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Oxidative activation of antioxidant defence - Université de Moncton

454Review TRENDS in Biochemical Sciences Vol.30 No.8 August 2005of sulfur redox-response systems in the antioxidant defenceof organisms including man.The chemical basis of redox regulationCellular antioxidant-defence activation processes areoften triggered by oxidative modification of an aminoacid side chain. The redox chemistry of amino acids suchas cysteine, methionine, phenylalanine, tyrosine andtryptophan, therefore, has a major role in cellular redoxsensing and the antioxidant response. From a chemicalperspective, the catalytic, sensing and response propertiesof sulfur and phenolic redox systems are based on theirability to undergo both reversible and irreversible redoxtransformations resulting in a range of different oxidationstates, each of which with distinct chemical properties.In cysteine, sulfur can occur in formal oxidation statesbetween K2 (thiol) and C4 (sulfonic acid) in vivo, implyinga possible stepwise change of six formal oxidationnumbers, whereas other sulfur-containing biomolecules,such as heparin, contain sulfur in a higher (C6) oxidationstate [1,11] (Table 1). Similarly, an aromatic ring such asphenylalanine can be oxidized to DOPA (3,4-dihydroxyphenylalanine,3-hydroxytyrosine) and subsequently toDOPA-quinone, a process that, in terms of formal chemistry,results in a loss of six electrons from the aromaticring [12] (Figure 1). In both cases, some of these modificationsare reversible, whereas others are irreversibleand might not serve as ‘sensors’.These changes in oxidation states are driven by differentredox mechanisms, such as hydroxylation, electrontransfer and exchange reactions. As far as ‘sensing’ isconcerned, such reactions only occur if the conditions areright, for example, at the appropriate intracellular redoxpotential and in the presence of specific oxidants. Theoccurrence of these redox modifications can, therefore,often be seen as a response to changes in the intracellularredox environment – and the amino acid being modifiedacts as a sensor for oxidative stress [13,14]. Not surprisingly,redox couples based on sulfur and phenols arefrequently found in antioxidant systems, where theyparticipate in various tasks ranging from simple electrondonation [e.g. cysteine in glutathione (GSH)] and antioxidantcatalysis (e.g. cysteine in glutathione reductaseand Prx enzymes) to regulation as part of complexbiochemical sensing and response (e.g. cysteine in redoxswitches) [15,16].The most primitive form of an antioxidant responseelement in proteins is perhaps found when oxidation of anamino acid side chain directly creates a chemical reducingspecies. At first, this might seem like a paradox, but it canbe explained by the fact that sulfur and phenolic redoxsystems can occur in three or more oxidation statesin vivo, and some of their more highly oxygenated statesare actually more reducing (i.e. better electron donors)than the lower ones (Table 1; Figure 1). As a consequence,oxidation of a range of amino acids, such as cysteine,phenylalanine, tyrosine and tryptophan, temporarilygenerates redox sites with both reducing and oxidizingproperties in otherwise redox inactive proteins suchas albumin. These sites include: protein-bound DOPA[12,17], formed by hydroxylation of tyrosine and phenylalanineresidues in the presence of hydroxyl radicals[18,19] and peroxynitrite [12]; 3-hydroxykynurenine,formed from tryptophan [20] and increased threefold inconcentration in the lung during viral pneumonia [21];and, possibly, thiyl radicals [22] and sulfenic acids, formedfrom cysteine [1]. Importantly, their ability to donateelectrons does not necessarily imply that they actually actas antioxidants in vivo.For example, the work of Dean and colleagues hasshown that oxidation of phenylalanine and tyrosineresidues of albumin results in protein-bound DOPA, itselfa good one- and two-electron donor responsible for mostof the reducing activity found in oxidatively modifiedalbumin samples [12,17,18]. DOPA, as an oxidation productof tyrosine, also occurs in the antioxidant pigmentmelanin [12]. Unlike the more complex antioxidantresponsepathways discussed later, these simple responseelements do not require propagation of a redox signal, butprovide additional reducing sites at the point of stress andmight also enter more complex catalytic cycles. Becauseof the low yield of such ‘simple’ response systems – it isestimated that only w0.02% of tyrosine residues are oxidizedto DOPA in human blood and mammalian organs [12]– they are unlikely to play a major part in normal cellfunction, but might become important as a last line ofantioxidant defence after more complex antioxidantsystems have failed and ROS concentrations reach criticallevels. Interestingly, protein-bound DOPA has recentlyattracted renewed interest because it can also function asa redox catalyst and participate in Fenton-type reactions,for example, in the reduction of peroxide to hydroxylFormula Formal oxidationTable 1. Oxidation states of cysteine during oxidative modification aCysteineRedox behaviour in biological systems (as far as known)modification b state (RZC1)Thiol RSH K2 Very common sulfur oxidation state, reducing, catalyticThiyl radical RS † K1 Reducing and oxidizing, catalyticDisulfide RSSR K1 Very common sulfur oxidation state, weak oxidant, catalyticSulfenic acid RSOH 0 Reducing and oxidizing, serves as redox sensor and switch in peroxiredoxinSulfinic acid RS(O)OH C2 Oxidizing, but generally redox inactive in vivo, exception: sulfiredoxin-catalysed reductionSulfonic acid RS(O) 2 OH C4 Redox inactive under physiological conditionsThiosulfinate RS(O)SR C1, K1 Oxidizing, readily reduced in presence of thiolsThiosulfonate RS(O) 2 SR C3, K1 Oxidizing, readily reduced in presence of thiolsa All of these cysteine modifications have an in vivo role to varying extents. Whereas the thiol with a formal oxidation state assigned as K2(RZC1) is reducing, the oxidativelyformed intermediate oxidation states might act as oxidants and reductants. The resulting pro-oxidant and antioxidant properties are complex and modifications such as thiylradicals, disulfides and sulfenic acids can act in both ways, depending on their redox environment. In certain cases, such as for sulfenic acids, intermediate oxidation statesalso endow redox-sensing properties.b Common redox behavior of these oxidation states under physiological conditions is indicated. Only a selection of oxidation states is listed and is necessarily incomplete.www.sciencedirect.com


Review TRENDS in Biochemical Sciences Vol.30 No.8 August 2005 455HNRONHROHNONHRO[O]HNRONHROHNONHROOHPhenylalanine - containing sequenceTyrosine - containing sequence[O]HNOO •+H + , +1 e –HNOOHH + , 1 e –HNOOH –H + , −1 e –OHSemiquinoneDOPA–H + , −1 e –2 e –+H + , +1 e –Tyrosyl radicalO •HNOOOH1,4-additionONOHOIndolinequinolDOPA quinone2 e – 2 e –OOOONONOIndolinequinoneIndolequinoneFigure 1. Oxidation of phenylalanine and tyrosine residues to generate a cascade of protein-bound reducing species, including protein-bound DOPA and indoline quinol.Formation of indoline quinol via 1,4-addition generates another reducing species able to donate a total of four additional electrons. It should be noted that such reducingspecies might not necessarily act as antioxidants in the cell, but could participate in Fenton-type chemistry resulting in highly damaging hydroxyl radicals. The extent offormation and precise biological role of many of these chemical species is still poorly defined and constitutes an important biochemical research question.radicals [23]. The resulting pro-oxidant activity considerablycomplicates the DOPA redox response, a situationmirrored in the kynurenine pathway. Both providesignificant scope for future research in this still controversialarea of protein redox chemistry [24,25]. Thisresearch could, for example, take a closer look at the prooxidantand antioxidant properties of these simple redoxresponsesystems. To date, little is known about the extentof these modifications in vivo, their partners inside theliving cell and the role they have in normal cellularmetabolism and oxidative stress [12,23].A similar situation occurs when GSH is oxidized to thethiyl radical (GS † ), which then reacts with another GSHmolecule to form the reducing glutathione disulfideradical anion (GSSG †K ) in a pH-dependent equilibrium[26–28]. This radical has been detected by electronparamagnetic resonance spectroscopy [29]; it might havean in vivo role, although details about its chemistry andwww.sciencedirect.com


Review TRENDS in Biochemical Sciences Vol.30 No.8 August 2005 457sulfenic acid becomes over-oxidized by the naturalperoxide substrate of the enzyme to sulfinic acid [40].This inactivates Prx and the cell, now devoid of one of itsmajor antioxidant enzymes, might succumb to thestressors and undergo controlled cell death (apoptosis).Prx has, thus, also been called a ‘floodgate’ protein that,once overwhelmed by the stressors, opens the door tosevere oxidative damage and cell death [16].Interestingly, Prx activity can be reinstated by thealmost unique reducing properties of the Srx protein,which provides an intriguing chemical solution to otherwisedifficult sulfinic acid reduction under physiologicalconditions (Eqns 1–4) [14,31,41].Prx-SO K 2 CATP 4K /Prx-SðOÞ-OPO 2K3 CADP 3K Eqn 1Prx-SðOÞ-OPO 2K3 CSrx-SH/Prx-SðOÞ-S-Srx CHPO 2K4Eqn 2Prx-SðOÞ-S-Srx CRSH/Prx-SðOÞH CRS-S-Srx Eqn 3Prx-SðOÞH/Prx-SOH Eqn 4This reaction involves the initial phosphorylation of thesulfinic acid by ATP in the presence of Srx to generate aphosphate leaving group (Eqn 1), which is then replaced inthe second step by a Srx cysteine (Eqn 2). The resultingdisulfide-S-monoxide (thiosulfinate) [42] is readily reducedto the catalytically active sulfenic acid in the presence of a(as yet unspecified) thiol (Eqns 3 and 4). This elegant sulfinicacid reduction chemistry, functioning without any directelectron transfer, is at the heart of a considerably morecomplex cellular signalling pathway involving Prx, Srx,peroxide and thiol levels, and apoptosis. These pathways areonly just emerging, and have been fueled by recent landmarkstudies on Prx and Srx [15,16,31,38,41]. The nextsection will, therefore, consider how cysteine redox chemistrycan be used to build an efficient antioxidant networkconsisting of multiple proteins and enzymes.GSH- and Trx-reduction pathwaysAs discussed, our understanding of the sulfur-based antioxidantresponse has recently undergone major advances,not least triggered by the discovery of Srx proteins in 2003[31], and this has revolutionized our understanding ofenzymic, sulfur-centred, antioxidant systems. It hasbecome clear that there are two parallel, yet interdependentenzymic systems: the better-known system is basedaround GSH as a reducing substrate (and will be calledthe ‘GSH pathway’), and the more recently discoveredsystem is focused on Trx [43–45] as the reductant(Figure 2). Interestingly, the GSH system is more effectivein reducing small disulfide molecules and in reactingdirectly with ROS, whereas Trx is more effective inreducing the exposed disulfides of proteins. Therefore,the Trx system can also be seen as an antioxidant defencefor (accidentally) oxidized cysteine proteins (for a recentreview see Ref. [46]).Reduced GSH (g-Glu-Cys-Gly) is amongst the mostimportant intracellular antioxidants and is present at millimolarconcentrations within human cells [47]. It exists inequilibrium with its disulfide form (GSSG), and the ratioof GSH to GSSG could be used as an indicator of the redoxstatus of the cell. Several important human antioxidantdefencesystems are based around GSH; here, we highlightonly the major ones.The antioxidant system centred on the seleniumdependentenzyme glutathione peroxidase (GPx), whichis coupled with GSH, is, together with catalase and Prx, amajor cellular reducer of hydrogen peroxide (for a review,see Ref. [48])(Figure 2). Apart from serving as an electrondonor, GSH is also used by other enzymes, among themglutathione-S-transferase (GST) [49], which catalyses theconjugation of GSH to a wide variety of electrophiles suchas lipid hydroperoxides and their alkenal breakdown products(e.g. 4-hydroxynonenal), thereby removing thesetoxic products of free radical reactions [50,51]. A largeproportion of the human population displays a homozygousdeletion in two GST genes (GSTM1 and GSTT1)and this null phenotype is associated with malignanciesand inflammatory bowel disease [52], which underlinesthe importance of the GST-centred antioxidant defence.GSH-dependent defence relies, of course, on the availabilityof GSH, and systems involved in the reduction ofGSSG are essential, including NADPH-dependent GSSGreductase (GR) and GSSG transport from the cell. From amechanistic point of view, human GR is a 104-kDa dimericenzyme that achieves reduction of GSSG by a combinationof a thiol–disulfide exchange reaction (to reduce GSSG toGSH while forming an intramolcular disulfide in the GRactive site from two cysteine residues), two-electron transfer(from FADH 2 to reduce the GR disulfide) and hydridetransfer from NADPH to FAD [53]. These redox processesare mirrored in the Trx pathway.Human Trx (a member of the thioredoxin superfamilyof proteins), also known as adult leukaemia-derived factor(ADF), is a 12-kDa protein with a strongly reducing coupleof two cysteine residues in its active site [46,54]. Inahuman T-cell line (Jurkat), this protein is induced byoxidative stress and has an important role in the redoxregulation of key transcription factors (see later) [44,54].It is, therefore, regarded as an important ‘oxysensor’within cells, whereby its sensing ability is mostly theresult of its cysteine redox chemistry and its ability toreact with a wide range of different proteins [43]. Asmentioned, Trx has the capacity to repair oxidized proteinsby reducing protein disulfides at the expense of theoxidation of its own redox-active cysteine residues. Thelatter are reduced by thioredoxin reductase (TrxR) [55].Human TrxR, a 100–130-kDa dimeric flavoprotein thatcontains redox-active cysteine and selenocysteine residues,can regenerate the reduced form of Trx by a series ofthiol–disulfide and selenol–disulfide exchange reactions,electron transfer from FADH 2 to the active-site disulfideand hydride transfer from NADPH to FAD. As in the GSHpathway, reduction of H 2 O 2 by NADPH is ultimatelyachieved, but in this case via Prx, Trx and TrxR.Although the underlying sulfur-centred redox transformationsare similar for the GSH and Trx pathways andboth pathways link antioxidant defence to the cellularenergy metabolism, differences in the major players alongthese two antioxidant pathways – GPx, GSH and GRwww.sciencedirect.com


458Review TRENDS in Biochemical Sciences Vol.30 No.8 August 2005versus Prx, Trx and TrxR – make them interesting from aregulatory point of view. This is an innovative area ofcurrent research with many questions still remaining. Forexample, it still needs to be seen if, and under whichintracellular conditions, the Trx pathway (which is normallyinvolved in the reduction of proteins) becomes activeas a major peroxide-removal system similar to the GSHpathway. In addition, it is unclear if Trx ‘switches’ itssubstrate preference from oxidized proteins to Prx underoxidative-stress conditions, and if the resulting increaseof oxidized proteins then triggers a cellular response suchas apoptosis. The recent discovery of the Srx protein,which possibly uses GSH as its reducing substrate, hasfurther complicated the situation by adding a second Prxregulatory protein that reduces the sulfinic acid to sulfenicacid, whereas Trx reduces the sulfenic acid in Prx to thiol.The emerging regulatory pathway involving cysteine(and selenocysteine) proteins and their associated sulfur(selenium) redox chemistry is mapped out in Figure 2.At present, such pathways are still incomplete and theinteraction of their individual components is not fullyunderstood. Nevertheless, the interplay of such enzymeensembles seem to be simple compared with the considerablymore complex regulatory systems involving geneexpression. An example of the latter, again with cysteineat the centre, is discussed in the next section. It should benoted that the description of such a network of proteins isnecessarily incomplete and can only be used to highlight afew selected biochemical issues.Antioxidant regulation at gene levelA key feature of cellular responses to oxidative stress isthe increased expression of certain genes, some of whichencode antioxidant proteins. Not all antioxidant genes aretranscriptionally upregulated by oxidative stress in allorganisms under all oxidative stress conditions, althoughin bacteria and yeast there are well-characterized examplesof the oxidative-stress-mediated induction of antioxidantgenes, such as the Escherichia coli SoxR and OxyRtranscription factors [56–58].In mammalian systems, there seems to be a surprisinglylimited repertoire of antioxidant genes that areactually induced by oxidative stress [59]. Many antioxidantproteins are expressed in the absence of oxidativestress and, therefore, provide a defence system ready torespond to oxidative stress should it occur. Some proteinsthat can be conditionally upregulated in specific mammaliancell types by oxidative stress include Trx [45], Prx[60,61], manganese-superoxide dismutase [62], hemeoxygenase [63] and ferritin H subunits (ferritin beingthe major iron-sequestering protein within mammaliancells) [64]. Thus, the possibility of redox control of geneexpression as part of a cellular response has been consideredfor several years, although in mammalian cellsthis redox response is mainly directed towards theinflammatory response, apoptosis and cell-cycle control.Indeed, several important human transcription factorsare redox regulated, including nuclear factor-kB (NF-kB)and activator protein-1 (AP-1) [65,66]. These proteins,along with other redox-regulated transcription factors,have been implicated in the transcriptional regulation of awide range of genes involved in human disease processessuch as inflammation and tissue degradation [67,68]. Asrecent research has shown, redox regulation of theseprocesses is far from trivial, with NF-kB and AP-1 relyingon a combination of oxidative and reductive activation orinduction steps [66,69] (Figure 3).In the case of human NF-kB, the DNA-binding nuclearform of the protein is most commonly a heterodimer madeup of one Rel-A (p65) subunit and one p50 subunit [70,71].NF-κB target genesIL-1 ELAM-1IL-6 ICAM-1IL-8 C-mycTNF-α iNOSVCAM-1 COX-2CytokinesLPSPMAOxygenradicals/secondmessengersIκB–NF–κBp50SRTrxSHTranscriptionp50ΙκBp65p65κB binding siteCell membraneNuclear membraneFigure 3. Redox control of the human transcription factor, NF-kB. A wide variety of stimuli, such as the cytokine tumour necrosis factor-a (TNFa), lipopolysaccharide (LPS) andphorbol myristate acetate (PMA) lead to the activation of NF-kB. The intracellular signalling pathway leading to NF-kB activation involves oxidation, possibly of a proteinphosphatase, although this might not always be a common pathway of activation for all cell types and stimuli. The accumulation of phosphorylated inhibitor of NF-kB (IkB)promotes the ubiquitination and proteolysis of IkB, leading to the release of human NF-kB from the IkB–NF-kB complex. This, in turn, results in the exposure of nuclearlocationsequences on the p50 and p65 subunits. The p50 subunit contains a crucial Cys62 residue in the form of a disulfide (indicated by ‘-SR’). Once inside the nucleus,thioredoxin (Trx) catalyses the reduction of Cys62 (indicated by ‘-SH’) of the p50 subunit within NF-kB, which can then bind to a kB-binding site in DNA. The binding of NF-kBpromotes the transcription of a wide range of genes, examples of the proteins encoded by these genes are listed – many are involved in the inflammatory response. Forfurther details, see Ref. [81].www.sciencedirect.com


Review TRENDS in Biochemical Sciences Vol.30 No.8 August 2005 459In non-stimulated cells, NF-kB exists in an inactive,cytosolic form bound to its inhibitor, IkB (Figure 3).Activators of NF-kB, such as tumour necrosis factor-a(TNFa), interleukin (IL)-1, viruses, lipopolysaccharidesand ionizing radiation, induce the dissociation of IkB fromthe IkB–NF-kB complex and positively charged nuclearlocationsequences (NLS) in p50 and p65 are unmasked.NF-kB is then translocated to the nucleus, where itcontrols gene expression.Baeuerle and colleagues [72] highlighted the importanceof oxidative stress in regulating the activation ofNF-kB by showing that NF-kB activity is induced by H 2 O 2in a human T-cell line, an effect blocked by the antioxidantN-acetylcysteine. The oxidative-stress-induced activationof NF-kB is crucially dependent on the phosphorylationof specific serine residues in IkB. Although the precisemechanism by which oxidative stress induces IkB phosphorylationis still unclear, it might involve the inactivationof a protein phosphatase such as PP2A [73]. Suchphosphatases are known to be susceptible to oxidativeinactivation, possibly involving an oxidation-sensitiveiron or cysteine moiety [58]. Whereas oxidation plays apart in the dissociation of the IkB–NF-kB complex, NF-kBalso requires Trx for DNA binding [74]. Trx reducesoxidatively modified Cys62 in human NF-kB, which is acrucial residue for DNA binding. To explain the observationthat activation of NF-kB itself can occur in responseto both ROS (such as H 2 O 2 ) and Trx, Hayashi et al. [75]pointed out that ROS oxidatively induce the expression ofTrx (see later), which might, in turn, reductively activateNF-kB. The correct sequence of oxidative and reductiveevents, in addition to the precise intracellular location oftheir occurrence, is therefore complicated, yet of utmostimportance in the regulation of NF-kB (Figure 3).A similarly complicated situation that requires carefulconsideration of the precise order and location of activationevents is also found in the case of AP-1 [76]. AP-1 isa dimer composed of the proto-oncogene products Fos andJun, the mRNA levels of which (for c-fos and c-jun) in bothhuman fibroblasts and T cells are strongly induced inresponse to H 2 O 2 and other oxidative stresses such as UVlight and ionizing radiation. The AP-1 site is found in thehuman genes encoding collagenase, stromelysin, transforminggrowth factors TGFa and TGFb, IL-2 and tissueinhibitor of matrix metalloproteinases-1. The activation ofAP-1 seems to involve the activation of kinase-signallingcascades by mechanisms similar to those discussed earlierthat involve the oxidative inactivation of protein phosphatases.Similar to NF-kB, AP-1 binding to DNA issubsequently modulated by the reduction of a singleconserved, oxidatively modified cysteine residue in theDNA-recognition site, and redox modification of thisdomain might be part of the mechanism controllingtranscriptional activity [77].Interestingly, nuclear protein Ref-1 is able to reduce theFos and Jun heterodimer, thus stimulating DNA bindingin vitro [78]. Therefore, AP-1 activity might be controlledby Ref-1, and Abate and colleagues [78] have shownthat the oxidation of Ref-1, probably at cysteine residues,significantly diminishes its ability to stimulate theDNA-binding activity of AP-1. However, upon the additionof Trx, the stimulatory activity of Ref-1 is restored andAP-1 binding resumed [78,79]. Trx alone is unable toenhance AP-1 binding to DNA, suggesting that itincreases the reducing efficiency of Ref-1 rather thanacting directly on the Fos and Jun subunits of AP-1. Notsurprisingly, Ref-1 has also been implicated in NF-kBactivation, exerting its effects on the p50 subunit in muchthe same manner as for AP-1 [77,80].Trx might, therefore, also be involved in the regulationof NF-kB and AP-1 [45], in addition to its involvementin the antioxidant pathways discussed in the previoussection. The prominent role of Trx in the antioxidantresponse is underlined by the fact that the protein itselfis subject to strong transcriptional induction by oxidativestress. This is associated with the presence within the Trxpromoter region of a cis-regulatory element that is responsiveto oxidative stress, in addition to binding sites forAP-1, NF-kB and cAMP-response-element-binding (CREB)transcription factors [44,54]. Interestingly, Trx expressionseems to be partly controlled by proteins whose activity, inturn, is controlled by Trx.Overall, the interplay of NF-kB, AP-1, Ref-1, Trx andalso TrxR, Prx and Srx already provides a small subnetworkof redox-sensitive cysteine proteins, all of whichuse thiol oxidation and reduction to sense, counteract –and also capitulate to – oxidative stress. In vivo, thesituation is, of course, likely to be considerably morecomplex, with numerous more proteins involved and bothredox and non-redox interactions.Concluding remarks and future perspectivesThe need for an intact redox balance has led to theevolution of several effective intracellular antioxidantdefence systems that can sense elevated levels of oxidativestress and swiftly reinstate a healthy redox environment.These antioxidant systems can range from simple responsesystems based on amino acids, such as the protein-boundDOPA system, to more complex cysteine ‘redox switches’and, ultimately, highly complicated response and feedbackmechanisms that involve numerous proteins and genes.Therefore, when considering the elements that maintainthe healthy redox balance of cells, the complexity of theresponse systems should not be underestimated; in addition,the chemistry of groups such as thiols or phenols,which is at the heart of these systems, frequently provideseffective, yet amazingly simple, answers to complex biochemicalproblems, and so should not be forgotten.Future biochemical research will undoubtedly result inthe discovery of more complex intracellular redox-controland antioxidant-response systems. At the same time,chemistry will be able to shed light on the mechanismsthat govern these systems. As for the recent renaissancein sulfur redox biochemistry, partially triggered by thediscovery of Srx, the chemistry of these systems willenable us to rationalize new discoveries and also stimulatefurther biochemical research. In the medium term, thiswill not only foster our understanding of basic biochemicalprocesses, but also provide insight into disease causationand potential drug design. Together, research into intracellularredox processes associated with oxidative stresswww.sciencedirect.com


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(1994) Two different cellular redox systems regulatethe DNA-binding activity of the p50 subunit of NF-kB in vitro. Gene145, 197–20381 Winyard, P.G. et al., eds (2000) Free Radicals and Inflammation,BirkhauserElsevier joins major health information initiativeElsevier has joined with scientific publishers and leading voluntary health organizations to create patientINFORM, a groundbreakinginitiative to help patients and caregivers close a crucial information gap. patientINFORM is a free online service dedicated todisseminating medical research and is scheduled to launch in 2005.Elsevier will provide the voluntary health organizations with increased online access to our peer-reviewed biomedical journalsimmediately upon publication, together with content from back issues. The voluntary health organizations will integrate the informationinto materials for patients and link to the full text of selected research articles on their websites.patientINFORM has been created to allow patients seeking the latest information about treatment options online access to themost up-to-date, reliable research available for specific diseases.‘Not only will patientINFORM connect patients and their caregivers with the latest research, it will help them to put it into context. Bymaking it easier to understand research findings, patientINFORM will empower patients to have a more productive dialogue with theirphysicians and make well-informed decisions about care’, said Harmon Eyre, M.D., national chief medical officer of the American CancerSociety.For more information, visit www.patientinform.orgwww.sciencedirect.com

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