ICAM-1 and VCAM-1 Expression Induced by TNF-α Are Inhibited by a Glutathione Peroxidase Mimic

d’Alessio, Patrizia; Moutet, Marc; Coudrier, Evelyne; Darquenne, Sophie; Chaudière, Jean

doi:10.1016/s0891-5849(97)00396-1

Cited by 56 publications

(21 citation statements)

References 18 publications

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“…These findings suggest that manoeuvres designed to increase mucosal GSH content may be useful to withstand the lethal consequences of oxidative stress that may contribute to attenuate the activation and recruitment of related factors that participate in the development of IBD, including VCAM-1 and ICAM-1 (Sans et al, 1999). In line with this, recent findings have shown the beneficial role of a GSH peroxidase mimic (D'Alessio et al, 1998) in attenuating the TNF-␣-induced expression of ICAM-1 and VCAM-1.…”

Section: Replenishment Of Glutathione Improves Mucosal Functionmentioning

confidence: 54%

Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis

Ardite

Sans

Panés

et al. 2000

Laboratory Investigation

106

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SUMMARY:Because reactive oxygen species (ROS) have been implicated as mediators of inflammatory bowel disease (IBD), the purpose of the present work was to determine the functional role of mucosal GSH in the trinitrobenzenesulfonic acid in 50% ethanol (TNBSϩethanol)-induced colitis in rats. Mucosal samples were taken to evaluate the temporal relationship between the extent of injury, the levels of glutathione (GSH) during acute colitis induced by TNBSϩethanol, and the effect of N-acetylcysteine (NAC) administration. In vitro assays revealed the interaction of TNBS with GSH leading to the almost instantaneous disappearance of GSH, while the reductive metabolism of TNBS by GSSG reductase generated ROS. Mucosal samples from TNBSϩethanol-treated rats indicated a direct correlation between GSH depletion and injury detected as soon as 30 minutes after TNBSϩethanol administration that persisted 24 hours post treatment. Although, short term depletion of mucosal GSH per se by diethylmaleate did not result in mucosal injury, the oral administration of NAC (40 mM) 4 hours after TNBSϩethanol treatment increased GSH stores (2-fold), decreasing the extent of mucosal injury (60 -70%) examined at 24 hours post treatment. However, an equimolar dose of dithiothreitol failed to increase GSH levels and protect mucosa from TNBSϩethanol-induced injury. Interestingly, GSH levels in TNBSϩethanol-treated rats recovered by 1-2 weeks, an effect that was accounted for by an increase of ␥-glutamylcysteine synthetase (␥-GCS) activity due to an induction of ␥-GCS-heavy subunit chain mRNA. Thus, TNBS promotes two independent mechanisms of injury, GSH depletion and ROS generation, both being required for the manifestation of mucosal injury as GSH limitation renders intestine susceptible to the TNBS-induced ROS overgeneration. Accordingly, in vivo administration of NAC attenuates the acute colitis through increased mucosal GSH levels, suggesting that GSH precursors may be of relevance in the acute relapse of IBD. (Lab Invest 2000, 80:735-744).I nflammatory bowel disease (IBD) is a chronic inflammatory disorder whose etiology is not completely understood. Several factors are recognized to contribute to its development including an overgeneration of reactive oxygen species (ROS). Production of ROS from several sources initiate a cytotoxic cascade of events that culminate in cell death. Thus, stimulated inflammatory cells present in the inflamed mucosa are capable of producing superoxide anion and hydrogen peroxide (Harris et al, 1992;McKenzie et al, 1996;Simmonds and Rampton, 1993).The xantine oxidase pathway and the oxidation of arachidonic acid in colonocytes constitute additional sources of ROS (Biemond et al, 1988;Markowitz et al, 1988;Sedghi et al, 1993). The interaction of these species with specific vascular or interstitial components yield potent chemoattractants for inflammatory phagocytes, establishing a self-amplifying cycle of ROS production that may overwhelm defense strategies resulting in tissue damage (Lewis et al, 1988;Shingu and ...

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Section: Replenishment Of Glutathione Improves Mucosal Functionmentioning

confidence: 54%

Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis

Ardite

Sans

Panés

et al. 2000

Laboratory Investigation

106

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“…Cytokineinduced endothelial cell vascular cell adhesion molecule-1 expression is inhibited by the thiol N-acetylcysteine (592), the metal-chelator pyrrolidine dithiocarbamate (592), or a glutathione peroxidase mimic (181). Intracellular O 2 Ϫ ⅐ generation appears critical to cytokine-induced upregulation of vascular cell adhesion molecule-1, as it is inhibited by cellular overexpression of SOD (145).…”

Section: Adhesion Moleculesmentioning

confidence: 99%

Role of Oxidative Modifications in Atherosclerosis

Stocker¹,

Keaney²

2004

Physiological Reviews

2,249

1,776

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This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an “oxidative response to inflammation” model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

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“…The candidate drug was 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074; formerly BXT-51072), a low-molecular-weight, orally active, organoselenium catalytic mimic of the enzyme glutathione peroxidase that is being developed for the treatment of inflammatory disorders characterized by the involvement of reactive oxygen species [36][37][38][39][40][41]. One possible indication is the treatment of acute coronary syndromes.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of oral midazolam clearance by boosting doses of ritonavir, and by 4,4‐dimethyl‐benziso‐(2H)‐selenazine (ALT‐2074), an experimental catalytic mimic of glutathione oxidase

Greenblatt

Peters

Oleson

et al. 2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The viral protease inhibitor ritonavir is known to inhibit clearance of intravenous midazolam.• ALT-2074, a catalytic mimic of glutathione oxidase, inhibits human cytochrome P450 3A (CYP3A) isoforms in vitro. WHAT THIS STUDY ADDS• Short-term administration of low-dose ritonavir increases area under the plasma concentration curve following oral midazolam by a factor of 28.• Therefore ritonavir is an appropriate positive control inhibitor for clinical drug interaction studies involving CYP3A substrates.• Midazolam clearance is weakly inhibited by ALT-2074, consistent with its in vitro profile. AIMSWe evaluated whether 'boosting' doses of ritonavir can serve as a positive control inhibitor for pharmacokinetic drug-drug interaction studies involving cytochrome P450 3A (CYP3A). The study also determined whether 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074), an investigational organoselenium compound that acts as a catalytic mimic of glutathione oxidase, inhibits CYP3A metabolism in vivo. METHODSThirteen healthy volunteers received single 3-mg oral doses of midazolam on three occasions: in the control condition, during co-treatment with low-dose ritonavir (three oral doses of 100 mg over 24 h), and during co-treatment with ALT-2074 (three oral doses of 80 mg over 24 h). RESULTSRitonavir increased mean (ϮSE) total area under the curve (AUC) for midazolam by a factor of 28.4 Ϯ 4.2 (P < 0.001), and reduced oral clearance to 4.2 Ϯ 0.5% of control (P < 0.001). In contrast, ALT-2074 increased midazolam AUC by 1.25 Ϯ 0.11 (P < 0.05), and reduced oral clearance to 88 Ϯ 8% of control. CONCLUSIONSLow-dose ritonavir produces extensive CYP3A inhibition exceeding that of ketoconazole (typically 10-to 15-fold midazolam AUC enhancement), and is a suitable positive control index inhibitor for drug-drug interaction studies. ALT-2074 inhibits CYP3A metabolism to a small degree that is of uncertain clinical importance.

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ICAM-1 and VCAM-1 Expression Induced by TNF-α Are Inhibited by a Glutathione Peroxidase Mimic

Cited by 56 publications

References 18 publications

Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis

Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis

Role of Oxidative Modifications in Atherosclerosis

Inhibition of oral midazolam clearance by boosting doses of ritonavir, and by 4,4‐dimethyl‐benziso‐(2H)‐selenazine (ALT‐2074), an experimental catalytic mimic of glutathione oxidase

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