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Miljković R, Marinković E, Prodić I, Kovačević A, Protić-Rosić I, Vasić M, Lukić I, Gavrović-Jankulović M, Stojanović M. Ameliorative Effect of Banana Lectin in TNBS-Induced Colitis in C57BL/6 Mice Relies on the Promotion of Antioxidative Mechanisms in the Colon. Biomolecules 2025; 15:476. [PMID: 40305159 PMCID: PMC12024995 DOI: 10.3390/biom15040476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/22/2025] [Accepted: 03/05/2025] [Indexed: 05/02/2025] Open
Abstract
Background: The global burden of inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, is constantly rising. As IBDs significantly reduce patients' quality of life, prevention and efficient treatment of IBDs are of paramount importance. Although the molecular mechanisms underlying IBD pathogenesis are still not completely understood, numerous studies indicate the essential role of oxidative stress in the progression of the diseases. Objective: The aim of this study was to investigate whether prophylactic administration of recombinant banana lectin (rBanLec) could positively affect antioxidative mechanisms in the colon and thus prevent or alleviate the severity of experimental colitis induced in C57BL/6 mice. Methods: The prophylactic potential of rBanLec, a mannose-binding lectin with immunomodulatory properties, was investigated in a model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in C57BL/6 mice. Mice received rBanLec at various doses (0.1, 1 and 10 μg/mL) before the induction of colitis. The severity of the disease was assessed by weight loss and reduction in colon length, and correlated with histopathological findings, cytokine milieu, and oxidative stress markers in the colon. Results: The obtained results revealed that pretreatment with a low dose of rBanLec (0.1 μg/mL) significantly reduced the severity of TNBS-induced colitis, as indicated by reduced weight loss, less severe histopathological damage, and a favorable anti-inflammatory cytokine milieu (increased IL-10 and TGFβ). In addition, rBanLec pretreatment improved the activity of antioxidant enzymes (SOD, CAT, and GST) and reduced markers of oxidative stress such as nitric oxide levels at the peak of the disease. In contrast, higher doses of rBanLec exacerbated inflammatory responses. Conclusions: Our findings indicate that at low doses rBanLec can alleviate the severity of colitis by modulating oxidative stress and promoting anti-inflammatory cytokine responses, positioning rBanLec as a potential candidate for treating IBDs.
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Grants
- 451-03-66/2024-03/200177 Ministry of Science, Technological Development and Innovation, Serbia
- 451-03-66/2024-03/200007 Ministry of Science, Technological Development and Innovation, Serbia
- 451-03-66/2024-03/200168 Ministry of Science, Technological Development and Innovation, Serbia
- 451-03-136/2025-03/ 200177 Ministry of Science, Technological Development and Innovation, Serbia
- 451-03-136/2025-03/ 200007 Ministry of Science, Technological Development and Innovation, Serbia
- 451-03-136/2025-03/ 200168 Ministry of Science, Technological Development and Innovation, Serbia
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Affiliation(s)
- Radmila Miljković
- Department of Research and Development, Institute of Virology, Vaccines and Sera “Torlak”, 11221 Belgrade, Serbia; (R.M.); (I.P.); (A.K.); (M.V.); (I.L.)
| | - Emilija Marinković
- Institute for Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Ivana Prodić
- Department of Research and Development, Institute of Virology, Vaccines and Sera “Torlak”, 11221 Belgrade, Serbia; (R.M.); (I.P.); (A.K.); (M.V.); (I.L.)
| | - Ana Kovačević
- Department of Research and Development, Institute of Virology, Vaccines and Sera “Torlak”, 11221 Belgrade, Serbia; (R.M.); (I.P.); (A.K.); (M.V.); (I.L.)
| | - Isidora Protić-Rosić
- Department of Biochemistry, Faculty of Chemistry, University of Belgrade, 11158 Belgrade, Serbia; (I.P.-R.); (M.G.-J.)
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria
| | - Marko Vasić
- Department of Research and Development, Institute of Virology, Vaccines and Sera “Torlak”, 11221 Belgrade, Serbia; (R.M.); (I.P.); (A.K.); (M.V.); (I.L.)
| | - Ivana Lukić
- Department of Research and Development, Institute of Virology, Vaccines and Sera “Torlak”, 11221 Belgrade, Serbia; (R.M.); (I.P.); (A.K.); (M.V.); (I.L.)
| | - Marija Gavrović-Jankulović
- Department of Biochemistry, Faculty of Chemistry, University of Belgrade, 11158 Belgrade, Serbia; (I.P.-R.); (M.G.-J.)
| | - Marijana Stojanović
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia
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Silva RCMC. The dichotomic role of cytokines in aging. Biogerontology 2024; 26:17. [PMID: 39621124 DOI: 10.1007/s10522-024-10152-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 10/30/2024] [Indexed: 12/11/2024]
Abstract
The chronic inflammation present in aged individuals is generally depicted as a detrimental player for longevity. Here, it is discussed several beneficial effects associated with the cytokines that are chronically elevated in inflammaging. These cytokines, such as IL-1β, type I interferons, IL-6 and TNF positively regulate macroautophagy, mitochondrial function, anti-tumor immune responses and skeletal muscle biogenesis, possibly contributing to longevity. On the other side, the detrimental and antagonistic role of these cytokines including the induction of sarcopenia, tissue damage and promotion of tumorigenesis are also discussed, underscoring the dichotomy associated with inflammaging and its players. In addition, it is discussed the role of the anti-inflammatory cytokine IL-10 and other cytokines that affect aging in a more linear way, such as IL-11, which promotes senescence, and IL-4 and IL-15, which promotes longevity. It is also discussed more specific regulators of aging that are downstream cytokines-mediated signaling.
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Khezri MR, Esmaeili A, Ghasemnejad-Berenji M. Role of Bmal1 and Gut Microbiota in Alzheimer's Disease and Parkinson's Disease Pathophysiology: The Probable Effect of Melatonin on Their Association. ACS Chem Neurosci 2023; 14:3883-3893. [PMID: 37823531 DOI: 10.1021/acschemneuro.3c00418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023] Open
Abstract
In recent years, the role of new factors in the pathophysiology of neurodegenerative diseases has been investigated. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases worldwide. Although pathological changes such as the accumulation of aggregated proteins in the brain and inflammatory responses are known as the main factors involved in the development of these diseases, new studies show the role of gut microbiota and circadian rhythm in the occurrence of these changes. However, the association between circadian rhythm and gut microbiota in AD and PD has not yet been investigated. Recent results propose that alterations in circadian rhythm regulators, mainly Bmal1, may regulate the abundance of gut microbiota. This correlation has been linked to the regulation of the expression of immune-related genes and Bmal-1 mediated oscillation of IgA and hydrogen peroxide production. These data seem to provide new insight into the molecular mechanism of melatonin inhibiting the progression of AD and PD. Therefore, this manuscript aims to review the role of the gut microbiota and circadian rhythm in health and AD and PD and also presents a hypothesis on the effect of melatonin on their communication.
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Affiliation(s)
- Mohammad Rafi Khezri
- Faculty of Pharmacy. Urmia University of Medical Sciences, Urmia 571478334, Iran
| | - Ayda Esmaeili
- Department of Clinical Pharmacy, School of Pharmacy, Urmia University of Medical Sciences, Urmia 5715799313, Iran
| | - Morteza Ghasemnejad-Berenji
- Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia 5715799313, Iran
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4
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Jalandra R, Makharia GK, Sharma M, Kumar A. Inflammatory and deleterious role of gut microbiota-derived trimethylamine on colon cells. Front Immunol 2023; 13:1101429. [PMID: 36726978 PMCID: PMC9885123 DOI: 10.3389/fimmu.2022.1101429] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
Trimethylamine (TMA) is produced by the intestinal microbiota as a by-product of metabolism of dietary precursors. TMA has been implicated in various chronic health conditions. However, the effect of TMA in the colon and the underlying mechanism was not clear. In this study, TMA exhibited toxic effects in vitro as well as in vivo. TMA-induced oxidative stress causes DNA damage, and compromised cell membrane integrity leading to the release of LDH outside the cells which ultimately leads to cell death. Besides, TMA also exhibited pronounced increase in cell cycle arrest at G2/M phase in both HCT116 and HT29 cell lines. TMA was found to be genotoxic and cytotoxic as the TMA concentration increased from 0.15 mM. A decreased ATP intracellular content was observed after 24 h, 48 h, and 72 h treatment in a time and dose-dependent manner. For in vivo research, TMA (100 mM, i.p. and intra-rectal) once a week for 12 weeks caused significant changes in cellular morphology of colon and rectum epithelium as assessed by H & E staining. TMA also significantly increased the infiltration of inflammatory cells in the colon and rectal epithelium indicating the severity of inflammation. In addition, TMA caused extensive mucosal damage and distortion in the epithelium, decrease in length of small intestine compared to control mice. In conclusion, these results highlight the detrimental effects of TMA in the colon and rectal epithelium.
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Affiliation(s)
- Rekha Jalandra
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi, India
- Department of Zoology, Maharshi Dayanand University, Rohtak, India
| | - Govind K. Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Minakshi Sharma
- Department of Zoology, Maharshi Dayanand University, Rohtak, India
| | - Anil Kumar
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi, India
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Benson LN, Liu Y, Deck K, Mora C, Mu S. IFN- γ Contributes to the Immune Mechanisms of Hypertension. KIDNEY360 2022; 3:2164-2173. [PMID: 36591357 PMCID: PMC9802558 DOI: 10.34067/kid.0001292022] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 10/19/2022] [Indexed: 12/31/2022]
Abstract
Hypertension is the leading cause of cardiovascular disease and the primary risk factor for mortality worldwide. For more than half a century, researchers have demonstrated that immunity plays an important role in the development of hypertension; however, the precise mechanisms are still under investigation. The current body of knowledge indicates that proinflammatory cytokines may play an important role in contributing to immune-related pathogenesis of hypertension. Interferon gamma (IFN-γ), in particular, as an important cytokine that modulates immune responses, has been recently identified as a critical regulator of blood pressure by several groups, including us. In this review, we focus on exploring the role of IFN-γ in contributing to the pathogenesis of hypertension, outlining the various immune producers of this cytokine and described signaling mechanisms involved. We demonstrate a key role for IFN-γ in hypertension through global knockout studies and related downstream signaling pathways that IFN-γ production from CD8+ T cell (CD8T) in the kidney promoting CD8T-stimulated salt retention via renal tubule cells, thereby exacerbating hypertension. We discuss potential activators of these T cells described by the current literature and relay a novel hypothesis for activation.
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Affiliation(s)
- Lance N. Benson
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Yunmeng Liu
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Katherine Deck
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Christoph Mora
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Shengyu Mu
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Herfindal AM, Rocha SDC, Papoutsis D, Bøhn SK, Carlsen H. The ROS-generating enzyme NADPH oxidase 1 modulates the colonic microbiota but offers minor protection against dextran sulfate sodium-induced low-grade colon inflammation in mice. Free Radic Biol Med 2022; 188:298-311. [PMID: 35752373 DOI: 10.1016/j.freeradbiomed.2022.06.234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/13/2022] [Accepted: 06/19/2022] [Indexed: 10/17/2022]
Abstract
The enzyme NADPH oxidase 1 (NOX1) is a major producer of superoxide which together with other reactive oxygen and nitrogen species (ROS/RNS) are implicated in maintaining a healthy epithelial barrier in the gut. While previous studies have indicated NOX1's involvement in microbial modulation in the small intestine, less is known about the effects of NOX1-dependent ROS/RNS formation in the colon. We investigated the role of NOX1 in the colon of NOX1 knockout (KO) and wild type (WT) mice, under mild and subclinical low-grade colon inflammation induced by 1% dextran sulfate sodium (DSS). Ex vivo imaging of ROS/RNS in the colon revealed that absence of NOX1 strongly decreased ROS/RNS production, particularly during DSS treatment. Furthermore, while absence of NOX1 did not affect disease activity, some markers of inflammation (mRNA: Tnfa, Il6, Ptgs2; protein: lipocalin 2) in the colonic mucosa tended to be higher in NOX1 KO than in WT mice following DSS treatment. Lack of NOX1 also extensively modulated the bacterial community in the colon (16S rRNA gene sequencing), where NOX1 KO mice were characterized mainly by lower α-diversity (richness and evenness), higher abundance of Firmicutes, Akkermansia, and Oscillibacter, and lower abundance of Bacteroidetes and Alistipes. Together, our data suggest that NOX1 is pivotal for colonic ROS/RNS production in mice both during steady-state (i.e., no DSS treatment) and during 1% DSS-induced low-grade inflammation and for modulation of the colonic microbiota, with potential beneficial consequences for intestinal health.
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Affiliation(s)
- Anne Mari Herfindal
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, P. O. Box 5003, N-1432, Ås, Norway.
| | - Sérgio Domingos Cardoso Rocha
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, P. O. Box 5003, N-1432, Ås, Norway; Faculty of Biosciences, Norwegian University of Life Sciences, P. O. Box 5003, N-1432, Ås, Norway.
| | - Dimitrios Papoutsis
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, P. O. Box 5003, N-1432, Ås, Norway.
| | - Siv Kjølsrud Bøhn
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, P. O. Box 5003, N-1432, Ås, Norway.
| | - Harald Carlsen
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, P. O. Box 5003, N-1432, Ås, Norway.
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7
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Xia F, Li Y, Deng L, Ren R, Ge B, Liao Z, Xiang S, Zhou B. Alisol B 23-Acetate Ameliorates Lipopolysaccharide-Induced Intestinal Barrier Dysfunction by Inhibiting TLR4-NOX1/ROS Signaling Pathway in Caco-2 Cells. Front Pharmacol 2022; 13:911196. [PMID: 35774596 PMCID: PMC9237229 DOI: 10.3389/fphar.2022.911196] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/24/2022] [Indexed: 01/13/2023] Open
Abstract
Alisol B 23-Acetate (AB23A) is a naturally occurring triterpenoid, which can be indicated in the rhizome of medicinal and dietary plants from Alisma species. Previous studies have demonstrated that AB23A could inhibit intestinal permeability by regulating tight junction (TJ)-related proteins. Even so, the AB23A protective mechanism against intestinal barrier dysfunction remains poorly understood. This investigation seeks to evaluate the AB23A protective effects on intestinal barrier dysfunction and determine the mechanisms for restoring intestinal barrier dysfunction in LPS-stimulated Caco-2 monolayers. According to our findings, AB23A attenuated the inflammation by reducing pro-inflammatory cytokines production like IL-6, TNF-α, IL-1β, and prevented the paracellular permeability by inhibiting the disruption of TJ in LPS-induced Caco-2 monolayers after treated with LPS. AB23A also inhibited LPS-induced TLR4, NOX1 overexpression and subsequent ROS generation in Caco-2 monolayers. Transfected with NOX1-specific shRNA diminished the up-regulating AB23A effect on ZO-1 and occludin expression. Moreover, transfected with shRNA of TLR4 not only enhanced ZO-1 and occludin expression but attenuated NOX1 expression and ROS generation. Therefore, AB23A ameliorates LPS-induced intestinal barrier dysfunction by inhibiting TLR4-NOX1/ROS signaling pathway in Caco-2 monolayers, suggesting that AB23A may have positive impact on maintaining the intestinal barrier’s integrity.
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Affiliation(s)
- Fan Xia
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- *Correspondence: Fan Xia, ; Benjie Zhou,
| | - Yuxin Li
- Department of Pharmacology, Guangdong Medical University, Zhanjiang, China
| | - Lijun Deng
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Ruxia Ren
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Bingchen Ge
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Ziqiong Liao
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Shijian Xiang
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Benjie Zhou
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- *Correspondence: Fan Xia, ; Benjie Zhou,
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8
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Ghosh A, Sarkar A, Paul P, Patel P. The rise in cases of mucormycosis, candidiasis and aspergillosis amidst COVID19. FUNGAL BIOL REV 2021; 38:67-91. [PMID: 34548877 PMCID: PMC8445778 DOI: 10.1016/j.fbr.2021.09.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 09/05/2021] [Accepted: 09/08/2021] [Indexed: 12/15/2022]
Abstract
The Coronavirus outbreak globally has changed the medical system and also led to a shortage of medical facilities in both developing and underdeveloped countries. The COVID19 disease, being novel in nature along with high infectivity and frequent mutational rate, has been termed to be fatal across the globe. The advent of infection by SARS-CoV-2 has brought a myriad of secondary complications and comorbidities resulting in additional challenges to the health care system induced by novel therapeutic procedures. The emerging variant with respect to the Indian subcontinent and the associated genetic mutations have worsened the situation at hand. Proper clinical management along with epidemiological studies and clinical presentations in scientific studies and trials is necessary in order to combat the simultaneous waves of emerging strains. This article summarizes three of the major fungal outbreaks in India namely mucormycosis, candidiasis and aspergillosis, and elaborates their subtypes, pathogenesis, symptoms and treatment and detection techniques. A detail of future therapeutics under consideration are also elaborated along with a general hypothesis on how COVID19 is related to immunological advances leading to major widespread fungal infection in the country. The factors that contribute in promoting virus proliferation and invasive fungal infections include cell-mediated immunity, associated immunocompromised conditions and treatment protocols that slows down immune mechanisms. To better comprehend a fungal or bacterial outbreak, it is very important to conduct audits mediated through multicenter national and state research teams for recognizing patterns and studying current cases of fungal infection in both healthy and comorbid groups of COVID19 patients.
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Affiliation(s)
- Asmita Ghosh
- Department of Biotechnology, Heritage Institute of Technology, Kolkata 700107, West Bengal, India
| | - Anusua Sarkar
- Department of Biotechnology, Heritage Institute of Technology, Kolkata 700107, West Bengal, India
| | - Pubali Paul
- Department of Biotechnology, Heritage Institute of Technology, Kolkata 700107, West Bengal, India
| | - Parth Patel
- H. K. College of Pharmacy, Jogeshwari West, Mumbai 400102, Maharashtra, India
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9
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Mantilla-Rojas C, Yu M, Rinella ES, Lynch RM, Perry A, Jaimes-Alvarado J, Anderson KR, Barba E, Bourgeois EJ, Konganti K, Threadgill DW. A molecular subtype of colorectal cancers initiates independently of epidermal growth factor receptor and has an accelerated growth rate mediated by IL10-dependent anergy. Oncogene 2021; 40:3047-3059. [PMID: 33767440 PMCID: PMC9113393 DOI: 10.1038/s41388-021-01752-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 02/28/2021] [Accepted: 03/08/2021] [Indexed: 02/01/2023]
Abstract
Although epidermal growth factor receptor (EGFR)-targeted therapies are approved for colorectal cancer (CRC) treatment, only 15% of CRC patients respond to EGFR inhibition. Here, we show that colorectal cancers (CRC) can initiate and grow faster through an EGFR-independent mechanism, irrespective of the presence of EGFR, in two different mouse models using tissue-specific ablation of Egfr. The growth benefit in the absence of EGFR is also independent of Kras status. An EGFR-independent gene expression signature, also observed in human CRCs, revealed that anergy-inducing genes are overexpressed in EGFR-independent polyps, suggesting increased infiltration of anergic lymphocytes promotes an accelerated growth rate that is partially caused by escape from cell-mediated immune responses. Many genes in the EGFR-independent gene expression signature are downstream targets of interleukin 10 receptor alpha (IL10RA). We further show that IL10 is detectable in serum from mice with EGFR-independent colon polyps. Using organoids in vitro and Src ablation in vivo, we show that IL10 contributes to growth of EGFR-independent CRCs, potentially mediated by the well-documented role of SRC in IL10 signaling. Based on these data, we show that the combination of an EGFR inhibitor with an anti-IL10 neutralizing antibody results in decreased cell proliferation in organoids and in decreased polyp size in pre-clinical models harboring EGFR-independent CRCs, providing a new therapeutic intervention for CRCs resistant to EGFR inhibitor therapies.
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Affiliation(s)
- Carolina Mantilla-Rojas
- Interdisciplinary Program in Genetics, Texas A&M University, College Station, TX, USA
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA
| | - Ming Yu
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Erica S Rinella
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
- GeneDx, Gaithersburg, MD, USA
| | - Rachel M Lynch
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
| | - Amie Perry
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA
- Thompson Bishop Sparks State Diagnostic Laboratory, Auburn, AL, USA
| | - Jorge Jaimes-Alvarado
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA
| | - Kathryn R Anderson
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA
| | - Estefania Barba
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA
| | - Evann J Bourgeois
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA
| | - Kranti Konganti
- Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX, USA
| | - David W Threadgill
- Interdisciplinary Program in Genetics, Texas A&M University, College Station, TX, USA.
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA.
- Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX, USA.
- Department of Biochemistry & Biophysics and Department of Nutrition, Texas A&M University, College Station, TX, 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: 24] [Impact Index Per Article: 4.8] [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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Silva CB, Gómez JP, do Vale GT, Simplicio JA, Gonzaga NA, Tirapelli CR. Interleukin-10 limits the initial steps of the cardiorenal damage induced by ethanol consumption. Life Sci 2020; 242:117239. [DOI: 10.1016/j.lfs.2019.117239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/17/2019] [Accepted: 12/26/2019] [Indexed: 10/25/2022]
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12
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DeVallance E, Branyan KW, Lemaster KC, Anderson R, Marshall KL, Olfert IM, Smith DM, Kelley EE, Bryner RW, Frisbee JC, Chantler PD. Exercise training prevents the perivascular adipose tissue-induced aortic dysfunction with metabolic syndrome. Redox Biol 2019; 26:101285. [PMID: 31374361 PMCID: PMC6669320 DOI: 10.1016/j.redox.2019.101285] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/22/2019] [Accepted: 07/25/2019] [Indexed: 12/20/2022] Open
Abstract
The aim of the study was to determine the effects of exercise training on improving the thoracic perivascular adipose tissue (tPVAT) phenotype (inflammation, oxidative stress, and proteasome function) in metabolic syndrome and its subsequent actions on aortic function. Methods Lean and obese (model of metabolic syndrome) Zucker rats (n=8/group) underwent 8-weeks of control conditions or treadmill exercise (70% of max speed, 1 h/day, 5 days/week). At the end of the intervention, the tPVAT was removed and conditioned media was made. The cleaned aorta was attached to a force transducer to assess endothelium-dependent and independent dilation in the presence or absence of tPVAT-conditioned media. tPVAT gene expression, inflammatory /oxidative phenotype, and proteasome function were assessed. Results The main findings were that Ex induced: (1) a beige-like, anti-inflammatory tPVAT phenotype; (2) a greater abundance of •NO in tPVAT; (3) a reduction in tPVAT oxidant production; and (4) an improved tPVAT proteasome function. Regarding aortic function, endothelium-dependent dilation was greater in exercised lean and obese groups vs. controls (p < 0.05). Lean control tPVAT improved aortic relaxation, whereas obese control tPVAT decreased aortic relaxation. In contrast, the obese Ex-tPVAT increased aortic dilation, whereas the lean Ex-tPVAT did not affect aortic dilation. Conclusion Overall, exercise had the most dramatic impact on the obese tPVAT reflecting a change towards an environment with less oxidant load, less inflammation and improved proteasome function. Such beneficial changes to the tPVAT micro-environment with exercise likely played a significant role in mediating the improvement in aortic function in metabolic syndrome following 8 weeks of exercise.
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Affiliation(s)
- Evan DeVallance
- Division of Exercise Physiology, WVU School of Medicine, Morgantown, WV, USA
| | - Kayla W Branyan
- Division of Exercise Physiology, WVU School of Medicine, Morgantown, WV, USA
| | - Kent C Lemaster
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Ray Anderson
- Department of Biochemistry, WVU School of Medicine, Morgantown, WV, USA
| | - Kent L Marshall
- Division of Exercise Physiology, WVU School of Medicine, Morgantown, WV, USA
| | - I Mark Olfert
- Division of Exercise Physiology, WVU School of Medicine, Morgantown, WV, USA
| | - David M Smith
- Department of Biochemistry, WVU School of Medicine, Morgantown, WV, USA
| | - Eric E Kelley
- Department of Physiology & Pharmacology, WVU School of Medicine, Morgantown, WV, USA
| | - Randy W Bryner
- Division of Exercise Physiology, WVU School of Medicine, Morgantown, WV, USA
| | - Jefferson C Frisbee
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Paul D Chantler
- Division of Exercise Physiology, WVU School of Medicine, Morgantown, WV, USA; Department of Neuroscience, WVU School of Medicine, Morgantown, WV, USA.
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13
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Stalin J, Garrido-Urbani S, Heitz F, Szyndralewiez C, Jemelin S, Coquoz O, Ruegg C, Imhof BA. Inhibition of host NOX1 blocks tumor growth and enhances checkpoint inhibitor-based immunotherapy. Life Sci Alliance 2019; 2:2/4/e201800265. [PMID: 31249132 PMCID: PMC6599972 DOI: 10.26508/lsa.201800265] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 06/13/2019] [Accepted: 06/13/2019] [Indexed: 01/17/2023] Open
Abstract
Blocking NOX1 with the novel small molecule inhibitor GKT771 inhibits tumor growth in mice by targeting tumor lymph/angiogenesis and promoting antitumor immune cells recruitment. GKT771 emerges as a novel and promising anticancer drug worth translating into the clinics. NADPH oxidases catalyze the production of reactive oxygen species and are involved in physio/pathological processes. NOX1 is highly expressed in colon cancer and promotes tumor growth. To investigate the efficacy of NOX1 inhibition as an anticancer strategy, tumors were grown in immunocompetent, immunodeficient, or NOX1-deficient mice and treated with the novel NOX1-selective inhibitor GKT771. GKT771 reduced tumor growth, lymph/angiogenesis, recruited proinflammatory macrophages, and natural killer T lymphocytes to the tumor microenvironment. GKT771 treatment was ineffective in immunodeficient mice bearing tumors regardless of their NOX-expressing status. Genetic ablation of host NOX1 also suppressed tumor growth. Combined treatment with the checkpoint inhibitor anti-PD1 antibody had a greater inhibitory effect on colon carcinoma growth than each compound alone. In conclusion, GKT771 suppressed tumor growth by inhibiting angiogenesis and enhancing the recruitment of immune cells. The antitumor activity of GKT771 requires an intact immune system and enhances anti-PD1 antibody activity. Based on these results, we propose blocking of NOX1 by GKT771 as a potential novel therapeutic strategy to treat colorectal cancer, particularly in combination with checkpoint inhibition.
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Affiliation(s)
- Jimmy Stalin
- Department of Pathology and Immunology, Medical Faculty, University of Geneva, Geneva, Switzerland .,Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Sarah Garrido-Urbani
- Department of Pathology and Immunology, Medical Faculty, University of Geneva, Geneva, Switzerland
| | - Freddy Heitz
- Genkyotex S.A Forum 2, Archamps Technopole, Saint-Julien-en-Genevois, France
| | | | - Stephane Jemelin
- Department of Pathology and Immunology, Medical Faculty, University of Geneva, Geneva, Switzerland
| | - Oriana Coquoz
- Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Curzio Ruegg
- Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Beat A Imhof
- Department of Pathology and Immunology, Medical Faculty, University of Geneva, Geneva, Switzerland .,Medicity Research Laboratory, University of Turku, Turku, Finland
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14
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Abstract
Inflammatory bowel diseases (IBD), categorized as ulcerative colitis (UC), Crohn's disease (CD), or IBD-undetermined (IBDU), are increasing in incidence. IBD is understood to result from environmental factors interacting with a pre-existing genetic susceptibility. Approximately 1% of all patients with inflammatory bowel disease (IBD) are diagnosed before the age of 6 years, designated as very-early-onset IBD (VEOIBD). This cohort of patients is distinguished from other age groups by differences in disease phenotype and by a higher burden of genetic mutations. Recent studies have linked mutations in NADPH oxidase function to VEOIBD and even pediatric IBD. Loss-of-function NOX2 variants expressed in phagocytes and NOX1/DUOX2 variants expressed in intestinal epithelial cells have been associated with VEOIBD and pediatric and adult IBD in patients. Cell and animal studies suggest a protective role for these reactive oxygen species (ROS)-producing enzymes in intestinal homeostasis-a paradigm that challenges the conventional concept that only increased ROS result in cell and tissue damage. Examining the role of NADPH oxidases in VEOIBD may improve our understanding of the pathophysiology of this disease and will uncover new therapeutic possibilities.
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Affiliation(s)
- Emily Stenke
- Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland
| | - Billy Bourke
- Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland.,Department of Paediatric Gastroenterology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland
| | - Ulla G Knaus
- Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland.
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15
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Interleukin-4 and interleukin-13 increase NADPH oxidase 1-related proliferation of human colon cancer cells. Oncotarget 2018; 8:38113-38135. [PMID: 28498822 PMCID: PMC5503519 DOI: 10.18632/oncotarget.17494] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 04/17/2017] [Indexed: 01/01/2023] Open
Abstract
Human colon cancers express higher levels of NADPH oxidase 1 [NOX1] than adjacent normal epithelium. It has been suggested that reactive oxygen species [ROS] derived from NOX1 contribute to DNA damage and neoplastic transformation in the colon, particularly during chronic inflammatory stress. However, the mechanism(s) underlying increased NOX1 expression in malignant tumors or chronic inflammatory states involving the intestine are poorly characterized. We examined the effects of two pro-inflammatory cytokines, IL-4 and IL-13, on the regulation of NOX1. NOX1 expression was increased 4- to 5-fold in a time- and concentration-dependent manner by both cytokines in human colon cancer cell lines when a functional Type II IL-4 receptor was present. Increased NOX1 transcription following IL-4/IL-13 exposure was mediated by JAK1/STAT6 signaling, was associated with a ROS-related inhibition of protein tyrosine phosphatase activity, and was dependent upon activation and specific binding of GATA3 to the NOX1 promoter. NOX1-mediated ROS production increased cell cycle progression through S-phase leading to a significant increase in cellular proliferation. Evaluation of twenty pairs of surgically-resected colon cancers and their associated uninvolved adjacent colonic epithelium demonstrated a significant increase in the active form of NOX1, NOX1-L, in tumors compared to normal tissues, and a significant correlation between the expression levels of NOX1 and the Type II IL-4 receptor in tumor and the uninvolved colon. These studies imply that NOX1 expression, mediated by IL-4/IL-13, could contribute to an oxidant milieu capable of supporting the initiation or progression of colonic cancer, suggesting a role for NOX1 as a therapeutic target.
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16
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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: 198] [Impact Index Per Article: 24.8] [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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17
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Wolak M, Bojanowska E, Staszewska T, Ciosek J, Juszczak M, Drobnik J. The role of histamine in the regulation of the viability, proliferation and transforming growth factor β1 secretion of rat wound fibroblasts. Pharmacol Rep 2016; 69:314-321. [PMID: 28178593 DOI: 10.1016/j.pharep.2016.11.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 11/08/2016] [Accepted: 11/14/2016] [Indexed: 11/26/2022]
Abstract
BACKGROUND Inflammation mediators play a regulatory role in repair processes. The study will examine the influence of histamine on wound fibroblast metabolic activity, viability, proliferation, and TGFβ1 secretion. The study also will identify the histamine receptor involved in regulation of the tested repair processes. METHODS Fibroblasts were obtained from the granulation tissue of wounds or intact dermis of rats. The MTT and BrdU assays were used to examine the effect of histamine (10-8M-10-4M) on the viability and metabolic activity of fibroblasts, and on their proliferative capacity. The influence of histamine receptor antagonists (i.e., ketotifen, ranitidine, ciproxifan and JNJ7777120) and agonists (2-pyridylethlamine dihydrochloride, amthamine dihydrobromide) was also investigated. The TGFβ1 and histamine receptors H1 were evaluated by enzyme-linked immunosorbent assay. RESULTS Histamine significantly increased granulation tissue fibroblast viability and metabolic activity at 10-8 and 10-6M but did not change their proliferative activity. Only the blockade of the H1 receptor removed this effect of histamine. H1 receptor agonist (2-pyridylethlamine dihydrochloride) increased cell viability, thereby mimicking histamine action. Both Histamine (10-4M) and 2-pyridylethlamine dihydrochloride increased TGFβ1 concentration in cell culture medium. However, ketotifen blocked histamine-induced augmentation of TGFβ1. H1 receptor expression on wound fibroblasts was confirmed. CONCLUSION The regulatory influence of histamine on wound fibroblast function (viability/metabolic activity or secretion of TGFβ1) is dependent on H1 receptor stimulation. Contrary to wound fibroblasts, these cells express a very low level of H1 receptors when isolated from intact dermis and histamine is unable to modify their metabolic activity.
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Affiliation(s)
- Monika Wolak
- Department of Behavioral Pathophysiology, Chair of General and Experimental Pathology Medical University of Lodz, Łódź, Poland
| | - Ewa Bojanowska
- Department of Behavioral Pathophysiology, Chair of General and Experimental Pathology Medical University of Lodz, Łódź, Poland
| | - Teresa Staszewska
- Department of Behavioral Pathophysiology, Chair of General and Experimental Pathology Medical University of Lodz, Łódź, Poland
| | - Joanna Ciosek
- Laboratory of Connective Tissue Metabolism, Department of Neuropeptide Research, Chair of General and Experimental Pathology, Medical University of Lodz, Łódź, Poland
| | - Marlena Juszczak
- Department of Pathophysiology and Experimental Neuroendocrinology, Chair of General and Experimental Pathology, Medical University of Lodz, Łódź, Poland
| | - Jacek Drobnik
- Laboratory of Connective Tissue Metabolism, Department of Neuropeptide Research, Chair of General and Experimental Pathology, Medical University of Lodz, Łódź, Poland.
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18
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Andriamihaja M, Lan A, Beaumont M, Audebert M, Wong X, Yamada K, Yin Y, Tomé D, Carrasco-Pozo C, Gotteland M, Kong X, Blachier F. The deleterious metabolic and genotoxic effects of the bacterial metabolite p-cresol on colonic epithelial cells. Free Radic Biol Med 2015; 85:219-27. [PMID: 25881551 DOI: 10.1016/j.freeradbiomed.2015.04.004] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 03/20/2015] [Accepted: 04/06/2015] [Indexed: 11/21/2022]
Abstract
p-Cresol that is produced by the intestinal microbiota from the amino acid tyrosine is found at millimolar concentrations in the human feces. The effects of this metabolite on colonic epithelial cells were tested in this study. Using the human colonic epithelial HT-29 Glc(-/+) cell line, we found that 0.8mM p-cresol inhibits cell proliferation, an effect concomitant with an accumulation of the cells in the S phase and with a slight increase of cell detachment without necrotic effect. At this concentration, p-cresol inhibited oxygen consumption in HT-29 Glc(-/+) cells. In rat normal colonocytes, p-cresol also inhibited respiration. Pretreatment of HT-29 Glc(-/+) cells with 0.8mM p-cresol for 1 day resulted in an increase of the state 3 oxygen consumption and of the cell maximal respiratory capacity with concomitant increased anion superoxide production. At higher concentrations (1.6 and 3.2mM), p-cresol showed similar effects but additionally increased after 1 day the proton leak through the inner mitochondrial membrane, decreasing the mitochondrial bioenergetic activity. At these concentrations, p-cresol was found to be genotoxic toward HT-29 Glc(-/+) and also LS-174T intestinal cells. Lastly, a decreased ATP intracellular content was observed after 3 days treatment. p-Cresol at 0.8mM concentration inhibits colonocyte respiration and proliferation. In response, cells can mobilize their "respiratory reserve." At higher concentrations, p-cresol pretreatment uncouples cell respiration and ATP synthesis, increases DNA damage, and finally decreases the ATP cell content. Thus, we have identified p-cresol as a metabolic troublemaker and as a genotoxic agent toward colonocytes.
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Affiliation(s)
- Mireille Andriamihaja
- UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France
| | - Annaïg Lan
- UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France
| | - Martin Beaumont
- UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France
| | - Marc Audebert
- INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France
| | - Ximena Wong
- Department of Nutrition, Faculty of Medicine University of Chile, Santiago, Chile
| | - Kana Yamada
- UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France
| | - Yulong Yin
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Daniel Tomé
- UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France
| | | | - Martin Gotteland
- Department of Nutrition, Faculty of Medicine University of Chile, Santiago, Chile; Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile
| | - Xiangfeng Kong
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - François Blachier
- UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France.
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19
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de Diego-Cabero N, Mereu A, Menoyo D, Holst JJ, Ipharraguerre IR. Bile acid mediated effects on gut integrity and performance of early-weaned piglets. BMC Vet Res 2015; 11:111. [PMID: 25972097 PMCID: PMC4436113 DOI: 10.1186/s12917-015-0425-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 05/05/2015] [Indexed: 01/06/2023] Open
Abstract
Background Early weaning (EW) results in a transient period of impaired integrity of the intestinal mucosa that may be associated with reduced plasma concentration of glucagon-like peptide-(GLP) 2. We have previously shown that intragastric infusion of chenodeoxycholic acid (CDC) increases circulating GLP-2 in early-weaned piglets. The aim of this study was to expand previous work to establish whether feeding piglets a cereal-based diet supplemented with CDC can improve gut integrity and animal performance immediately after EW. A cohort of 36 piglets weaned at 20 days of age, 6.2 ± 0.34 kg of body weight (BW) were randomly assigned (n = 18) to receive a standard prestarter diet or the same diet supplemented with 60 mg of CDC per kg of initial BW for ad libitum intake until day 14 postweaning. Thereafter, all pigs were fed the same untreated starter diet for 21 days until the end of the study on day 35. On days 1, 7 and 14 blood samples were collected from 6 pigs per treatment to measure plasma GLP-2. On day 15, 6 pigs per treatment were euthanized to obtain intestinal tissue samples for later histological and gene expression analyses. Results Supplementing the diet with CDC tended to increase plasma GLP-2 (P < 0.07; 39 %) and the weight of the large intestine (P < 0.10; 11 %), and increased ileal crypt depth (P < 0.04; 15 %) after 14 days of treatment exposure. Although feed intake and BW gain were not affected by treatments, feeding CDC induced the expression of the cytokines TNF-α (P < 0.02; 1.9 fold), IL-6 (P < 0.01; 2.4 fold), and IL-10 (P < 0.006; 2.2 fold) and the tight junctional protein ZON-1 (P < 0.02; 1.5 fold) in the distal small intestine. Conclusions This study showed that the oral administration of CDC to early-weaned pigs has the potential to improve the protection of the intestinal mucosa independently of relevant changes in gut growth.
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Affiliation(s)
- Nuria de Diego-Cabero
- Departamento de Producción Animal, Universidad Politécnica de Madrid, E.T.S. Ingenieros Agrónomos, Ciudad Universitaria S/N, Madrid, 28040, Spain.
| | | | - David Menoyo
- Departamento de Producción Animal, Universidad Politécnica de Madrid, E.T.S. Ingenieros Agrónomos, Ciudad Universitaria S/N, Madrid, 28040, Spain.
| | - Jens J Holst
- The NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark.
| | - Ignacio R Ipharraguerre
- Lucta S.A., Montornés del Vallés, Barcelona, 08170, Spain. .,Institute of Human Nutrition and Food Science, Christian-Albrechts-University, D-24118, Kiel, Germany.
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20
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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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Borghi SM, Pinho-Ribeiro FA, Zarpelon AC, Cunha TM, Alves-Filho JC, Ferreira SH, Cunha FQ, Casagrande R, Verri WA. Interleukin-10 limits intense acute swimming-induced muscle mechanical hyperalgesia in mice. Exp Physiol 2015; 100:531-44. [PMID: 25711612 DOI: 10.1113/ep085026] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 02/23/2015] [Indexed: 01/04/2023]
Abstract
NEW FINDINGS What is the central question of this study? This study investigated the role of the endogenous anti-inflammatory cytokine interleukin-10 in intense acute swimming-induced muscle mechanical hyperalgesia in mice. What is the main finding and its importance? Endogenous interleukin-10 has a key role in limiting exercise-induced muscle pain in a model presenting similarities to delayed-onset muscle soreness in mice. Interleukin-10 reduced muscle pain by diminishing leucocyte recruitment, hyperalgesic cytokine production, oxidative stress and myocyte damage. Interleukin-10 (IL-10) is an antihyperalgesic cytokine. In this study, IL-10-deficient (IL-10(-/-) ) mice were used to investigate the role of endogenous IL-10 in intense acute swimming-induced muscle mechanical hyperalgesia, which presents similarities with delayed-onset muscle soreness. An intense acute swimming session of 1 or 2 h induced significant muscle mechanical hyperalgesia in a time-dependent manner in wild-type mice compared with the sham group 24 h after the session, which was further increased in IL-10(-/-) mice (P ˂ 0.05). Intraperitoneal treatment of wild-type mice with IL-10 (1-10 ng) reduced muscle mechanical hyperalgesia in a dose-dependent manner and reversed the enhanced muscle hyperalgesia in IL-10(-/-) mice (P ˂ 0.05). The 2 h swimming session induced increases in tumour necrosis factor-α, interleukin-1β and IL-10 production in the soleus muscle. However, tumour necrosis factor-α and interleukin-1β production in the soleus muscle were even higher in IL-10(-/-) mice between 2 and 6 h after the stimulus (P ˂ 0.05). There was no statistical difference in the levels of the antihyperalgesic cytokines interleukin-4, interleukin-5, interleukin-13 and transforming growth factor-β between wild-type and IL-10(-/-) mice (P ˃ 0.05). Interleukin-10 deficiency also resulted in increased myeloperoxidase activity, greater depletion of reduced glutathione levels, increased superoxide anion production and the maintenance of high plasma concentrations of creatine kinase (until 24 h after the swimming session) in soleus muscle (P ˂ 0.05). These results demonstrate that endogenous IL-10 controls intense acute swimming-induced muscle mechanical hyperalgesia by limiting oxidative stress and cytokine production.
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Affiliation(s)
- Sergio M Borghi
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
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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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Li TT, Ogino S, Qian ZR. Toll-like receptor signaling in colorectal cancer: Carcinogenesis to cancer therapy. World J Gastroenterol 2014; 20:17699-17708. [PMID: 25548469 PMCID: PMC4273121 DOI: 10.3748/wjg.v20.i47.17699] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 08/27/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.
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Shimizu S, Ishigamori R, Fujii G, Takahashi M, Onuma W, Terasaki M, Yano T, Mutoh M. Involvement of NADPH oxidases in suppression of cyclooxygenase-2 promoter-dependent transcriptional activities by sesamol. J Clin Biochem Nutr 2014; 56:118-22. [PMID: 25759517 PMCID: PMC4345183 DOI: 10.3164/jcbn.14-89] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 09/15/2014] [Indexed: 01/22/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) has been shown to play an important role in colon carcinogenesis. Moreover, one of the components of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, NADPH oxidase 1 (NOX1), dominantly expressed in the colon, is implicated in the pathogenesis of colon cancer. We have reported that sesamol, one of the lignans in sesame seeds, suppressed COX-2 gene transcriptional activity in human colon cancer cells, and also suppressed intestinal polyp formation in Apc-mutant mice. In the present study, we investigated the involvement of NADPH oxidase in the inhibition of COX-2 transcriptional activity by sesamol. We found that several NADPH oxidase inhibitors, such as apocynin, showed suppressive effects on COX-2 transcriptional activity. Moreover, sesamol significantly suppressed NOX1 mRNA levels in a dose-dependent manner. In addition, we demonstrated that knockdown of NOX1 successfully suppressed COX-2 transcriptional activity. These results suggest that inhibition of NADPH oxidase, especially NOX1, may be involved in the mechanism of the suppression of COX-2 transcriptional activity by sesamol.
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Affiliation(s)
- Satomi Shimizu
- Division of Cancer Prevention Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan ; Graduate School of Life Sciences, Toyo University, 1-1-1 Izumino, Itakura-machi, Oga-gun, Gunma 374-0193, Japan
| | - Rikako Ishigamori
- Division of Cancer Prevention Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Gen Fujii
- Division of Cancer Prevention Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Mami Takahashi
- Central Animal Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Wakana Onuma
- Division of Cancer Prevention Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan ; School of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
| | - Masaru Terasaki
- Department of Health and Environmental Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
| | - Tomohiro Yano
- Graduate School of Life Sciences, Toyo University, 1-1-1 Izumino, Itakura-machi, Oga-gun, Gunma 374-0193, Japan
| | - Michihiro Mutoh
- Division of Cancer Prevention Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
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Ramonaite R, Skieceviciene J, Juzenas S, Salteniene V, Kupcinskas J, Matusevicius P, Borutaite V, Kupcinskas L. Protective action of NADPH oxidase inhibitors and role of NADPH oxidase in pathogenesis of colon inflammation in mice. World J Gastroenterol 2014; 20:12533-12541. [PMID: 25253955 PMCID: PMC4168088 DOI: 10.3748/wjg.v20.i35.12533] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 02/11/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in colon epithelial cells in the pathogenesis of acute and chronic colon inflammation in a mouse model of dextran sulphate sodium (DSS)-induced colitis.
METHODS: Balb/c mice were divided into three groups: 8 mice with acute DSS-induced colitis (3.5% DSS solution; 7 d), 8 mice with chronic DSS-induced colitis (3.5% DSS solution for 5 d + water for 6 d; 4 cycles; total: 44 d) and 12 mice without DSS supplementation as a control group. Primary colonic epithelial cells were isolated using chelation method. The cells were cultivated in the presence of mediators (lipopolysaccharide (LPS), apocynin or diphenyleneiodonium). Viability of cells was assessed by fluorescent microscopy. Production of reactive oxygen species (ROS) by the cells was measured fluorometrically using Amplex Red. Production of tumour necrosis factor-alpha (TNF-α) by the colonic epithelial cells was analysed by ELISA. Nox1 gene expression was assessed by real-time PCR.
RESULTS: Our study showed that TNF-α level was increased in unstimulated primary colonic cells both in the acute and chronic colitis groups, whereas decreased viability, increased ROS production, and expression of Nox1 was characteristic only for chronic DSS colitis mice when compared to the controls. The stimulation by LPS increased ROS generation via NADPH oxidase and decreased cell viability in mice with acute colitis. Treatment with NADPH oxidase inhibitors increased cell viability and decreased the levels of ROS and TNF-α in the LPS-treated cells isolated from mice of both acute and chronic colitis groups.
CONCLUSION: Our study revealed the importance of NADPH oxidase in the pathogenesis of both acute and chronic inflammation of the colon.
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Zhang H, Xue Y, Wang H, Huang Y, Du M, Yang Q, Zhu MJ. Mast cell deficiency exacerbates inflammatory bowel symptoms in interleukin-10-deficient mice. World J Gastroenterol 2014; 20:9106-9115. [PMID: 25083083 PMCID: PMC4112873 DOI: 10.3748/wjg.v20.i27.9106] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 01/07/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To test the role of mast cells in gut inflammation and colitis using interleukin (IL)-10-deficient mice as an experimental model.
METHODS: Mast cell-deficient (KitW-sh/W-sh) mice were crossbred with IL-10-deficient mice to obtain double knockout (DKO) mice. The growth, mucosal damage and colitis status of DKO mice were compared with their IL-10-deficient littermates.
RESULTS: DKO mice exhibited exacerbated colitis compared with their IL-10-deficient littermates, as shown by increased pathological score, higher myeloperoxidase content, enhanced Th1 type pro-inflammatory cytokines and inflammatory signaling, elevated oxidative stress, as well as pronounced goblet cell loss. In addition, deficiency in mast cells resulted in enhanced mucosal damage, increased gut permeability, and impaired epithelial tight junctions. Mast cell deficiency was also linked to systemic inflammation, as demonstrated by higher serum levels of tumor necrosis factor α and interferon γ in DKO mice than that in IL-10-deficient mice.
CONCLUSION: Mast cell deficiency in IL-10-deficient mice resulted in systematic and gut inflammation, impaired gut barrier function, and severer Th1-mediated colitis when compared to mice with only IL-10-deficiency. Inflammation and impaired gut epithelial barrier function likely form a vicious cycle to worsen colitis in the DKO mice.
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Esworthy RS, Kim BW, Chow J, Shen B, Doroshow JH, Chu FF. Nox1 causes ileocolitis in mice deficient in glutathione peroxidase-1 and -2. Free Radic Biol Med 2014; 68:315-25. [PMID: 24374371 PMCID: PMC3943970 DOI: 10.1016/j.freeradbiomed.2013.12.018] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 12/14/2013] [Accepted: 12/17/2013] [Indexed: 02/06/2023]
Abstract
We previously reported that mice deficient in two Se-dependent glutathione peroxidases, GPx1 and GPx2, have spontaneous ileocolitis. Disease severity depends on mouse genetic background. Whereas C57BL/6J (B6) GPx1/2-double-knockout (DKO) mice have moderate ileitis and mild colitis, 129S1Svlm/J (129) DKO mice have severe ileocolitis. Because GPx's are antioxidant enzymes, we hypothesized that elevated reactive oxygen species trigger inflammation in these DKO mice. To test whether NADPH oxidase 1 (Nox1) contributes to colitis, we generated B6 triple-KO (TKO) mice to study their phenotype. Because the Nox1 gene is X-linked, we analyzed the effects of Nox1 on male B6 TKO mice and female B6 DKO mice with the Nox1(+/-) (het-TKO) genotype. We found that the male TKO and female het-TKO mice are virtually disease-free when monitored from 8 through 50 days of age. Male TKO and female het-TKO mice have nearly no signs of disease (e.g., lethargy and perianal alopecia) that are often exhibited in the DKO mice; further, the slower growth rate of DKO mice is almost completely eliminated in male TKO and female het-TKO mice. Male TKO and female het-TKO mice no longer have the shortened small intestine present in the DKO mice. Finally, the pathological characteristics of the DKO ileum, including the high level of crypt apoptosis (analyzed by apoptotic figures, TUNEL, and cleaved caspase-3 immunohistochemical staining), high numbers of Ki-67-positive crypt epithelium cells, and elevated levels of monocytes expressing myeloperoxidase, are all significantly decreased in male TKO mice. The attenuated ileal and colonic pathology is also evident in female het-DKO mice. Furthermore, the male DKO ileum has eightfold higher TNF cytokine levels than TKO ileum. Nox1 mRNA is highly elevated in both B6 and 129 DKO ileum compared to wild-type mouse ileum. Taking these results together, we propose that ileocolitis in the DKO mice is caused by Nox1, which is induced by TNF. The milder disease in female het-TKO intestine is probably due to random or imprinted X-chromosome inactivation, which produces mosaic Nox1 expression.
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Affiliation(s)
- Robert S Esworthy
- Department of Radiation Biology and Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Byung-Wook Kim
- Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Joni Chow
- Department of Radiation Biology and Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Binghui Shen
- Department of Radiation Biology and Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | | | - Fong-Fong Chu
- Department of Radiation Biology and Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
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Mangerich A, Dedon PC, Fox JG, Tannenbaum SR, Wogan GN. Chemistry meets biology in colitis-associated carcinogenesis. Free Radic Res 2013; 47:958-86. [PMID: 23926919 PMCID: PMC4316682 DOI: 10.3109/10715762.2013.832239] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The intestine comprises an exceptional venue for a dynamic and complex interplay of numerous chemical and biological processes. Here, multiple chemical and biological systems, including the intestinal tissue itself, its associated immune system, the gut microbiota, xenobiotics, and metabolites meet and interact to form a sophisticated and tightly regulated state of tissue homoeostasis. Disturbance of this homeostasis can cause inflammatory bowel disease (IBD)-a chronic disease of multifactorial etiology that is strongly associated with increased risk for cancer development. This review addresses recent developments in research into chemical and biological mechanisms underlying the etiology of inflammation-induced colon cancer. Beginning with a general overview of reactive chemical species generated during colonic inflammation, the mechanistic interplay between chemical and biological mediators of inflammation, the role of genetic toxicology, and microbial pathogenesis in disease development are discussed. When possible, we systematically compare evidence from studies utilizing human IBD patients with experimental investigations in mice. The comparison reveals that many strong pathological and mechanistic correlates exist between mouse models of colitis-associated cancer, and the clinically relevant situation in humans. We also summarize several emerging issues in the field, such as the carcinogenic potential of novel inflammation-related DNA adducts and genotoxic microbial factors, the systemic dimension of inflammation-induced genotoxicity, and the complex role of genome maintenance mechanisms during these processes. Taken together, current evidence points to the induction of genetic and epigenetic alterations by chemical and biological inflammatory stimuli ultimately leading to cancer formation.
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Affiliation(s)
- Aswin Mangerich
- Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
- Department of Biology, Molecular Toxicology Group, University of Konstanz, D-78457 Konstanz, Germany
| | - Peter C. Dedon
- Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
- Center for Environmental Health Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
| | - James G. Fox
- Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
- Center for Environmental Health Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
| | - Steven R. Tannenbaum
- Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
- Center for Environmental Health Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
| | - Gerald N. Wogan
- Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
- Center for Environmental Health Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
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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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Interleukin 10 antioxidant effect decreases leukocytes/endothelial interaction induced by tumor necrosis factor α. Shock 2013; 39:83-8. [PMID: 23247124 DOI: 10.1097/shk.0b013e318278ae36] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Little is known about the endothelial mechanisms involved in the anti-inflammatory effects of interleukin 10 (IL-10). The goal of this study was to evaluate the effects of IL-10 on endothelial oxidative stress and endothelial inflammation induced by tumor necrosis factor α (TNF-α). Production of reactive oxygen species (ROS) in perfused human umbilical vein endothelial cells (HUVECs) was studied by fluorescent microscopy using dichlorodihydrofluorescein diacetate. Tumor necrosis factor α (1 ng/mL) was added to the perfusion medium in the absence and presence of IL-10 (1 ng/mL). The role of phosphatidylinositol 3-kinase (PI3-kinase) was assessed using wortmannin and LY 2940002 (inhibitors of PI3-kinase). Specific inhibition of p110 α and p110 γ/δ PI3-kinase subunits was studied using A66 and TG100-115. As well, levels of ceramide and intercellular adhesion molecule 1 (ICAM-1) expression were measured. Finally, the effect of IL-10 on TNF-α-induced leukocyte/endothelium interaction was examined using an ex vivo perfused vessel model. Interleukin 10 significantly reduced dichlorodihydrofluorescein diacetate fluorescence induced by TNF-α in HUVECs (12.5% ± 3.2% vs. 111.7% ± 21.6% at 60 min). Pretreatment by LY2940002 or wortmannin restored ROS production induced by TNF-α in the presence of IL-10. In HUVECs treated by TNF-α + IL-10, inhibition of p110 α PI3-kinase subunit significantly increased ROS production, whereas p110 γ/δ inhibition did not have a significant effect. Pretreatment with IL-10 significantly decreased TNF-α-induced increased levels of ceramide (TNF-α vs. TNF-α + IL-10: 6,278 ± 1,013 vs. 1,440 ± 130 pmol/mg prot), as well as ICAM-1 expression and leukocyte adhesion (TNF-α vs. TNF-α + IL-10: 26.8 ± 2.6 vs. 6.7 ± 0.4 adherent leukocytes/field at 15 min). Interleukin 10 decreases the level of inflammation induced by TNF-α in endothelial cells by reducing the TNF-α-induced ROS production, ICAM-1 expression, and leukocyte adhesion to the endothelium. The antioxidant effect of IL-10 is mediated through PI3-kinase and is paralleled by a decrease in ceramide synthesis induced by TNF-α.
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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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Aroor A, McKarns S, Nistala R, DeMarco V, Gardner M, Garcia-Touza M, Whaley-Connell A, Sowers JR. DPP-4 Inhibitors as Therapeutic Modulators of Immune Cell Function and Associated Cardiovascular and Renal Insulin Resistance in Obesity and Diabetes. Cardiorenal Med 2013; 3:48-56. [PMID: 23946724 DOI: 10.1159/000348756] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 02/07/2013] [Indexed: 12/21/2022] Open
Abstract
The prevalence of obesity and diabetes continues to rise in the United States and worldwide. These findings parallel the expansion of childhood obesity and diabetes. Obesity is a central component of the cardiorenal metabolic syndrome (CRS) which increases the risk for cardiovascular disease (CVD) and chronic kidney disease (CKD). The hallmark of obesity, CRS, and early type 2 diabetes is insulin resistance, a result of decreased insulin metabolic signaling due, in part, to enhanced serine phosphorylation and/or proteasome-mediated degradation of the insulin receptor substrate. Cardiovascular and renal insulin resistance significantly contributes to endothelial dysfunction, impaired cardiac diastolic and vascular relaxation, glomerular injury, and tubular dysfunction. In this context, multiple factors including oxidative stress, increased inflammation, and inappropriate activation of the renin-angiotensin-aldosterone and the sympathetic nervous system contribute to overweight- and obesity-induced systemic and tissue insulin resistance. One common link between obesity and the development of insulin resistance appears to be a low-grade inflammatory response resulting from dysfunctional innate and adaptive immunity. In this regard, there has been recent work on the role of dipeptidyl peptidase-4 (DPP-4) in modulating innate and adaptive immunity. The direct effects of DPP-4 on immune cells and the indirect effects through GLP-1-dependent and -independent pathways suggest effects of DPP-4 inhibition may have beneficial effects beyond glycemic control in improving CVD and renal outcomes. Accordingly, this review addresses new insights into the role of DPP-4 in immune modulation and the potential beneficial effects of DPP-4 inhibitors in insulin resistance and associated CVD and CKD prevention.
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Latorre E, Mendoza C, Matheus N, Castro M, Grasa L, Mesonero JE, Alcalde AI. IL-10 modulates serotonin transporter activity and molecular expression in intestinal epithelial cells. Cytokine 2013; 61:778-84. [PMID: 23410504 DOI: 10.1016/j.cyto.2013.01.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Revised: 11/16/2012] [Accepted: 01/13/2013] [Indexed: 12/29/2022]
Abstract
Serotonin is a neuromodulator mainly synthesized by intestinal enterochromaffin cells that regulate overall intestinal physiology. The serotonin transporter (SERT) determines the final serotonin availability and has been described as altered in inflammatory bowel diseases. IL-10 is an anti-inflammatory cytokine that is involved in intestinal inflammatory processes and also contributes to intestinal mucosa homeostasis. The regulation of SERT by pro-inflammatory factors is well known; however, the effect of IL-10 on the intestinal serotoninergic system mediated by SERT remains unknown. Therefore, the aim of the present study is to determine whether IL-10 affects SERT activity and expression in enterocyte-like Caco-2 cells. Treatment with IL-10 was assessed and SERT activity was determined by 5-HT uptake. SERT mRNA and protein expression was analyzed using quantitative RT-PCR and western blotting. The results showed that IL-10 induced a dual effect on SERT after 6h of treatment. On one hand, IL-10, at a low concentration, inhibited SERT activity, and this effect might be explained by a non-competitive inhibition of SERT. On the other hand, IL-10, at a high concentration, increased SERT activity and molecular expression in the membrane of the cells. This effect was mediated by the IL-10 receptor and triggered by the PI3K intracellular pathway. Our results demonstrate that IL-10 modulates SERT activity and expression, depending on its extracellular conditions. This study may contribute to understand serotoninergic responses in intestinal pathophysiology.
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Affiliation(s)
- Eva Latorre
- Department of Pharmacology and Physiology, Faculty of Veterinary Sciences, Universidad de Zaragoza, Miguel Servet 177, 50013 Zaragoza, Spain
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Madureira PA, Waisman DM. Annexin A2: the importance of being redox sensitive. Int J Mol Sci 2013; 14:3568-94. [PMID: 23434659 PMCID: PMC3588059 DOI: 10.3390/ijms14023568] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2013] [Revised: 01/30/2013] [Accepted: 01/31/2013] [Indexed: 12/28/2022] Open
Abstract
Hydrogen peroxide (H2O2) is an important second messenger in cellular signal transduction. H2O2-dependent signalling regulates many cellular processes, such as proliferation, differentiation, migration and apoptosis. Nevertheless, H2O2 is an oxidant and a major contributor to DNA damage, protein oxidation and lipid peroxidation, which can ultimately result in cell death and/or tumourigenesis. For this reason, cells have developed complex antioxidant systems to scavenge ROS. Recently, our laboratory identified the protein, annexin A2, as a novel cellular redox regulatory protein. Annexin A2 possesses a reactive cysteine residue (Cys-8) that is readily oxidized by H2O2 and subsequently reduced by the thioredoxin system, thereby enabling annexin A2 to participate in multiple redox cycles. Thus, a single molecule of annexin A2 can inactivate several molecules of H2O2. In this report, we will review the studies detailing the reactivity of annexin A2 thiols and the importance of these reactive cysteine(s) in regulating annexin A2 structure and function. We will also focus on the recent reports that establish novel functions for annexin A2, namely as a protein reductase and as a cellular redox regulatory protein. We will further discuss the importance of annexin A2 redox regulatory function in disease, with a particular focus on tumour progression.
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Affiliation(s)
- Patrícia A. Madureira
- Centre for Molecular and Structural Biomedicine, University of Algarve, Campus of Gambelas, Faro, 8005-139, Portugal; E-Mail:
| | - David M. Waisman
- Departments of Biochemistry & Molecular Biology and Pathology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-902-494-1803; Fax: +1-902-494-1355
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O'Leary DP, Bhatt L, Woolley JF, Gough DR, Wang JH, Cotter TG, Redmond HP. TLR-4 signalling accelerates colon cancer cell adhesion via NF-κB mediated transcriptional up-regulation of Nox-1. PLoS One 2012; 7:e44176. [PMID: 23071493 PMCID: PMC3469572 DOI: 10.1371/journal.pone.0044176] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Accepted: 07/30/2012] [Indexed: 01/03/2023] Open
Abstract
Surgery induced inflammation is a potent promoter of tumour recurrence and metastasis in colorectal cancer. The recently discovered family of Nox enzymes represent a major source of endogenous reactive oxygen species (ROS) and are now heavily implicated in tumour cell metastasis. Interestingly, Nox enzymes can be ‘purposefully’ activated by inflammatory cytokines and growth factors which are present in abundance in the peri-operative window. As colon cancer cells express Nox enzymes and Toll-like receptor 4 (TLR-4), we hypothesised that LPS may potentiate the ability of colon cancer cells to metastasise via Nox enzyme mediated redox signalling. In support of this hypothesis, this paper demonstrates that LPS induces a significant, transient increase of endogenous ROS in SW480, SW620 and CT-26 colon cancer cells. This increase in LPS-induced ROS activity is completely abrogated by a Nox inhibitor, diphenyleneiodonium (DPI), Nox1 siRNA and an NF-κB inhibitor, Dihydrochloride. A significant increase in Nox1 and Nox2 protein expression occurs following LPS treatment. Inhibition of NF-κB also attenuates the increase of Nox1 and Nox2 protein expression. The sub-cellular location of LPS-induced ROS generation lies mainly in the endoplasmic reticulum. LPS activates the PI3K/Akt pathway via Nox generated ROS and this signal is inhibited by DPI. This LPS activated Nox mechanism facilitates a significant increase in SW480 colon cancer cell adhesion to collagen I, which is inhibited by DPI, Nox1 siRNA and a PI3K inhibitor. Altogether, these data suggest that the LPS-Nox1 redox signalling axis plays a crucial role in facilitation of colon cancer cell adhesion, thus increasing the metastatic potential of colon cancer cells. Nox1 may represent a valuable target in which to prevent colon cancer metastasis.
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Affiliation(s)
- D Peter O'Leary
- Department of Academic Surgery, Cork University Hospital, Cork, Ireland.
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Rath E, Haller D. Mitochondria at the interface between danger signaling and metabolism: role of unfolded protein responses in chronic inflammation. Inflamm Bowel Dis 2012; 18:1364-77. [PMID: 22183876 DOI: 10.1002/ibd.21944] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Accepted: 10/19/2011] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel diseases (IBDs), like many other chronic diseases, feature multiple cellular stress responses including endoplasmic reticulum (ER) unfolded protein response (UPR). Maintaining protein homeostasis is indispensable for cell survival and, consequently, distinct signaling pathways have evolved to transmit organelle stress. While the ER UPR, aiming to restore ER homeostasis after challenges to ER function, has been extensively studied in the context of chronic diseases, only recently the related mitochondrial UPR (mtUPR), induced by disturbances of mitochondrial proteostasis, has drawn some attention. ER and mitochondria are in close contact and interact physically and functionally. Accumulating data have placed mitochondria at the center of diverse cellular functions and suggest mitochondria as integrators of signaling pathways such as autophagy and inflammation. Consequently, it is likely that mitochondrial stress and ER stress cannot be regarded separately and that mitochondrial stress, as well as ER stress, participates in the pathology of IBD. Protein homeostasis is particularly sensitive toward infections, oxidative stress, and energy deficiency. Thus, environmental disturbances impacting organelle function lead to the concerted activation of distinct UPRs. The metabolic status might therefore serve as an innate mechanism to sense the epithelial environment, including luminal-derived and host-derived factors. This review highlights mtUPR and its interrelation with ER UPR, focuses on recent studies identifying mitochondria as integrators of cellular danger signaling, and, furthermore, illustrates the importance ER UPR and mitochondrial dysfunction in IBD.
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Affiliation(s)
- Eva Rath
- Technische Universität München, Chair for Biofunctionality, ZIEL, Research Center for Nutrition and Food Science, CDD, Center for Diet and Disease, Freising-Weihenstephan, Germany
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Yasuda M, Kato S, Yamanaka N, Iimori M, Utsumi D, Kitahara Y, Iwata K, Matsuno K, Amagase K, Yabe-Nishimura C, Takeuchi K. Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1133-42. [PMID: 22403796 DOI: 10.1152/ajpgi.00535.2011] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although NADPH oxidase 1 (NOX1) has been shown to be highly expressed in the gastrointestinal tract, the physiological and pathophysiological roles of this enzyme are not yet fully understood. In the present study, we investigated the role of NOX1 in the pathogenesis of intestinal mucositis induced by the cancer chemotherapeutic agent 5-fluorouracil (5-FU) in mice. Intestinal mucositis was induced in Nox1 knockout (Nox1KO) and littermate wild-type (WT) mice via single, daily administration of 5-FU for 5 days. In WT mice, 5-FU caused severe intestinal mucositis characterized by a shortening of villus height, a disruption of crypts, a loss of body weight, and diarrhea. In Nox1KO mice, however, the severity of mucositis was significantly reduced, particularly with respect to crypt disruption. The numbers of apoptotic caspase-3- and caspase-8-activated cells in the intestinal crypt increased 24 h after the first 5-FU administration but were overall significantly lower in Nox1KO than in WT mice. Furthermore, the 5-FU-mediated upregulation of TNF-α, IL-1β, and NOX1 and the production of reactive oxygen species were significantly attenuated in Nox1KO mice compared with that in WT mice. These findings suggest that NOX1 plays an important role in the pathogenesis of 5-FU-induced intestinal mucositis. NOX1-derived ROS production following administration of 5-FU may promote the apoptotic response through upregulation of inflammatory cytokines.
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Affiliation(s)
- Masashi Yasuda
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
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Zhu H, Li YR. Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence. Exp Biol Med (Maywood) 2012; 237:474-80. [PMID: 22442342 DOI: 10.1258/ebm.2011.011358] [Citation(s) in RCA: 332] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) comprises primarily the chronic relapsing inflammatory disorders, Crohn's disease and ulcerative colitis, with the former affecting any part of the gastrointestinal tract and the latter mainly afflicting the colon. The precise etiology of IBD remains unclear, and it is thought that interactions among various factors, including genetic factors, the host immune system and environmental factors, cause disruption of intestinal homeostasis, leading to dysregulated inflammatory responses of the gut. As inflammation is intimately related to formation of reactive intermediates, including reactive oxygen and nitrogen species (ROS/RNS), oxidative stress has been proposed as a mechanism underlying the pathophysiology of IBD. This review is intended to summarize succinctly recent new experimental and clinical evidence supporting oxidative stress as a pathophysiological component of IBD and point to the potential of using antioxidant compounds as promising therapeutic modalities of human IBD. The sources of ROS/RNS and the redox signaling mechanism underlying oxidative stress and inflammation in IBD are discussed to provide insight into the molecular basis of oxidative stress as a pathophysiological factor in IBD.
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Affiliation(s)
- Hong Zhu
- Laboratory of Molecular and Cellular Pharmacology and Toxicology, Department of Pharmacology, EVCOM, Virginia Tech Corporate Research Center RBII, Blacksburg, VA 24060, USA.
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García C, Gine E, Aller MA, Revuelta E, Arias JL, Vara E, Arias J. Multiple organ inflammatory response to portosystemic shunt in the rat. Cytokine 2011; 56:680-7. [DOI: 10.1016/j.cyto.2011.08.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Revised: 06/16/2011] [Accepted: 08/23/2011] [Indexed: 01/07/2023]
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Expanding the beneficial pleiotropic repertoire of interleukin-10. J Hypertens 2011; 29:2061-3. [DOI: 10.1097/hjh.0b013e32834c3041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Schoultz I, Söderholm JD, McKay DM. Is metabolic stress a common denominator in inflammatory bowel disease? Inflamm Bowel Dis 2011; 17:2008-18. [PMID: 21830276 DOI: 10.1002/ibd.21556] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Accepted: 10/04/2010] [Indexed: 01/06/2023]
Abstract
The enteric epithelium represents the major boundary between the outside world and the body, and in the colon it is the interface between the host and a vast and diverse microbiota. A common feature of inflammatory bowel disease (IBD) is decreased epithelial barrier function, and while a cause-and-effect relationship can be debated, prolonged loss of epithelial barrier function (whether this means the ability to sense bacteria or exclude them) would contribute to inflammation. While there are undoubtedly individual nuances in IBD, we review data in support of metabolic stress--that is, perturbed mitochondrial function--in the enterocyte as a contributing factor to the initiation of inflammation and relapses in IBD. The postulate is presented that metabolic stress, which can arise as a consequence of a variety of stimuli (e.g., infection, bacterial dysbiosis, and inflammation also), will reduce epithelial barrier function and perturb the enterocyte-commensal flora relationship and suggest that means to negate enterocytic metabolic stress should be considered as a prophylactic or adjuvant therapy in IBD.
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Affiliation(s)
- Ida Schoultz
- Gastrointestinal Research Group, Department of Physiology & Pharmacology, The Calvin, Phoebe and Joan Snyder Institute of Infection Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada
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Singh S, Swarnkar S, Goswami P, Nath C. Astrocytes and microglia: responses to neuropathological conditions. Int J Neurosci 2011; 121:589-97. [PMID: 21827229 DOI: 10.3109/00207454.2011.598981] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Activated astrocytes and microglia, hallmark of neurodegenerative diseases release different factors like array of pro and anti-inflammatory cytokines, free radicals, anti-oxidants, and neurotrophic factors during neurodegeneration which further contribute to neuronal death as well as in survival mechanisms. Astrocytes act as double-edged sword exerting both detrimental and neuroprotective effects while microglial cells are attributed more in neurodegenerative mechanisms. The dual and insufficient knowledge about the precise role of glia in neurodegeneration showed the need for further investigations and thorough review of the function of glia in neurodegeneration. In this review, we consolidate and categorize the glia-released factors which contribute in degenerative and protective mechanisms during neuropathological conditions.
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Affiliation(s)
- Sarika Singh
- Toxicology Division, Central Drug Research Institute-CSIR-CDRI, Lucknow, India.
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Emami CN, Mittal R, Wang L, Ford HR, Prasadarao NV. Recruitment of dendritic cells is responsible for intestinal epithelial damage in the pathogenesis of necrotizing enterocolitis by Cronobacter sakazakii. THE JOURNAL OF IMMUNOLOGY 2011; 186:7067-79. [PMID: 21551359 DOI: 10.4049/jimmunol.1100108] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cronobacter sakazakii is a Gram-negative pathogen associated with the cases of necrotizing enterocolitis (NEC) that result from formula contamination. In a mouse model of NEC, we demonstrate that C. sakazakii infection results in epithelial damage by recruiting greater numbers of dendritic cells (DCs) than macrophages and neutrophils in the gut and suppresses DC maturation, which requires outer membrane protein A (OmpA) expression in C. sakazakii. Pretreatment of intestinal epithelial cell monolayers with supernatant from OmpA(+) C. sakazakii/DC culture markedly enhanced membrane permeability and enterocyte apoptosis, whereas OmpA(-) C. sakazakii/DC culture supernatant had no effect. Analysis of OmpA(+) C. sakazakii/DC coculture supernatant revealed significantly greater TGF-β production compared with the levels produced by OmpA(-) C. sakazakii infection. TGF-β levels were elevated in the intestinal tissue of mice infected with OmpA(+) C. sakazakii. Cocultures of CaCo-2 cells and DCs in a "double-layer" model followed by infection with OmpA(+) C. sakazakii significantly enhanced monolayer leakage by increasing TGF-β production. Elevated levels of inducible NO synthase (iNOS) were also observed in the double-layer infection model, and abrogation of iNOS expression prevented the C. sakazakii-induced CaCo-2 cell monolayer permeability despite the presence of DCs or OmpA(+) C. sakazakii/DC supernatant. Blocking TGF-β activity using a neutralizing Ab suppressed iNOS production and prevented apoptosis and monolayer leakage. Depletion of DCs in newborn mice protected against C. sakazakii-induced NEC, whereas adoptive transfer of DCs rendered the animals susceptible to infection. Therefore, C. sakazakii interaction with DCs in intestine enhances the destruction of the intestinal epithelium and the onset of NEC due to increased TGF-β production.
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Affiliation(s)
- Claudia N Emami
- Department of Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
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Inflammation and cellular stress: a mechanistic link between immune-mediated and metabolically driven pathologies. Eur J Nutr 2011; 50:219-33. [PMID: 21547407 DOI: 10.1007/s00394-011-0197-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 04/04/2011] [Indexed: 12/21/2022]
Abstract
BACKGROUND Multiple cellular stress responses have been implicated in chronic diseases such as obesity, diabetes, cardiovascular, and inflammatory bowel diseases. Even though phenotypically different, chronic diseases share cellular stress signaling pathways, in particular endoplasmic reticulum (ER) unfolded protein response (UPR). RESULTS AND METHODS The purpose of the ER UPR is to restore ER homeostasis after challenges of the ER function. Among the triggers of ER UPR are changes in the redox status, elevated protein synthesis, accumulation of unfolded or misfolded proteins, energy deficiency and glucose deprivation, cholesterol depletion, and microbial signals. Numerous mouse models have been used to characterize the contribution of ER UPR to several pathologies, and ER UPR-associated signaling has also been demonstrated to be relevant in humans. Additionally, recent evidence suggests that the ER UPR is interrelated with metabolic and inflammatory pathways, autophagy, apoptosis, and mitochondrial stress signaling. Furthermore, microbial as well as nutrient sensing is integrated into the ER-associated signaling network. CONCLUSION The data discussed in the present review highlight the interaction of ER UPR with inflammatory pathways, metabolic processes and mitochondrial function, and their interrelation in the context of chronic diseases.
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Chen JR, Lazarenko OP, Shankar K, Blackburn ML, Lumpkin CK, Badger TM, Ronis MJJ. Inhibition of NADPH oxidases prevents chronic ethanol-induced bone loss in female rats. J Pharmacol Exp Ther 2011; 336:734-42. [PMID: 21098090 PMCID: PMC3061541 DOI: 10.1124/jpet.110.175091] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 11/18/2010] [Indexed: 12/13/2022] Open
Abstract
Previous in vitro data suggest that ethanol (EtOH) activates NADPH oxidase (Nox) in osteoblasts leading to accumulation of reactive oxygen species (ROS). This might be a mechanism underlying inhibition of bone formation and increased bone resorption observed in vivo after EtOH exposure. In a rat model in which cycling females were infused intragastrically with EtOH-containing liquid diets, EtOH significantly decreased bone formation and stimulated osteoblast-dependent osteoclast differentiation. These effects were reversed by exogenous 17-β-estradiol coadministration. Moreover, coadministration of N-acetyl cysteine (NAC), an antioxidant, or diphenylene iodonium (DPI), a specific Nox inhibitor, also abolished chronic EtOH-associated bone loss. EtOH treatment up-regulated mRNA levels of Nox1, 2, 4, and the receptor activator of nuclear factor-κB ligand (RANKL), an essential factor for differentiation of osteoclasts in bone. Protein levels of Nox4, a major Nox isoform expressed in nonphagocytic cells, was also up-regulated by EtOH in bone. 17-β-Estradiol, NAC, and DPI were able to normalize EtOH-induced up-regulation of Nox and RANKL. In vitro experiments demonstrated that EtOH directly up-regulated Nox expression in osteoblasts. Pretreatment of osteoblasts with DPI eliminated EtOH-induced RANKL promoter activity. Furthermore, EtOH induced RANKL gene expression, and RANKL promoter activation in osteoblasts was ROS-dependent. These data suggest that inhibition of Nox expression and activity may be critical for prevention of chronic EtOH-induced osteoblast-dependent bone loss.
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Affiliation(s)
- Jin-Ran Chen
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Jiang F, Zhang Y, Dusting GJ. NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev 2011; 63:218-42. [PMID: 21228261 DOI: 10.1124/pr.110.002980] [Citation(s) in RCA: 447] [Impact Index Per Article: 31.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
NADPH oxidase (Nox) has a dedicated function of generating reactive oxygen species (ROS). Accumulating evidence suggests that Nox has an important role in signal transduction in cellular stress responses. We have reviewed the current evidence showing that the Nox system can be activated by a collection of chemical, physical, and biological cellular stresses. In many circumstances, Nox activation fits to the cellular stress response paradigm, in that (1) the response can be initiated by various forms of cellular stresses; (2) Nox-derived ROS may activate mitogen-activated protein kinases (extracellular signal-regulated kinase, p38) and c-Jun NH(2)-terminal kinase, which are the core of the cell stress-response signaling network; and (3) Nox is involved in the development of stress cross-tolerance. Activation of the cell survival pathway by Nox may promote cell adaptation to stresses, whereas Nox may also convey signals toward apoptosis in irreversibly injured cells. At later stage after injury, Nox is involved in tissue repair by modulating cell proliferation, angiogenesis, and fibrosis. We suggest that Nox may have an integral role in cell stress responses and the subsequent tissue repair process. Understanding Nox-mediated redox signaling mechanisms may be of prominent significance at the crossroads of directing cellular responses to stress, aiming at either enhancing the stress resistance (in such situations as preventing ischemia-reperfusion injuries and accelerating wound healing) or sensitizing the stress-induced cytotoxicity for proliferative diseases such as cancer. Therefore, an optimal outcome of interventions on Nox will only be achieved when this is dealt with in a timely and disease-and stage-specific manner.
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Affiliation(s)
- Fan Jiang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, Shandong 250012, China.
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Qi XF, Teng YC, Yoon YS, Kim DH, Cai DQ, Lee KJ. Reactive oxygen species are involved in the IFN-γ-stimulated production of Th2 chemokines in HaCaT keratinocytes. J Cell Physiol 2010; 226:58-65. [DOI: 10.1002/jcp.22303] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Morgan MJ, Liu ZG. Reactive oxygen species in TNFalpha-induced signaling and cell death. Mol Cells 2010; 30:1-12. [PMID: 20652490 PMCID: PMC6608586 DOI: 10.1007/s10059-010-0105-0] [Citation(s) in RCA: 135] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Accepted: 06/17/2010] [Indexed: 12/29/2022] Open
Abstract
TNFalpha is a pleotropic cytokine that initiates many downstream signaling pathways, including NF-kappaB activation, MAP kinase activation and the induction of both apoptosis and necrosis. TNFalpha has shown to lead to reactive oxygen species generation through activation of NADPH oxidase, through mitochondrial pathways, or other enzymes. As discussed, ROS play a role in potentiation or inhibition of many of these signaling pathways. We particularly discuss the role of sustained JNK activation potentiated by ROS, which generally is supportive of apoptosis and "necrotic cell death" through various mechanisms, while ROS could have inhibitory or stimulatory roles in NF-kappaB signaling.
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Affiliation(s)
- Michael J. Morgan
- Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Zheng-gang Liu
- Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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Kim JS, Yeo S, Shin DG, Bae YS, Lee JJ, Chin BR, Lee CH, Baek SH. Glycogen synthase kinase 3β and β-catenin pathway is involved in toll-like receptor 4-mediated NADPH oxidase 1 expression in macrophages. FEBS J 2010; 277:2830-7. [DOI: 10.1111/j.1742-4658.2010.07700.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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