Probucol

Pfuetze, Karl D.; Dujovne, Carlos A.

doi:10.1007/s11883-000-0094-0

Cited by 22 publications

(15 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A). The ability of both probucol and ␣-tocopherol to function as lipid peroxide antioxidants confirms previously published observations (Wang and Quinn, 1999;Pfuetze and Dujovne, 2000). Because ROS play an important role in the pathogenesis of RA and other inflammatory diseases, we examined the ability of AGIX-4207 to inhibit intracellular levels of ROS in multiple cell types involved in RA including endothelial (HPAEC), monocytes (U937), and synoviocytes (FLSs).…”

Section: Resultssupporting

confidence: 84%

See 1 more Smart Citation

AGIX-4207 [2-[4-[[1-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic Acid], a Novel Antioxidant and Anti-Inflammatory Compound: Cellular and Biochemical Characterization of Antioxidant Activity and Inhibition of Redox-Sensitive Inflammatory Gene Expression

Kunsch¹,

Luchoomun²,

Chen³

et al. 2005

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

The pathogenesis of chronic inflammatory diseases, including rheumatoid arthritis, is regulated, at least in part, by modulation of oxidation-reduction (redox) homeostasis and the expression of redox-sensitive inflammatory genes including adhesion molecules, chemokines, and cytokines. (1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]-thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid] is a novel, orally active, phenolic antioxidant and anti-inflammatory compound with antirheumatic properties. To elucidate its anti-inflammatory mechanisms, we evaluated AGIX-4207 for a variety of cellular, biochemical, and molecular properties. AGIX-4207 exhibited potent antioxidant activity toward lipid peroxides in vitro and displayed enhanced cellular uptake relative to a structurally related drug, probucol. This resulted in potent inhibition of cellular levels of reactive oxygen species in multiple cell types. AGIX-4207 selectively inhibited tumor necrosis factor (TNF)-␣-inducible levels of the redox-sensitive genes, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, with less inhibition of E-selectin, and no effect on intracellular adhesion molecule-1 expression in endothelial cells. In addition, AGIX-4207 inhibited cytokine-induced levels of monocyte chemoattractant protein-1, interleukin (IL)-6, and IL-8 from endothelial cells and human fibroblast-like synoviocytes as well as lipopolysaccharide-induced release of TNF-␣, IL-1␤, and IL-6 from human peripheral blood mononuclear cells. AGIX-4207 did not inhibit TNF-␣-induced nuclear translocation of nuclear factor of the -enhancer in B cells (NF-B), suggesting that the mechanism of action is independent of this redoxsensitive transcription factor. Taken together, these results provide a mechanistic framework for understanding the anti-inflammatory and antirheumatic activity of AGIX-4207 and provide further support for the view that inhibition of redoxsensitive inflammatory gene expression is an attractive approach for the treatment of chronic inflammatory diseases.Leukocyte trafficking to areas of tissue injury and infection is required for the initiation of an effective immune response aimed at tissue repair. This normally self-limiting process is mediated by a highly regulated series of cell-cell interactions between leukocytes and the vascular endothelium. In part, these interactions are controlled by inducible cellular adhesion molecules on the endothelium including vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion moleThis work was supported by AtheroGenics, Inc. Article, publication date, and citation information can be found at

show abstract

Section: Resultssupporting

confidence: 84%

“…Probucol is a well studied lipid antioxidant with low-density lipoprotein-modulating and antiatherosclerotic properties (Pfuetze and Dujovne, 2000). We have recently described the synthesis of several series of probucol derivatives with biological activity (Meng et al, 2002(Meng et al, , 2004.…”

Section: Resultsmentioning

confidence: 99%

AGIX-4207 [2-[4-[[1-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic Acid], a Novel Antioxidant and Anti-Inflammatory Compound: Cellular and Biochemical Characterization of Antioxidant Activity and Inhibition of Redox-Sensitive Inflammatory Gene Expression

Kunsch¹,

Luchoomun²,

Chen³

et al. 2005

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…4 However, it is difficult to draw definitive conclusions about the role of lipoprotein metabolism and atherosclerosis in the CHD in dKO mice solely from the beneficial effects of probucol, because this drug exhibits multiple, pleiotropic activities (anti-oxidant, antiinflammatory, cardioprotective in the absence of dyslipidemia). [43][44][45] Second, a lipid-rich atherogenic diet can induce in SR-BI KO/ApoeR61 h/h mice fatal CHD that is remarkably similar to that in chow-fed dKO mice. SR-BI KO/ApoeR61 h/h mice have low, rather than no, plasma apoE, rendering them susceptible to diet-induced hyperlipidemia, atherosclerosis and CHD.…”

Section: Discussionmentioning

confidence: 95%

Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice

Karackattu

Trigatti

Krieger

2006

ATVB

View full text Add to dashboard Cite

Objective-SR-BI/apolipoprotein (apo) E double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, and premature death. Here we determined the effects on this pathology of hepatic lipase (HL) deficiency, which has been shown to significantly modulate atherosclerosis. Method and Results-The SR-BI/apoE/HL triple knockout (tKO) mice generated for this study lived significantly longer (37%) than corresponding dKO controls (average lifespans: 63.0Ϯ0.8 versus 46.0Ϯ0.3 days), despite their increased plasma cholesterol levels. At 6 weeks of age, compared with dKO mice, tKOs exhibited significantly less aortic root and coronary artery occlusive atherosclerosis, and improved cardiac structure and function. However, by 9 weeks of age the hearts of tKO mice exhibited lipid-rich coronary occlusions, myocardial infarctions, and cardiac dysfunction essentially identical to that of 6-week-old dKO mice. Conclusions-HL-deficiency delays the onset and/or progression of atherosclerosis via a SR-BI-independent mechanism.Extent of occlusive coronary arterial lesions was more closely associated with cardiac dysfunction and lifespan than the amount of aortic root atherosclerosis, suggesting that these occlusions in dKO mice are responsible for ischemia, myocardial infarctions, and premature death. Key Words: atherosclerosis Ⅲ hepatic lipase Ⅲ high density lipoprotein receptor Ⅲ myocardial infarction T hough apolipoprotein E (apoE) or low-density lipoprotein receptor (LDLR) knockout (KO) murine models of dyslipidemia are often used to study lipoprotein metabolism and atherosclerosis, 1 they usually do not exhibit spontaneous occlusive coronary artery disease, myocardial infarction (MI), cardiac dysfunction and premature death, hallmarks of human coronary heart disease (CHD). Double knockout (dKO) mice deficient in the high-density lipoprotein (HDL) receptor (scavenger receptor class B type I, SR-BI) and apoE exhibit extensive aortic sinus atherosclerosis (advanced plaques with fibrous caps 2 that contain macrophages [unpublished data, 2005]), occlusive coronary arterial atherosclerosis (cellular and acellular plaques containing lipid [including cholesterol clefts], collagen, and fibrin deposits 3 ), and acute CHD when young (4 to 6 weeks old). 2-4 At 6 weeks of age, dKO hearts exhibit multiple, large infarctions with extensive fibrosis around the ventricular outflow tract and patchy MIs in the apex, right ventricular wall and interventricular septum. 3 In addition, they are hypertrophic with LV dilation, and exhibit severe dysfunction, including multiple electrocardiographic (ECG) abnormalities (ST elevation and depression, anesthesia induced conductance abnormalities (eg, bradyarrhythmias, AV blocks)), a 70% reduction in ϮdP/dT, and 50% reduced ejection fraction. The dKO mice die between 5 and 8 weeks of age (mean 6 weeks). 2,3 Similarities between dKO and human CHD raised the possibility that these mice may help to ...

show abstract

“…4 Probucol is an antioxidant drug that exhibits antiatherosclerotic and antirestenotic activity in patients with cardiovascular disease. 5 However, treatment with probucol was associated with several side effects, including prolongation of the cardiac QT interval and decreased circulating HDL levels. 5 Recently, a new class of chemically and metabolically-stable probucol derivatives has been synthesized that retain antioxidant activity and display enhanced cellular antioxidant and antiinflammatory activity compared with probucol, which may be attributable to enhanced cellular uptake.…”

mentioning

confidence: 99%

A Novel Class of Antioxidants Inhibit LPS Induction of Tissue Factor by Selective Inhibition of the Activation of ASK1 and MAP Kinases

Luyendyk

Piper

Tencati

et al. 2007

ATVB

View full text Add to dashboard Cite

Objective-Oxidative stress contributes to the pathogenesis of many diseases, including atherosclerosis and sepsis. We have previously described a novel class of therapeutic compounds with antioxidant and antiinflammatory properties. However, at present, the intracellular targets of these compounds have not been identified. The purpose of this study was to elucidate the mechanism by which 2 structurally-related antioxidants (AGI-1067 and AGI-1095) inhibit LPS induction of tissue factor (TF) expression in human monocytic cells and endothelial cells. Methods and Results-We found that succinobucol (AGI-1067) and AGI-1095 inhibited LPS induction of TF expression in both monocytic cells and endothelial cells. These compounds also reduced LPS induction of nuclear AP-1 and expression of Egr-1 without affecting nuclear translocation of NF-B. Importantly, these antioxidants inhibited LPS activation of the redox-sensitive kinase, apoptosis signal-regulating kinase-1 (ASK1) and the mitogen-activated protein kinases (MAPKs) p38, ERK1/2, and JNK1/2. Conclusions-AGI-1067 and AGI-1095 inhibit TF gene expression in both monocytic cells and endothelial cells through a mechanism that involves the inhibition of the redox-sensitive MAP3K, ASK1. These compounds selectively reduce the activation/induction of MAPK, AP-1, and Egr-1 without affecting NF-B nuclear translocation. (Arterioscler Thromb

show abstract

Probucol

Cited by 22 publications

References 41 publications

Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice

A Novel Class of Antioxidants Inhibit LPS Induction of Tissue Factor by Selective Inhibition of the Activation of ASK1 and MAP Kinases

Contact Info

Product

Resources

About