cytoplasmic structures in neutrophils of patients with Shwachman-Diamond syndrome. Haematologica 2012; 97:1057-63. [PMID: 22271888 DOI: 10.3324/haematol.2011.048462] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Shwachman-Diamond syndrome is an autosomal recessive disorder in which severe bone marrow dysfunction causes neutropenia and an increased risk of leukemia. Recently, novel particulate cytoplasmic structures, rich in ubiquitinated and proteasomal proteins, have been detected in epithelial cells and neutrophils from patients with Helicobacter pylori gastritis and several epithelial neoplasms. DESIGN AND METHODS Blood neutrophils from 13 cases of Shwachman-Diamond syndrome - ten with and three without SBDS gene mutation - and ten controls were investigated by confocal microscopy and ultrastructural immunocytochemistry using antibodies against ubiquitinated proteins, proteasomes, p62 protein, and Helicobacter pylori VacA, urease and outer membrane proteins. RESULTS Many extensively disseminated particulate cytoplasmic structures, accounting for 22.78 ± 5.57% (mean ± standard deviation) of the total cytoplasm, were found in blood neutrophils from mutated Shwachman-Diamond syndrome patients. The particulate cytoplasmic structures showed immunoreactivity for polyubiquitinated proteins and proteasomes, but no reactivity for Helicobacter pylori products, which are present in particulate cytoplasmic structures of Helicobacter pylori-positive gastritis. Neutrophils from patients with Shwachman-Diamond syndrome frequently showed p62-positive autophagic vacuoles and apoptotic changes in 5% of cells. No particulate cytoplasmic structures were observed in most control neutrophils; however, in a few cells from two cases we noted focal development of minute particulate cytoplasmic structures, accounting for 0.74 ± 0.56% of the total cytoplasm (P<0.001 versus particulate cytoplasmic structures from mutated Shwachman-Diamond syndrome patients). Neutrophils from non-mutated Shwachman-Diamond-syndrome-like patients resembled controls in two cases, and a third case showed particulate cytoplasmic structure patterns intermediate between those in controls and those in mutated Shwachman-Diamond syndrome patients. CONCLUSIONS Particulate cytoplasmic structures are a prominent feature of neutrophils from patients with Shwachman-Diamond syndrome. They may help us to understand the mechanism of granulocyte dysfunction and the neoplastic risk of the disease.
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Affiliation(s)
- Vittorio Necchi
- Department of Human Pathology and Genetics, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
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