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Hepatic Myofibroblasts: A Heterogeneous and Redox-Modulated Cell Population in Liver Fibrogenesis. Antioxidants (Basel) 2022; 11:antiox11071278. [PMID: 35883770 PMCID: PMC9311931 DOI: 10.3390/antiox11071278] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 12/19/2022] Open
Abstract
During chronic liver disease (CLD) progression, hepatic myofibroblasts (MFs) represent a unique cellular phenotype that plays a critical role in driving liver fibrogenesis and then fibrosis. Although they could originate from different cell types, MFs exhibit a rather common pattern of pro-fibrogenic phenotypic responses, which are mostly elicited or sustained both by oxidative stress and reactive oxygen species (ROS) and several mediators (including growth factors, cytokines, chemokines, and others) that often operate through the up-regulation of the intracellular generation of ROS. In the present review, we will offer an overview of the role of MFs in the fibrogenic progression of CLD from different etiologies by focusing our attention on the direct or indirect role of ROS and, more generally, oxidative stress in regulating MF-related phenotypic responses. Moreover, this review has the purpose of illustrating the real complexity of the ROS modulation during CLD progression. The reader will have to keep in mind that a number of issues are able to affect the behavior of the cells involved: a) the different concentrations of reactive species, b) the intrinsic state of the target cells, as well as c) the presence of different growth factors, cytokines, and other mediators in the extracellular microenvironment or of other cellular sources of ROS.
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2
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Gonos ES, Kapetanou M, Sereikaite J, Bartosz G, Naparło K, Grzesik M, Sadowska-Bartosz I. Origin and pathophysiology of protein carbonylation, nitration and chlorination in age-related brain diseases and aging. Aging (Albany NY) 2019; 10:868-901. [PMID: 29779015 PMCID: PMC5990388 DOI: 10.18632/aging.101450] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 05/08/2018] [Indexed: 12/11/2022]
Abstract
Non-enzymatic protein modifications occur inevitably in all living systems. Products of such modifications accumulate during aging of cells and organisms and may contribute to their age-related functional deterioration. This review presents the formation of irreversible protein modifications such as carbonylation, nitration and chlorination, modifications by 4-hydroxynonenal, removal of modified proteins and accumulation of these protein modifications during aging of humans and model organisms, and their enhanced accumulation in age-related brain diseases.
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Affiliation(s)
- Efstathios S Gonos
- National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens 11635, Greece
| | - Marianna Kapetanou
- National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens 11635, Greece.,Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Athens 15701, Greece
| | - Jolanta Sereikaite
- Department of Chemistry and Bioengineering, Faculty of Fundamental Sciences, Vilnius Gediminas Technical University, Vilnius 2040, Lithuania
| | - Grzegorz Bartosz
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, Poland
| | - Katarzyna Naparło
- Department of Analytical Biochemistry, Faculty of Biology and Agriculture, University of Rzeszow, Rzeszow 35-601, Poland
| | - Michalina Grzesik
- Department of Analytical Biochemistry, Faculty of Biology and Agriculture, University of Rzeszow, Rzeszow 35-601, Poland
| | - Izabela Sadowska-Bartosz
- Department of Analytical Biochemistry, Faculty of Biology and Agriculture, University of Rzeszow, Rzeszow 35-601, Poland
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3
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Zhang H, Forman HJ. 4-hydroxynonenal-mediated signaling and aging. Free Radic Biol Med 2017; 111:219-225. [PMID: 27876535 PMCID: PMC5438786 DOI: 10.1016/j.freeradbiomed.2016.11.032] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/14/2016] [Accepted: 11/17/2016] [Indexed: 02/07/2023]
Abstract
4-Hydroxy-2-nonenal (HNE), one of the major α, β-unsaturated aldehydes produced during lipid peroxidation, is a potent messenger in mediating signaling pathways. Lipid peroxidation and HNE production appear to increase with aging. Although the cause and effect relation remains arguable, aging is associated with significant changes in diverse signaling events, characterized by enhanced or diminished responses of specific signaling pathways. In this review we will discuss how HNE may contribute to aging-related alterations of signaling pathways.
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Affiliation(s)
- Hongqiao Zhang
- Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave, Los Angeles, CA 90089-0191, USA
| | - Henry Jay Forman
- Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave, Los Angeles, CA 90089-0191, USA.
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4
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Pinzani M, Luong TV. Pathogenesis of biliary fibrosis. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1279-1283. [PMID: 28754450 DOI: 10.1016/j.bbadis.2017.07.026] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 07/19/2017] [Accepted: 07/21/2017] [Indexed: 12/12/2022]
Abstract
Chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, and, ultimately, to the development of cirrhosis. However, the precise relationship between cholestasis, in its broad meaning, and liver tissue fibrosis is still poorly defined. Fibrogenesis is currently viewed as a dynamic process that appears strictly related to the extent and duration of parenchymal injury. This relationship is clearly evident in the presence of reiterative hepatocellular necrosis due to viral infection or alcohol abuse. It appears that "pure" intralobular intrahepatic cholestasis secondary to biliary secretory failure of the hepatocyte, in absence of hepatocellular damage, lobular inflammation and bile duct damage and/or proliferation, is not associated with marked and/or progressive liver tissue fibrosis. In contrast, marked and progressive liver tissue fibrosis always follows liver diseases characterized by chronic inflammatory bile duct damage as seen in PBC and PSC or chronic mechanical obstruction of the biliary tree. Overall, the fibrogenic process in these clinical conditions appears to be related to a more complex interaction between immune/inflammatory mechanisms, cytokine networks and the derangement of the homeostasis between epithelial and mesenchymal cells. The elucidation of these mechanisms is indeed crucial for the identification of potential diagnostic and therapeutic targets.
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Affiliation(s)
- Massimo Pinzani
- UCL Institute for Liver and Digestive Health, London NW3 2QG, United Kingdom.
| | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free Hospital, London NW3 2QG, United Kingdom
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5
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Camaré C, Pucelle M, Nègre-Salvayre A, Salvayre R. Angiogenesis in the atherosclerotic plaque. Redox Biol 2017; 12:18-34. [PMID: 28212521 PMCID: PMC5312547 DOI: 10.1016/j.redox.2017.01.007] [Citation(s) in RCA: 276] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/04/2017] [Accepted: 01/05/2017] [Indexed: 12/12/2022] Open
Abstract
Atherosclerosis is a multifocal alteration of the vascular wall of medium and large arteries characterized by a local accumulation of cholesterol and non-resolving inflammation. Atherothrombotic complications are the leading cause of disability and mortality in western countries. Neovascularization in atherosclerotic lesions plays a major role in plaque growth and instability. The angiogenic process is mediated by classical angiogenic factors and by additional factors specific to atherosclerotic angiogenesis. In addition to its role in plaque progression, neovascularization may take part in plaque destabilization and thromboembolic events. Anti-angiogenic agents are effective to reduce atherosclerosis progression in various animal models. However, clinical trials with anti-angiogenic drugs, mainly anti-VEGF/VEGFR, used in anti-cancer therapy show cardiovascular adverse effects, and require additional investigations.
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Affiliation(s)
- Caroline Camaré
- INSERM - I2MC, U-1048, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse cedex 4, France; Université Paul Sabatier Toulouse III, Faculty of Medicine, Biochemistry Departement, Toulouse, France; CHU Toulouse, Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France
| | - Mélanie Pucelle
- INSERM - I2MC, U-1048, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse cedex 4, France
| | - Anne Nègre-Salvayre
- INSERM - I2MC, U-1048, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse cedex 4, France.
| | - Robert Salvayre
- INSERM - I2MC, U-1048, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse cedex 4, France; Université Paul Sabatier Toulouse III, Faculty of Medicine, Biochemistry Departement, Toulouse, France; CHU Toulouse, Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France.
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6
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Longato L, Andreola F, Davies SS, Roberts JL, Fusai G, Pinzani M, Moore K, Rombouts K. Reactive gamma-ketoaldehydes as novel activators of hepatic stellate cells in vitro. Free Radic Biol Med 2017; 102:162-173. [PMID: 27890721 DOI: 10.1016/j.freeradbiomed.2016.11.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 11/14/2016] [Accepted: 11/21/2016] [Indexed: 11/28/2022]
Abstract
AIMS Products of lipid oxidation, such as 4-hydroxynonenal (4-HNE), are key activators of hepatic stellate cells (HSC) to a pro-fibrogenic phenotype. Isolevuglandins (IsoLG) are a family of acyclic γ-ketoaldehydes formed through oxidation of arachidonic acid or as by-products of the cyclooxygenase pathway. IsoLGs are highly reactive aldehydes which are efficient at forming protein adducts and cross-links at concentrations 100-fold lower than 4-hydroxynonenal. Since the contribution of IsoLGs to liver injury has not been studied, we synthesized 15-E2-IsoLG and used it to investigate whether IsoLG could induce activation of HSC. RESULTS Primary human HSC were exposed to 15-E2-IsoLG for up to 48h. Exposure to 5μM 15-E2-IsoLG in HSCs promoted cytotoxicity and apoptosis. At non-cytotoxic doses (50 pM-500nM) 15-E2-IsoLG promoted HSC activation, indicated by increased expression of α-SMA, sustained activation of ERK and JNK signaling pathways, and increased mRNA and/or protein expression of cytokines and chemokines, which was blocked by inhibitors of JNK and NF-kB. In addition, IsoLG promoted formation of reactive oxygen species, and induced an early activation of ER stress, followed by autophagy. Inhibition of autophagy partially reduced the pro-inflammatory effects of IsoLG, suggesting that it might serve as a cytoprotective response. INNOVATION This study is the first to describe the biological effects of IsoLG in primary HSC, the main drivers of hepatic fibrosis. CONCLUSIONS IsoLGs represent a newly identified class of activators of HSC in vitro, which are biologically active at concentrations as low as 500 pM, and are particularly effective at promoting a pro-inflammatory response and autophagy.
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Affiliation(s)
- Lisa Longato
- Regenerative Medicine & Fibrosis Group, Institute for Liver & Digestive Health, University College London, Royal Free, London, UK
| | - Fausto Andreola
- Liver Failure Group, Institute for Liver & Digestive Health, University College of London, Royal Free, London, UK
| | - Sean S Davies
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
| | - Jackson L Roberts
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
| | - Giuseppe Fusai
- Division of Surgery, University College London, Royal Free, London, UK
| | - Massimo Pinzani
- Regenerative Medicine & Fibrosis Group, Institute for Liver & Digestive Health, University College London, Royal Free, London, UK
| | - Kevin Moore
- Regenerative Medicine & Fibrosis Group, Institute for Liver & Digestive Health, University College London, Royal Free, London, UK
| | - Krista Rombouts
- Regenerative Medicine & Fibrosis Group, Institute for Liver & Digestive Health, University College London, Royal Free, London, UK.
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Mußbach F, Ungefroren H, Günther B, Katenkamp K, Henklein P, Westermann M, Settmacher U, Lenk L, Sebens S, Müller JP, Böhmer FD, Kaufmann R. Proteinase-activated receptor 2 (PAR2) in hepatic stellate cells - evidence for a role in hepatocellular carcinoma growth in vivo. Mol Cancer 2016; 15:54. [PMID: 27473374 PMCID: PMC4966804 DOI: 10.1186/s12943-016-0538-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 07/18/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Previous studies have established that proteinase-activated receptor 2 (PAR2) promotes migration and invasion of hepatocellular carcinoma (HCC) cells, suggesting a role in HCC progression. Here, we assessed the impact of PAR2 in HCC stromal cells on HCC growth using LX-2 hepatic stellate cells (HSCs) and Hep3B cells as model. METHODS PAR2 expression and function in LX-2 cells was analysed by RT-PCR, confocal immunofluorescence, electron microscopy, and [Ca(2+)]i measurements, respectively. The impact of LX-2-expressed PAR2 on tumour growth in vivo was monitored using HCC xenotransplantation experiments in SCID mice, in which HCC-like tumours were induced by coinjection of LX-2 cells and Hep3B cells. To characterise the effects of PAR2 activation in LX-2 cells, various signalling pathways were analysed by immunoblotting and proteome profiler arrays. RESULTS Following verification of functional PAR2 expression in LX-2 cells, in vivo studies showed that these cells promoted tumour growth and angiogenesis of HCC xenografts in mice. These effects were significantly reduced when F2RL1 (encoding PAR2) was downregulated by RNA interference (RNAi). In vitro studies confirmed these results demonstrating RNAi mediated inhibition of PAR2 attenuated Smad2/3 activation in response to TGF-β1 stimulation in LX-2 cells and blocked the pro-mitotic effect of LX-2 derived conditioned medium on Hep3B cells. Furthermore, PAR2 stimulation with trypsin or a PAR2-selective activating peptide (PAR2-AP) led to activation of different intracellular signalling pathways, an increased secretion of pro-angiogenic and pro-mitotic factors and proteinases, and an enhanced migration rate across a collagen-coated membrane barrier. Silencing F2RL1 by RNAi or pharmacological inhibition of Src, hepatocyte growth factor receptor (Met), platelet-derived growth factor receptor (PDGFR), p42/p44 mitogen activated protein kinase (MAPK) or matrix-metalloproteinases (MMPs) blocked PAR2-AP-induced migration. CONCLUSION PAR2 in HSCs plays a crucial role in promoting HCC growth presumably by mediating migration and secretion of pro-angiogenic and pro-mitotic factors. Therefore, PAR2 in stromal HSCs may have relevance as a therapeutic target of HCC.
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Affiliation(s)
- Franziska Mußbach
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany
| | - Hendrik Ungefroren
- First Department of Medicine, UKSH and University of Lübeck, Lübeck, Germany
| | - Bernd Günther
- Service Unit Small Animal, Research Center Lobeda (FZL), Jena University Hospital, Jena, Germany
| | | | | | | | - Utz Settmacher
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany
| | - Lennart Lenk
- Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany
| | - Susanne Sebens
- Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany
| | - Jörg P Müller
- Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
| | - Frank-Dietmar Böhmer
- Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
| | - Roland Kaufmann
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany.
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8
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Csala M, Kardon T, Legeza B, Lizák B, Mandl J, Margittai É, Puskás F, Száraz P, Szelényi P, Bánhegyi G. On the role of 4-hydroxynonenal in health and disease. Biochim Biophys Acta Mol Basis Dis 2015; 1852:826-38. [PMID: 25643868 DOI: 10.1016/j.bbadis.2015.01.015] [Citation(s) in RCA: 179] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 12/16/2014] [Accepted: 01/23/2015] [Indexed: 02/08/2023]
Abstract
Polyunsaturated fatty acids are susceptible to peroxidation and they yield various degradation products, including the main α,β-unsaturated hydroxyalkenal, 4-hydroxy-2,3-trans-nonenal (HNE) in oxidative stress. Due to its high reactivity, HNE interacts with various macromolecules of the cell, and this general toxicity clearly contributes to a wide variety of pathological conditions. In addition, growing evidence suggests a more specific function of HNE in electrophilic signaling as a second messenger of oxidative/electrophilic stress. It can induce antioxidant defense mechanisms to restrain its own production and to enhance the cellular protection against oxidative stress. Moreover, HNE-mediated signaling can largely influence the fate of the cell through modulating major cellular processes, such as autophagy, proliferation and apoptosis. This review focuses on the molecular mechanisms underlying the signaling and regulatory functions of HNE. The role of HNE in the pathophysiology of cancer, cardiovascular and neurodegenerative diseases is also discussed.
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Affiliation(s)
- Miklós Csala
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Budapest, Hungary
| | - Tamás Kardon
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Budapest, Hungary
| | - Balázs Legeza
- Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Beáta Lizák
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Budapest, Hungary
| | - József Mandl
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Budapest, Hungary
| | - Éva Margittai
- Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary
| | - Ferenc Puskás
- Department of Anesthesiology, University of Colorado, Denver, CO, USA
| | - Péter Száraz
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Péter Szelényi
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Budapest, Hungary
| | - Gábor Bánhegyi
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Budapest, Hungary.
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Dwivedi S, Sharma A, Patrick B, Sharma R, Awasthi YC. Role of 4-hydroxynonenal and its metabolites in signaling. Redox Rep 2013; 12:4-10. [PMID: 17263900 DOI: 10.1179/135100007x162211] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Available evidence from a multitude of studies on the effects of 4-hydroxynonenal (HNE) on cellular processes seem to converge on some common themes: (i) concentration-dependent opposing effects of HNE on key signaling components (e.g. protein kinase C, adenylate cyclase) predict that certain constitutive levels of HNE may be needed for normal cell functions - lowering of this constitutive HNE level in cells promotes proliferative machinery while an increase in this level promotes apoptotic signaling; (ii) HNE is a common denominator in stress-induced apoptosis caused by H(2)O(2), superoxide, UV, heat or oxidant chemicals such as doxorubicin; and (iii) HNE can modulate ligand-independent signaling by membrane receptors such as EGFR or Fas (CD95) and may act as a sensor of external stimuli for eliciting stress-response. Against a backdrop of various reported effects of HNE, in vitro and in vivo, we have critically evaluated the above mentioned hypotheses suggesting a key role of HNE in signaling.
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Affiliation(s)
- Seema Dwivedi
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555-0647, USA
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10
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Pizzimenti S, Ciamporcero E, Daga M, Pettazzoni P, Arcaro A, Cetrangolo G, Minelli R, Dianzani C, Lepore A, Gentile F, Barrera G. Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front Physiol 2013; 4:242. [PMID: 24027536 PMCID: PMC3761222 DOI: 10.3389/fphys.2013.00242] [Citation(s) in RCA: 246] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 08/15/2013] [Indexed: 01/07/2023] Open
Abstract
A great variety of compounds are formed during lipid peroxidation of polyunsaturated fatty acids of membrane phospholipids. Among them, bioactive aldehydes, such as 4-hydroxyalkenals, malondialdehyde (MDA) and acrolein, have received particular attention since they have been considered as toxic messengers that can propagate and amplify oxidative injury. In the 4-hydroxyalkenal class, 4-hydroxy-2-nonenal (HNE) is the most intensively studied aldehyde, in relation not only to its toxic function, but also to its physiological role. Indeed, HNE can be found at low concentrations in human tissues and plasma and participates in the control of biological processes, such as signal transduction, cell proliferation, and differentiation. Moreover, at low doses, HNE exerts an anti-cancer effect, by inhibiting cell proliferation, angiogenesis, cell adhesion and by inducing differentiation and/or apoptosis in various tumor cell lines. It is very likely that a substantial fraction of the effects observed in cellular responses, induced by HNE and related aldehydes, be mediated by their interaction with proteins, resulting in the formation of covalent adducts or in the modulation of their expression and/or activity. In this review we focus on membrane proteins affected by lipid peroxidation-derived aldehydes, under physiological and pathological conditions.
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Affiliation(s)
- Stefania Pizzimenti
- Dipartimento di Scienze Cliniche e Biologiche, Università di Torino Torino, Italy
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Novo E, Parola M. The role of redox mechanisms in hepatic chronic wound healing and fibrogenesis. FIBROGENESIS & TISSUE REPAIR 2012; 5:S4. [PMID: 23259696 PMCID: PMC3368756 DOI: 10.1186/1755-1536-5-s1-s4] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Under physiological conditions, intracellular and tissue levels of reactive oxygen species (ROS) are carefully controlled and employed as fine modulators of signal transduction, gene expression and cell functional responses (redox signaling). A significant derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, plays a role in the pathogenesis of human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis, including chronic liver diseases. In this chapter major concepts and mechanisms in redox signaling will be briefly recalled to introduce a number of selected examples of redox-related mechanisms that can actively contribute to critical events in the natural history of a chronic liver diseases, including induction of cell death, perpetuation of chronic inflammatory responses and fibrogenesis. A major focus will be on redox-dependent mechanisms involved in the modulation of phenotypic responses of activated, myofibroblast-like, hepatic stellate cells (HSC/MFs), still considered as the most relevant pro-fibrogenic cells operating in chronic liver diseases.
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Affiliation(s)
- Erica Novo
- Department of Experimental Medicine and Oncology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy ; Interuniversity Centre for Liver Pathophysiology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy
| | - Maurizio Parola
- Department of Experimental Medicine and Oncology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy ; Interuniversity Centre for Liver Pathophysiology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy
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12
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Winczura A, Zdżalik D, Tudek B. Damage of DNA and proteins by major lipid peroxidation products in genome stability. Free Radic Res 2012; 46:442-59. [PMID: 22257221 DOI: 10.3109/10715762.2012.658516] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Oxidative stress and lipid peroxidation (LPO) accompanying infections and chronic inflammation may induce several human cancers. LPO products are characterized by carbohydrate chains of different length, reactive aldehyde groups and double bonds, which make these molecules reactive to nucleic acids, proteins and cellular thiols. LPO-derived adducts to DNA bases form etheno-type and propano-type exocyclic rings, which have profound mutagenic potential, and are elevated in several cancer-prone diseases. Adducts of long chain LPO products to DNA bases inhibit transcription. Elimination from DNA of LPO-induced lesions is executed by several repair systems: base excision repair (BER), direct reversal by AlkB family proteins, nucleotide excision repair (NER) and recombination. Modifications of proteins with LPO products may regulate cellular processes like apoptosis, cell signalling and senescence. This review summarizes consequences of LPO products' presence in cell, particularly 4-hydroxy-2-nonenal, in terms of genomic stability.
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Affiliation(s)
- Alicja Winczura
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 02-106 Warsaw, Poland
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13
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Romero-Sarmiento Y, Soto-Rodríguez I, Arzaba-Villalba A, García HS, Alexander-Aguilera A. Effects of conjugated linoleic acid on oxidative stress in rats with sucrose-induced non-alcoholic fatty liver disease. J Funct Foods 2012. [DOI: 10.1016/j.jff.2011.10.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
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14
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Usatyuk PV, Natarajan V. Hydroxyalkenals and oxidized phospholipids modulation of endothelial cytoskeleton, focal adhesion and adherens junction proteins in regulating endothelial barrier function. Microvasc Res 2012; 83:45-55. [PMID: 21570987 PMCID: PMC3196796 DOI: 10.1016/j.mvr.2011.04.012] [Citation(s) in RCA: 223] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Revised: 04/27/2011] [Accepted: 04/28/2011] [Indexed: 10/18/2022]
Abstract
Lipid peroxidation of polyunsaturated fatty acids generates bioactive aldehydes, which exhibit pro- and anti-inflammatory effects in cells and tissues. Accumulating evidence indicates that 4-hydroxynonenal (4-HNE), a major aldehyde derived from lipid peroxidation of n-6 polyunsaturated fatty acids trigger signals that modulates focal adhesion and adherens junction proteins thereby inducing endothelial barrier dysfunction. Similarly, oxidized phospholipids (Ox-PLs) generated by lipid peroxidation of phospholipids with polyunsaturated fatty acids have been implicated in atherogenesis, inflammation and gene expression. Interestingly, physiological concentration of Ox-PLs is anti-inflammatory and protect against endotoxin- and ventilator-associated acute lung injury. Thus, excess generation of bioactive hydroxyalkenals and Ox-PLs during oxidative stress contributes to pathophysiology of various diseases by modulating signaling pathways that regulate pro- and anti-inflammatory responses and barrier regulation. This review summarizes the role of 4-HNE and Ox-PLs affecting cell signaling pathways and endothelial barrier dysfunction through modulation of the activities of proteins/enzymes by Michael adducts formation, enhancing the level of protein tyrosine phosphorylation of the target proteins, and by reorganization of cytoskeletal, focal adhesion, and adherens junction proteins. A better understanding of molecular mechanisms of hydroxyalkenals- and Ox-PLs-mediated pro-and anti-inflammatory responses and barrier function may lead to development of novel therapies to ameliorate oxidative stress related cardio-pulmonary disorders.
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Affiliation(s)
- Peter V. Usatyuk
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612
- Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL 60612
| | - Viswanathan Natarajan
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612
- Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL 60612
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Abstract
BACKGROUND/AIMS This study examines the modifying effects of thymoquinone (TQ), an agent with antioxidant and hypolipidemic properties, on reactive oxygen species, antioxidant activity, and steatosis in livers of hyperlipidemic rabbit. METHODS Oxidative stress was induced in New Zealand White rabbit by a high-cholesterol diet for 8 weeks. Four groups of six animals each were divided into a control group; a high cholesterol group (received 1% cholesterol diet); a high cholesterol/low TQ group (received 1% cholesterol diet plus TQ 10 mg/kg/day), and a high cholesterol/high TQ (20 mg/kg/day) group. Blood samples were taken at the end of the study and examined for fasting serum glucose, insulin, and aminotransaminases. Hepatic tissue samples were examined for malondialdehyde, protein carbonyls, antioxidant enzymes, and steatosis. RESULTS There was severe hepatic steatosis and elevated serum alanine aminotransferase in the high cholesterol group (group II) but not in the high cholesterol and low or high TQ groups (groups III, IV). The hepatic reactive oxygen species activity in the high cholesterol group was significantly higher while the antioxidant enzymes were lower (P<0.05) when compared with the control (group I) or either of the high cholesterol and TQ groups. CONCLUSION TQ attenuates hepatic oxidative stress in fatty liver injury induced by high-cholesterol diet in rabbits.
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16
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Gentilini A, Lottini B, Brogi M, Caligiuri A, Cosmi L, Marra F, Pinzani M. Evaluation of intracellular signalling pathways in response to insulin-like growth factor I in apoptotic-resistant activated human hepatic stellate cells. FIBROGENESIS & TISSUE REPAIR 2009; 2:1. [PMID: 19183465 PMCID: PMC2642760 DOI: 10.1186/1755-1536-2-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2008] [Accepted: 01/30/2009] [Indexed: 12/13/2022]
Abstract
Background Human hepatic stellate cells have been shown to be resistant to apoptotic stimuli. This is likely dependent on the activation of anti-apoptotic pathways upon transition of these cells to myofibroblast-like cells. In particular, previous studies have demonstrated an increased expression of the anti-apoptotic protein Bcl-2 and a decreased expression of the pro-apoptotic protein Bax during the transition of the hepatic stellate cell phenotype from quiescent to myofibroblast-like cells. However, the role and expression of other key anti-apoptotic and survival pathways elicited by polypeptide growth factors involved in the chronic wound healing process remain to be elucidated. In particular, insulin growth factor-I promotes chemotactic and mitogenic effects in activated human hepatic stellate cells and these effects are mediated by the activation of PI 3-K. The role of insulin growth factor-I as a survival factor in human hepatic stellate cells needs to be substantiated. The aim of this study was to evaluate the involvement of other key anti-apoptotic pathways such as PI-3K/Akt/p-Bad in response to insulin growth factor-I. Results Insulin growth factor-I induced activation of Akt followed by Bad phosphorylation after 15 minutes of incubation. These effects were PI-3k dependent since selective inhibitors of this molecule, wortmannin and LY294002, inhibited both Akt and Bad phosphorylation. The effect of insulin growth factor-I on the activation of two downstream targets of Akt activation, that is, GSK3 and FHKR, both implicated in the promotion of cell survival was also investigated. Both targets became phosphorylated after 15 minutes of incubation, and these effects were also PI-3K-dependent. Despite the activation of this survival pathway insulin growth factor-I did not have a remarkable biological effect, probably because other insulin growth factor-I-independent survival pathways were already maximally activated in the process of hepatic stellate cell activation. However, after incubation of the cells with a strong apoptotic stimuli such as Fas ligand+cycloheximide, a small percentage of hepatic stellate cells underwent programmed cell death that was partially rescued by insulin growth factor-I. Conclusion In addition to Bcl-2, several other anti-apoptotic pathways are responsible for human hepatic stellate cell resistance to apoptosis. These features are relevant for the progression and limited reversibility of liver fibrosis in humans.
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Affiliation(s)
- Alessandra Gentilini
- Dipartimento di Medicina Interna, Università degli Studi di Firenze, Florence, Italy.
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Formation of Toxic α,β-Unsaturated 4-Hydroxy-Aldehydes in Thermally Oxidized Fatty Acid Methyl Esters. J AM OIL CHEM SOC 2009. [DOI: 10.1007/s11746-008-1343-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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18
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Abstract
Uncontrolled production of collagen I is the main feature of liver fibrosis. Following a fibrogenic stimulus such as alcohol, hepatic stellate cells (HSC) transform into an activated collagen-producing cell. In alcoholic liver disease, numerous changes in gene expression are associated with HSC activation, including the induction of several intracellular signaling cascades, which help maintain the activated phenotype and control the fibrogenic and proliferative state of the cell. Detailed analyses for understanding the molecular basis of the collagen I gene regulation have revealed a complex process involving reactive oxygen species (ROS) as key mediators. Less is known, however, about the contribution of reactive nitrogen species (RNS). In addition, a series of cytokines, growth factors, and chemokines, which activate extracellular matrix (ECM)-producing cells through paracrine and autocrine loops, contribute to the fibrogenic response.
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Affiliation(s)
- R. Urtasun
- Mount Sinai School of Medicine, Box 1123, Department of Medicine/Division of Liver Diseases, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - L. Conde de la Rosa
- Mount Sinai School of Medicine, Box 1123, Department of Medicine/Division of Liver Diseases, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - N. Nieto
- Mount Sinai School of Medicine, Box 1123, Department of Medicine/Division of Liver Diseases, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
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19
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Novo E, Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. FIBROGENESIS & TISSUE REPAIR 2008; 1:5. [PMID: 19014652 PMCID: PMC2584013 DOI: 10.1186/1755-1536-1-5] [Citation(s) in RCA: 250] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2008] [Accepted: 10/13/2008] [Indexed: 12/24/2022]
Abstract
Reactive oxygen species (ROS) generated within cells or, more generally, in a tissue environment, may easily turn into a source of cell and tissue injury. Aerobic organisms have developed evolutionarily conserved mechanisms and strategies to carefully control the generation of ROS and other oxidative stress-related radical or non-radical reactive intermediates (that is, to maintain redox homeostasis), as well as to 'make use' of these molecules under physiological conditions as tools to modulate signal transduction, gene expression and cellular functional responses (that is, redox signalling). However, a derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, can play a significant role in the pathogenesis of major human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis. This review has been designed to first offer a critical introduction to current knowledge in the field of redox research in order to introduce readers to the complexity of redox signalling and redox homeostasis. This will include ready-to-use key information and concepts on ROS, free radicals and oxidative stress-related reactive intermediates and reactions, sources of ROS in mammalian cells and tissues, antioxidant defences, redox sensors and, more generally, the major principles of redox signalling and redox-dependent transcriptional regulation of mammalian cells. This information will serve as a basis of knowledge to introduce the role of ROS and other oxidative stress-related intermediates in contributing to essential events, such as the induction of cell death, the perpetuation of chronic inflammatory responses, fibrogenesis and much more, with a major focus on hepatic chronic wound healing and liver fibrogenesis.
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Affiliation(s)
- Erica Novo
- Dipartimento di Medicina e Oncologia Sperimentale and Centro Interuniversitario di Fisiopatologia Epatica, Università degli Studi di Torino, Corso Raffaello 30, 10125 Torino, Italy
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20
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Cannito S, Novo E, Compagnone A, Valfrè di Bonzo L, Busletta C, Zamara E, Paternostro C, Povero D, Bandino A, Bozzo F, Cravanzola C, Bravoco V, Colombatto S, Parola M. Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells. Carcinogenesis 2008; 29:2267-78. [PMID: 18791199 DOI: 10.1093/carcin/bgn216] [Citation(s) in RCA: 227] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) and hypoxia are considered as crucial events favouring invasion and metastasis of many cancer cells. In this study, different human neoplastic cell lines of epithelial origin were exposed to hypoxic conditions in order to investigate whether hypoxia per se may trigger EMT programme as well as to mechanistically elucidate signal transduction mechanisms involved. The following human cancer cell lines were used: HepG2 (from human hepatoblastoma), PANC-1 (from pancreatic carcinoma), HT-29 (from colon carcinoma) and MCF-7 (from breast carcinoma). Cancer cells were exposed to carefully controlled hypoxic conditions and investigated for EMT changes and signal transduction by using morphological, cell and molecular biology techniques. All cancer cells responded to hypoxia within 72 h by classic EMT changes (fibroblastoid phenotype, SNAIL and beta-catenin nuclear translocation and changes in E-cadherin) and by increased migration and invasiveness. This was involving very early inhibition of glycogen synthase kinase-3beta (GSK-3beta), early SNAIL translocation as well as later and long-lasting activation of Wnt/beta-catenin-signalling machinery. Experimental manipulation, including silencing of hypoxia-inducible factor (HIF)-1alpha and the specific inhibition of mitochondrial generation of reactive oxygen species (ROS), revealed that early EMT-related events induced by hypoxia (GSK-3beta inhibition and SNAIL translocation) were dependent on transient intracellular increased generation of ROS whereas late migration and invasiveness were sustained by HIF-1alpha- and vascular endothelial growth factor (VEGF)-dependent mechanisms. These findings indicate that in cancer cells, early redox mechanisms can switch on hypoxia-dependent EMT programme whereas increased invasiveness is sustained by late and HIF-1alpha-dependent release of VEGF.
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Affiliation(s)
- Stefania Cannito
- Dipartamento di Medicina e Oncologia Sperimentale and Centro Interuniversitario di Fisiopatologia Epatica, University of Torino, Torino, Italy
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21
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Wang Y, Jiang XY, Liu L, Jiang HQ. Phosphatidylinositol 3-kinase/Akt pathway regulates hepatic stellate cell apoptosis. World J Gastroenterol 2008; 14:5186-91. [PMID: 18777595 PMCID: PMC2744008 DOI: 10.3748/wjg.14.5186] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of phosphatidylinositol 3-kinase (PI 3-K)/Akt signaling pathway in the balance of HSC activation and apoptosis in rat hepatic stellate cells (HSC).
METHODS: An activated HSC cell line was used in this study. LY 294002, the PI 3-K/Akt signal pathway blocker was used to investigate the molecular events on apoptosis in HSC and to interpret the role of this pathway in HSC apoptosis. Immunocytochemistry, Western blot and reverse transcription polymerase chain reaction (RT-PCR) analysis were applied to detect the expression of PI 3-K, and simultaneously phosphorylated-Akt (p-Akt) and total-Akt were determined by Western blot. The HSC apoptosis was examined by annexin-V/propidium iodide double-labelled flow cytometry and transmission electron microscopy.
RESULTS: The apoptosis rates in LY 294002 (30.82% ± 2.90%) and LY 294002 + PDGF-BB (28.16% ± 2.58%) groups were significantly increased compared with those of control (9.02% ± 1.81%) and PDGF-BB (4.35% ± 1.18%). PDGF-BB augmented PI 3-K and p-Akt expression. LY 294002 significantly reduced the contents of PI 3-K and p-Akt. mRNA transcription evaluated by RT-PCR showed similar tendencies as protein expression.
CONCLUSION: Inhibition of PI 3-K/Akt signaling pathway induces apoptosis in HSC.
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22
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Awasthi YC, Sharma R, Sharma A, Yadav S, Singhal SS, Chaudhary P, Awasthi S. Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death. Free Radic Biol Med 2008; 45:111-8. [PMID: 18456001 PMCID: PMC2664084 DOI: 10.1016/j.freeradbiomed.2008.04.007] [Citation(s) in RCA: 271] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2008] [Revised: 04/02/2008] [Accepted: 04/06/2008] [Indexed: 11/26/2022]
Abstract
Within the last two decades, 4-hydroxynonenal has emerged as an important second messenger involved in the regulation of various cellular processes. Our recent studies suggest that HNE can induce apoptosis in various cells through the death receptor Fas (CD95)-mediated extrinsic pathway as well as through the p53-dependent intrinsic pathway. Interestingly, through its interaction with the nuclear protein Daxx, HNE can self-limit its apoptotic role by translocating Daxx to cytoplasm where it binds to Fas and inhibits Fas-mediated apoptosis. In this paper, after briefly describing recent studies on various biological activities of HNE, based on its interactions with Fas, Daxx, and p53, we speculate on possible mechanisms through which HNE may affect a multitude of cellular processes and draw a parallel between signaling roles of H(2)O(2) and HNE.
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Affiliation(s)
- Yogesh C Awasthi
- Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107-2699, USA.
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23
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Poli G, Schaur R, Siems W, Leonarduzzi G. 4-Hydroxynonenal: A membrane lipid oxidation product of medicinal interest. Med Res Rev 2008; 28:569-631. [DOI: 10.1002/med.20117] [Citation(s) in RCA: 509] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Thong-Ngam D, Samuhasaneeto S, Kulaputana O, Klaikeaw N. N-acetylcysteine attenuates oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis. World J Gastroenterol 2007; 13:5127-32. [PMID: 17876880 PMCID: PMC4434644 DOI: 10.3748/wjg.v13.i38.5127] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate attenuating properties of N-acetylcysteine (NAC) on oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis (NASH).
METHODS: Male Sprague-Dawley rats were randomly divided into three groups. Group 1 (control, n = 8) was free accessed to regular dry rat chow (RC) for 6 wk. Group 2 (NASH, n = 8) was fed with 100% fat diet for 6 wk. Group 3 (NASH + NAC20, n = 9) was fed with 100% fat diet plus 20 mg/kg per day of NAC orally for 6 wk. All rats were sacrificed to collect blood and liver samples at the end of the study.
RESULTS: The levels of total glutathione (GSH) and hepatic malondialdehyde (MDA) were increased significantly in the NASH group as compared with the control group (GSH; 2066.7 ± 93.2 vs 1337.5 ± 31.5 μmol/L and MDA; 209.9± 43.9 vs 3.8 ±1.7 μmol/g protein, respectively, P < 0.05). Liver histopathology from group 2 showed moderate to severe macrovesicular steatosis, hepatocyte ballooning, and necroinflammation. NAC treatment improved the level of GSH (1394.8 ± 81.2 μmol/L, P < 0.05), it did not affect MDA (150.1 ± 27.0 μmol/g protein), but led to a decrease in fat deposition and necroinflammation.
CONCLUSION: NAC treatment could attenuate oxidative stress and improve liver histology in rats with NASH.
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Affiliation(s)
- Duangporn Thong-Ngam
- Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
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25
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Parola M, Marra F, Pinzani M. Myofibroblast - like cells and liver fibrogenesis: Emerging concepts in a rapidly moving scenario. Mol Aspects Med 2007; 29:58-66. [PMID: 18022682 DOI: 10.1016/j.mam.2007.09.002] [Citation(s) in RCA: 132] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2007] [Accepted: 09/28/2007] [Indexed: 02/06/2023]
Abstract
Fibrotic progression of chronic liver diseases of different aetiology to the common advanced-stage of cirrhosis can be envisaged as a dynamic and highly integrated cellular response to chronic liver injury. Liver fibrosis is accompanied by perpetuation of liver injury, chronic hepatitis and persisting activation of tissue repair mechanisms, leading eventually to excess deposition of ECM components. Liver fibrogenesis (i.e., the process) is sustained by populations of highly proliferative, pro-fibrogenic and contractile MFs that, according to current literature, originate by a process of activation involving perisinusoidal HSC, portal fibroblasts and even bone marrow-derived MSC. In this short review emerging concepts in hepatic fibrogenesis and related molecular mechanisms, as provided by recent experimental and clinical studies, are presented.
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Affiliation(s)
- Maurizio Parola
- Dipartimento di Medicina e Oncologia Sperimentale, University of Torino, Corso Raffaello 30, 10125 Torino, Italy.
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26
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Novo E, Cannito S, Zamara E, Valfrè di Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, Colombatto S, Marra F, Pinzani M, Parola M. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 170:1942-53. [PMID: 17525262 PMCID: PMC1899450 DOI: 10.2353/ajpath.2007.060887] [Citation(s) in RCA: 163] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Pathological angiogenesis is associated with the fibrogenic progression of chronic liver diseases. Experimental data suggest that hypoxia and vascular endothelial growth factor (VEGF) may stimulate proliferation and synthesis of type I collagen in activated, myofibroblast-like rat hepatic stellate cells (HSC/MFs). In this study, we investigated whether hypoxia, recombinant VEGF, or angiopoietin 1 (Ang-1) may affect other crucial profibrogenic features. In human HSC/MFs, which constitutively express VEGF receptor-1 and -2 (VEGFR-1, VEGFR-2) and the Ang-1 receptor Tie-2, exposure to hypoxia, VEGF, or Ang-1 resulted in a Ras/Erk-dependent stimulation of chemokinesis and chemotaxis. Migration of human HSC/MFs under hypoxic conditions involved up-regulation of VEGF-A, Ang-1, and related receptors and was mainly dependent on VEGFR-2 (Flk-1). In specimens from either cirrhotic rat livers or from patients with hepatitis C virus-related cirrhosis, HSC/MFs expressed proangiogenic factors and related receptors in areas of active fibrogenesis (ie, at the leading or lateral edge of developing incomplete fibrotic septa). Data presented herein suggest that VEGF and Ang-1 may contribute to fibrogenesis by acting as hypoxia-inducible, autocrine, and paracrine factors able to recruit myofibroblast-like cells. Moreover, HSC/MFs, in addition to their established profibrogenic role, may also contribute to neoangiogenesis during chronic hepatic wound healing.
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Affiliation(s)
- Erica Novo
- Università degli Studi di Torino, Dipartimento Medicina e Oncologia Sperimentale, Corso Raffaello 30, 10125 Turin, Italy
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27
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Davis GL, Krawczynski K, Szabo G. Hepatitis C virus infection--pathobiology and implications for new therapeutic options. Dig Dis Sci 2007; 52:857-75. [PMID: 17333350 DOI: 10.1007/s10620-006-9484-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2006] [Accepted: 06/12/2006] [Indexed: 12/23/2022]
Abstract
Despite progress in therapeutic approaches for the elimination of hepatitis C, chronic hepatitis C virus infection remains an important cause of liver disease. Therapeutic intervention with the currently available interferon-based treatment regimens is quite successful, but treatment is difficult to tolerate and is contraindicated in many patients. A better understanding of the HCV biology, immunopathology, and liver disease will help to design better therapeutic strategies. The American Association for the Study of Liver Diseases sponsored a single-topic conference on hepatitis C virus infection on March 4 and 5, 2005, to enhance our current knowledge in the areas of basic and clinical research related to antiviral and immunomodulatory therapies in hepatitis C disease. The faculty consisted of 23 invited experts in the field of viral hepatitis. The program was divided into four sections including: (a) replicative mechanisms and models; (b) viral-host interactions; and (c) antiviral drug development and new strategies; and (d) back to the bedside-current issues. This report summarizes each of the presentations sections.
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Affiliation(s)
- Gary L Davis
- 4 Roberts, Hepatology, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA.
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28
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Nobili V, Manco M, Devito R, Ciampalini P, Piemonte F, Marcellini M. Effect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2006; 24:1553-61. [PMID: 17206944 DOI: 10.1111/j.1365-2036.2006.03161.x] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Few data are available on the effect of antioxidants in paediatric non-alcoholic fatty liver disease (NAFLD). AIM To compare the effect of a nutritional programme alone or combined with alpha-tocopherol and ascorbic acid on alanine aminotransferase (ALT) levels, and insulin resistance (IR) in biopsy-proven NAFLD children. METHODS IN a 12-month double-blind placebo study, 90 patients were prescribed a balanced calorie diet (25-30 cal/kg/d), physical exercise, and placebo (group A) or alpha-tocopherol 600 IU/day plus ascorbic acid 500 mg/day (group B). IR was estimated by the homeostasis model assessment (HOMA-IR). RESULTS At month 12, ALT (32.67 +/- 8.09 vs. 32.18 +/- 11.39 IU/L; P = NS), HOMA-IR (1.52 +/- 0.66 vs. 1.84 +/- 0.95 IU/L; P = NS), and weight loss (32% vs. 35% of excessive body weight; P = NS) did not differ between the two arms. Among subjects who lost >or=20% of their excessive weight, ALT and body weight percentage changes were significantly related (r(o) = 0.260; P = 0.03). In subjects, who lost more than 1.0 kg, HOMA-IR significantly decreased (2.20 +/- 0.21 to 1.57 +/- 0.13 in group A (P <or= 0.01; -8%); 2.91 +/- 0.24 to 1.88 +/- 0.16 in group B (-32%; P <or= 0.0001)). ALT decreased by 36% (59.13 +/- 4.11 vs. 30.27 +/- 1.46 IU/L; P <or= 0.001), and 42% (68.19 +/- 5.68 vs. 31.92 +/- 1.92 IU/L; P <or= 0.0001). In a multivariate analysis, fasting insulin changes in group A (P = 0.012; F = 7.150). CONCLUSIONS Diet and physical exercise in NAFLD children seem to lead to a significant improvement of liver function and glucose metabolism beyond any antioxidant therapy.
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Affiliation(s)
- V Nobili
- Liver Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
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29
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Abstract
Alcohol abuse is a main cause of liver fibrosis and cirrhosis in the western world. Although the major mechanisms of fibrogenesis are independent of the origin of liver injury, alcoholic liver fibrosis features distinctive characteristics, including the pronounced inflammatory response of immune cells due to elevated gut-derived endotoxin plasma levels, increased formation of reactive oxygen species (ROS), ethanol-induced pericentral hepatic hypoxia or formation of cell-toxic and pro-fibrogenic ethanol metabolites (e.g., acetaldehyde or lipid oxidation products). These factors are together responsible for increased hepatocellular cell death and activation of hepatic stellate cells (HSCs), the key cell type of liver fibrogenesis. To date, removing the causative agent is the most effective intervention to prevent the manifestation of liver cirrhosis. A novel experimental approach in fibrosis therapy is the selective induction of cell death in HSCs. Substances such as gliotoxin, anandamide or antibody against tissue inhibitor of metalloproteinase (TIMP)-1 can selectively induce cell death in activated HSCs. These new results in basic science are encouraging for the search of new antifibrotic treatment.
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Affiliation(s)
- Sören V Siegmund
- Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA
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30
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Lee JS, Kang Decker N, Chatterjee S, Yao J, Friedman S, Shah V. Mechanisms of nitric oxide interplay with Rho GTPase family members in modulation of actin membrane dynamics in pericytes and fibroblasts. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 166:1861-70. [PMID: 15920170 PMCID: PMC1602419 DOI: 10.1016/s0002-9440(10)62495-9] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Migration of pericytes such as hepatic stellate cells is fundamentally important for diverse biological and pathological processes including tumor invasion and fibrosis. In prototypical migratory cells such as fibroblasts, the small GTPases Rac1 and RhoA govern the assembly of lamellipodia and stress fibers, respectively, cytoskeletal structures that are integral to the cell migration process. The gaseous signaling molecule nitric oxide (NO) influences growth factor chemotactic responses, although this occurs primarily in cell-type-specific ways and through cell biological effects that are poorly characterized. In this study, we use complementary molecular and cell biological approaches to delineate important roles for Rac1, RhoA, and NO in migration of the human hepatic stellate cell line LX2 and primary rat hepatic stellate cells. Both platelet-derived growth factor (PDGF) and Rac1 overexpression drove migration through formation of actin-positive filopodia spikes in LX2 as compared to the formation of lamellipodia in fibroblasts. NO inhibited PDGF- and Rac1-driven migration in LX2 by abrogating filopodia formation and inhibited migration of fibroblasts by attenuating lamellipodial protrusions. Additionally, RhoA conferred resistance to NO inhibition of migration and restored chemotactic responses to PDGF in the absence of functional Rac1 in LX2. In conclusion, these studies identify novel crosstalk between small GTPases, cytoskeletal structures, and NO in pericyte-specific pathways, providing counterbalances in the chemotactic responses to growth factors.
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Affiliation(s)
- June Sung Lee
- GI Research Unit, Al 2-435, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
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Cipak A, Borovic S, Scukanec-Spoljar M, Kirac I, Zarkovic N. Possible involvement of 4-hydroxynonenal in splenocyte regulated liver regeneration. Biofactors 2005; 24:217-26. [PMID: 16403957 DOI: 10.1002/biof.5520240126] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Liver regeneration is a complex, systemic process regulated by humoral and cellular mechanisms. Inflammatory response to the extensive tissue damage, as in partial hepatectomy, plays important role during regeneration. Hence, it is assumed that the spleen might play a role in systemic inflammatory response involved in liver regeneration. On the other hand, liver damage and consequential regeneration are often associated with oxidative stress and lipid peroxidation. One of the end products of lipid peroxidation, 4-hydroxynonenal (HNE), is nowadays considered not only as a "second toxic messenger of free radicals" but also as a growth-regulating factor. We therefore studied in vitro interactions of the HNE-treated murine liver cells and autologous spleen cells. The spleen cells supported recovery of liver cells from the HNE cytotoxicity although spleen cells themselves exerted cytotoxic effects against the proliferating liver cells that were not treated with HNE. Our results imply that the cytokines secreted by activated immunocompetent cells may be responsible for the observed recovery of the HNE-damage liver cells, suggesting that HNE might be an important factor regulating cellular and cytokine mediated mechanisms of liver regeneration control.
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Affiliation(s)
- Ana Cipak
- Rudjer Boskovic Institute, Zagreb, Croatia.
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Abstract
Alcohol abuse is a major cause of liver fibrosis and cirrhosis in developed countries. Before alcoholic liver fibrosis becomes evident, the liver undergoes several stages of alcoholic liver disease including steatosis and steatohepatitis. Although the main mechanisms of fibrogenesis are independent of the etiology of liver injury, alcoholic liver fibrosis is distinctively characterized by a pronounced inflammatory response due to elevated gut-derived endotoxin plasma levels, an augmented generation of oxidative stress with pericentral hepatic hypoxia and the formation of cell-toxic and profibrogenic ethanol metabolites (e.g. acetaldehyde or lipid oxidation products). These factors, based on a complex network of cytokine actions, together result in increased hepatocellular damage and activation of hepatic stellate cells, the key cell type of liver fibrogenesis. Although to date removal of the causative agent, i.e. alcohol, still represents the most effective intervention to prevent the manifestation of alcoholic liver disease, sophisticated molecular approaches are underway, aiming to specifically blunt profibrogenic signaling pathways in liver cells or specifically induce cell death in activated hepatic stellate cells to decrease the scarring of the liver.
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Affiliation(s)
- Soren V Siegmund
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
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Leonarduzzi G, Robbesyn F, Poli G. Signaling kinases modulated by 4-hydroxynonenal. Free Radic Biol Med 2004; 37:1694-702. [PMID: 15528028 DOI: 10.1016/j.freeradbiomed.2004.08.027] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2004] [Accepted: 08/31/2004] [Indexed: 11/27/2022]
Abstract
The interaction of 4-hydroxynonenal (HNE) with a variety of kinases variously involved in cell signaling is now a matter of active investigation. In particular, findings with regard to the effect of HNE on different components of the protein kinase C family and the mitogen-activated protein kinase complex already provide reliable indications of a potential role of this aldehyde as a cell signal messenger. Such a role appears further supported by the clear-cut evidence of up-regulation of receptor tyrosine kinases and down-regulation of the nuclear factor kappa B system, produced by HNE concentrations actually detectable in pathophysiology.
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Affiliation(s)
- Gabriella Leonarduzzi
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Turin, Italy
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Barrera G, Pizzimenti S, Dianzani MU. 4-hydroxynonenal and regulation of cell cycle: effects on the pRb/E2F pathway. Free Radic Biol Med 2004; 37:597-606. [PMID: 15288118 DOI: 10.1016/j.freeradbiomed.2004.05.023] [Citation(s) in RCA: 230] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2004] [Revised: 05/17/2004] [Accepted: 05/21/2004] [Indexed: 10/26/2022]
Abstract
The hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, might negatively affect cell proliferation, arose from the observation that lipid peroxidation is very low in tumors. In leukemic cells HNE inhibited cell growth and reduced c-myc and c-myb expression. HNE also induced differentiation in different leukemic cell lines. In HL-60 human leukemic cells, HNE induced the accumulation of cells in the G(0)/G(1) phase of the cell cycle accompanied by a decrease of cyclins D1, D2, and A. Moreover, HNE caused an increase in p21 expression. As cyclin D/CDK2 and cyclin A/CDK2 phosphorylate pRB, these findings suggested that pRb phosphorylation could be affected by HNE. Hypophosphorylated pRb binds and inactivates the E2F transcription factors. HNE induced the dephosphorylation of pRb and the increase in pRb/E2F1 complexes, whereas pRb/E2F4 complexes were reduced, because HNE downregulated E2F4 protein expression. The analysis of E2F binding to the P2 c-myc promoter revealed that HNE caused a decrease in "free" E2F, as well as an increase in pRb (and pRB family members) bound to E2F, with consequent repression of the transcription. In conclusion, HNE reduces E2F transcriptional activity by modifying a number of genes involved in regulation of the pRb/E2F pathway.
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Affiliation(s)
- Giuseppina Barrera
- Department of Experimental Medicine and Oncology, Section of General Pathology, University of Turin, 10125 Torino, Italy
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36
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Imanishi Y, Maeda N, Otogawa K, Seki S, Matsui H, Kawada N, Arakawa T. Herb medicine Inchin-ko-to (TJ-135) regulates PDGF-BB-dependent signaling pathways of hepatic stellate cells in primary culture and attenuates development of liver fibrosis induced by thioacetamide administration in rats. J Hepatol 2004; 41:242-50. [PMID: 15288473 DOI: 10.1016/j.jhep.2004.04.005] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2003] [Revised: 03/24/2004] [Accepted: 04/02/2004] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIMS We studied the effect of Inchin-ko-to (TJ-135), a herb medicine that has been clinically used for liver cirrhosis in Japan, on liver fibrosis in a rat model and on the function of stellate cells. METHODS Rat liver fibrosis was generated by thioacetamide (TAA) administration. DNA synthesis was assessed by 5-bromo-2'-deoxyuridine incorporation assay. Protein expression was analysed by western blotting. Collagen and fibronectin mRNA expression were analysed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS TJ-135 improved liver fibrosis induced in rats by TAA administration. TJ-135 reduced collagen deposition and the expression of smooth muscle alpha-actin in fibrotic liver tissues and decreased the serum level of hyaluronic acid. In primary-cultured stellate cells, TJ-135 suppressed DNA synthesis and the expression of collagen alpha 1(I), collagen III, and fibronectin mRNAs. It hampered DNA synthesis and migration of PDGF-BB-stimulated stellate cells through inhibiting phosphorylation of PDGF receptor-beta and down-stream signaling pathways. Among TJ-135 components, 3-methyl-1,6,8-trihydroxyanthraquinone (emodin) derived from Rhei rhizoma was found to be the most active molecule. CONCLUSIONS TJ-135 and emodin regulate PDGF-dependent events in stellate cells and attenuate the development of liver fibrosis. Their clinical use may be beneficial for the therapy of human liver fibrosis.
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Affiliation(s)
- Yukihiro Imanishi
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan
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37
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Zamara E, Novo E, Marra F, Gentilini A, Romanelli RG, Caligiuri A, Robino G, Tamagno E, Aragno M, Danni O, Autelli R, Colombatto S, Dianzani MU, Pinzani M, Parola M. 4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells. J Hepatol 2004; 40:60-8. [PMID: 14672615 DOI: 10.1016/s0168-8278(03)00480-x] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND/AIMS 4-Hydroxynonenal (HNE) is a putative pro-fibrogenic product of oxidative stress able to elicit apoptosis and cytotoxicity in several cell types. This study has been performed to evaluate its 'in vivo' levels in injured liver and whether HNE may induce apoptosis and/or affect selected phenotypic responses in activated human hepatic stellate cells (HSC/MF). METHODS/RESULTS During the development of acute liver injury induced by CCl(4), liver tissue HNE levels were in the range 0.5-10 microM, as shown by high performance liquid chromatography analysis. Cultured human HSC/MF, developed cytotoxicity only if exposed to very high HNE concentrations (25-50 microM) without any sign of induction of classic, caspase-dependent apoptosis, as assessed by evaluating morphology and biochemical parameters of cell death. HNE, at non-cytotoxic doses, up-regulated procollagen type I and tissue inhibitor of metalloproteinases-1 gene expression and/or protein synthesis without significantly affecting chemotaxis (wound healing and haptotaxis assay), matrix metalloproteinases 1 and 2 mRNA expression and activity as well as basal DNA synthesis. CONCLUSIONS HNE, at concentrations compatible with those detected in vivo, does not elicit HSC/MF classic apoptosis but, rather, may act as a potent pro-fibrogenic stimulus for the expression of genes involved in excess extracellular matrix deposition and proposed as survival signals for HSC/MF.
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Affiliation(s)
- Elena Zamara
- Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino, Corso Raffaello 30, 10125 Turin, Italy
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Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98:2485-90. [PMID: 14638353 DOI: 10.1111/j.1572-0241.2003.08699.x] [Citation(s) in RCA: 466] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Nonalcoholic steatohepatitis (NASH) is a common cause of liver disease. Although usually indolent, this disease can progress to cirrhosis in some patients. There is currently no proven medical therapy for the treatment of NASH. The aim of our study was to evaluate the efficacy of combination alpha-tocopherol (vitamin E) and vitamin C in reducing histologic inflammation and fibrosis. METHODS This was a prospective, double-blind, randomized, placebo-controlled trial with a total enrollment of 49 patients; 45 patients completed the study. All patients were randomized to receive either vitamins E and C (1000 IU and 1000 mg, respectively) or placebo daily for 6 months, based on their initial histologic diagnosis of NASH. Additionally, all patients were given standard weight-loss counseling and encouraged to follow a low fat diet (<30 fat g/day). The pre- and posttreatment liver biopsies were reviewed by a single pathologist, who was blinded to the patient's medication. Biopsies were scored based on a modification of the scoring system published by Brunt et al. (Am J Gastroenterol 1999;94:2467-74). A score of 0-4 was possible for fibrosis, and a score of 0-6 was possible for inflammation and hepatocyte degeneration and necrosis. In addition, body mass index, glycohemoglobin, lipids, and liver enzymes were followed throughout the study. RESULTS Forty-five patients completed 6 months of therapy without significant side effects. Vitamin treatment resulted in a statistically significant improvement in fibrosis score (p=0.002). No changes were noted in inflammation with treatment. Vitamin E and vitamin C, in the doses used in this study, were well tolerated and were effective in improving fibrosis scores in NASH patients. No improvement in necroinflammatory activity or ALT was seen with this combination of drug therapy. A larger, multicenter, longer-term trial with vitamin E and vitamin C seems to be warranted.
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Affiliation(s)
- Stephen A Harrison
- Brooke Army Medical Center, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA
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39
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Abstract
4-hydroxynonenal is a major product of lipid peroxidation. It was firstly studied under the point of view of its toxicity, as it is an easily diffusable substance, thought to be able to explain the "far damages" seen in conditions of increased lipid peroxidation. Really, when used at concentration from 10 microM to 1 mM, usually referred to as high concentrations, the aldehyde is able to produce strong inhibitions of several enzymatic activities. When used, however, at concentration of 1 microM or lower, it displays a lot of activities regarding especially cell multiplication and differentiation. As the concentrations indicated above are usually found in normal tissues, these effects may be considered as physiological. As a low level of lipid peroxidation exists in normal tissues, the aldehyde displays signalling activities in normal cells. Among them, it is to consider the stimulation of neutrophil chemotaxis, the strong activation of plasmamembrane adenylate kinase, the strong activation of membrane phospholipase C, both in hepatocytes and neutrophils, the block in the expression of the oncogene c-myc in human leukemic cells, accompanied by differentiation of the same cells, the effects on the cyclins and the activity of E2F transcription factor, the strong increase of the expression of the gene for procollagen alfa1(I), occurring due to the activation of the c-jun/junkinases/AP-1 pathway. Moreover, it is able to block the activity of the PDGF-beta receptor. The last facts allow to think that a hydroxynonenal pathway works in the production of fibrosis.
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Affiliation(s)
- Mario Umberto Dianzani
- Department of Experimental Medicine and Oncology, Section of General Pathology, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.
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Abstract
The onset of lipid peroxidation within cellular membranes is associated with changes in their physiochemical properties and with the impairment of enzymatic functions located in the membrane environment. There is increasing evidence that aldehydic molecules generated endogenously during the process of lipid peroidation are causally involved in most of the pathophysiological effects associated with oxidative stress in cells and tissues. 4-Hydroxy-2-nonenal (HNE), among them, is believed to be largely responsible for cytopathological effects observed during oxidative stree in vivo and has achieved the status of one of the best recognized and most studied of the cytotoxic products of lipid peroxidation. In the present review, I provide a comprehensive summary of HNE, as the product and mediator or oxidative stress.
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Affiliation(s)
- Koji Uchida
- Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University 464-8601, Nagoya, Japan.
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42
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Abstract
Iron is an essential micronutrient. However, because human beings have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. Indeed, when iron-buffering capability is overwhelmed, oxidative stress-induced cell damage and fibrogenesis may arise, mainly in the liver, the main storage site for iron in the body. Results of recent studies have clearly shown that these pathologic events are induced by iron-generated reactive oxygen species and lipid peroxidation by-products. Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix components in the liver, is a dynamic process, from chronic liver damage to end-stage liver cirrhosis. Iron-induced oxidant stress is involved in this process (1) as the primary cause of parenchymal cell necrosis or (2) as activator of cells that are effectors [e.g., hepatic stellate cells, (myo)fibroblasts] or key mediators (e.g., Kupffer cells) of hepatic fibrogenesis (or through both mechanisms). Beyond their effect as direct cytotoxic agents, iron and free radicals may trigger increased synthesis of collagen in myofibroblast-like cells as well as activate granulocytes and Kupffer cells, resulting in an increased formation of cytokines and eicosanoids and further reactive oxygen species. This may constitute a cascade of amplifying loops, which perpetuate the fibrogenic process. The fibrogenic potential of iron is even more dramatic when iron acts in concert with other hepatotoxins such as alcohol. In this instance, even if tissue iron levels are only slightly elevated, the toxic effect of alcohol or its metabolites may be amplified and propagated with rapid acceleration of the liver disease. At the molecular level, the presence of catalytically active "free iron" may (1) contribute directly to the hepatotoxicity of alcohol or (2) enhance the generation of cytokine and fibrogenic mediators from resident Kupffer cells (or be involved in both ways). A challenge for future research is to develop therapeutic tools able to block "redox-active" free iron in the cell.
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Affiliation(s)
- Antonello Pietrangelo
- Centre for the Study of Iron Disorders, Department of Internal Medicine, University of Modena and Reggio Emilia, Policlinico, Via del Pozzo 71, 41100 Modena, Italy.
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Benlloch S, Beltrán B, Moreno R, Berenguer M. [Fibrogenesis and liver transplantation]. GASTROENTEROLOGIA Y HEPATOLOGIA 2003; 26:381-95. [PMID: 12809575 DOI: 10.1016/s0210-5705(03)70375-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- S Benlloch
- Servicio de Medicina Digestiva. Hospital La Fe. Valencia. España
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Liu XJ, Yang L, Mao YQ, Wang Q, Huang MH, Wang YP, Wu HB. Effects of the tyrosine protein kinase inhibitor genistein on the proliferation, activation of cultured rat hepatic stellate cells. World J Gastroenterol 2002; 8:739-45. [PMID: 12174389 PMCID: PMC4656331 DOI: 10.3748/wjg.v8.i4.739] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Hepatic stellate cell (HSC) plays a pivotal role in liver fibrosis and is considered as the therapeutic target for the treatment of hepatic fibrosis. Tyrosine protein kinase plays an important role in the proliferation, activation of HSC. The purpose of the study is to investigate the effects of the tyrosine protein kinase inhibitor genistein on the proliferation and activation of cultured rat HSC.
METHODS: Rat HSC were isolated from Wistar rats by in situ perfusion of collagenase and pronase and single-step density Nycodenz gradient. Culture-activated HSC were serum-starved and incubated with 10-9 to 10-5 mol/L concentration of genistein for 24, 48 or 72 h. In PDGF-induced HSC proliferation, HSC were stimulated with 10 μg·L-1 PDGF-BB for 15 min, and then treated with genistein for the same time. Cell proliferation was measured by MTT assay and based on flow cytometric analysis of cell cycle. The α-smooth muscle actin (α-SMA) expression in HSC was studied with confocal laser microscopy and flow cytometry. c-fos, c-jun and cyclin D1 expression in HSC was also detected by flow cytometry.
RESULTS: Genistein inhibited basal and PDGF-induced proliferation of HSC at the concentration of 10-8 to 10-5 mol/L, and treatment with 10-7 mol/L concentration of genistein for 48 h inhibited the HSC proliferation significantly (the inhibition rate was 70.3%, P < 0.05). Immunofluorescence detected by confocal laser microscopy and flow cytometry showed that treatment with 10-7 mol/L genistein for 48 h suppressed the expression of α-SMA significantly in HSC (the specific fluorescence intensity were 60.2 ± 21.5 vs 35.3 ± 11.6 and 12.8 ± 10.4 vs 9.54 ± 6.39, respectively, both P < 0.05). The intensity of c-fos, c-jun and cyclin D1 expression of HSCs treated with 10-7 mol/L genistein for 48 h was also significantly decreased compared with the controls.
CONCLUSION: Genistein influences proliferation of HSC, suppresses the expression of α-SMA in HSC and t inhibits the intensity of c-fos, c-jun and cyclin D1 expression of HSCs. Genistein has therapeutic potential against liver fibrosis.
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Affiliation(s)
- Xiao-Jing Liu
- Laboratory of Department of Internal Medicine, West China Hospital, Sichuan University, 37 Wainan Guoxueshang, Chengdu 610041, Sichuan Province, China.
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Affiliation(s)
- M Parola
- Dipartimento di Medicina e Oncologia Sperimentale, Sezione di Patologia Generale, Università degli Studi di Torino, Italy.
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Bonacchi A, Romagnani P, Romanelli RG, Efsen E, Annunziato F, Lasagni L, Francalanci M, Serio M, Laffi G, Pinzani M, Gentilini P, Marra F. Signal transduction by the chemokine receptor CXCR3: activation of Ras/ERK, Src, and phosphatidylinositol 3-kinase/Akt controls cell migration and proliferation in human vascular pericytes. J Biol Chem 2001; 276:9945-54. [PMID: 11136732 DOI: 10.1074/jbc.m010303200] [Citation(s) in RCA: 248] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Hepatic stellate cells (HSC) and glomerular mesangial cells (MC) are tissue-specific pericytes involved in tissue repair, a process that is regulated by members of the chemokine family. In this study, we explored the signal transduction pathways activated by the chemokine receptor CXCR3 in vascular pericytes. In HSC, interaction of CXCR3 with its ligands resulted in increased chemotaxis and activation of the Ras/ERK cascade. Activation of CXCR3 also stimulated Src phosphorylation and kinase activity and increased the activity of phosphatidylinositol 3-kinase and its downstream pathway, Akt. The increase in ERK activity was inhibited by genistein and PP1, but not by wortmannin, indicating that Src activation is necessary for the activation of the Ras/ERK pathway by CXCR3. Inhibition of ERK activation resulted in a decreased chemotactic and mitogenic effect of CXCR3 ligands. In MC, which respond to CXCR3 ligands with increased DNA synthesis, CXCR3 activation resulted in a biphasic stimulation of ERK activation, a pattern similar to the one observed in HSC exposed to platelet-derived growth factor, indicating that this type of response is related to the stimulation of cell proliferation. These data characterize CXCR3 signaling in pericytes and clarify the relevance of downstream pathways in the modulation of different biologic responses.
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Affiliation(s)
- A Bonacchi
- Dipartimento di Medicina Interna, University of Florence, Italy
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Robino G, Zamara E, Novo E, Dianzani MU, Parola M. 4-Hydroxy-2,3-alkenals as signal molecules modulating proliferative and adaptative cell responses. Biofactors 2001; 15:103-6. [PMID: 12016336 DOI: 10.1002/biof.5520150211] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- G Robino
- Department of Experimental Medicine and Oncology, University of Torino, Italy
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