Anti-Inflammatory Activity of 15-Deoxy-Δ<sup>12,14</sup>-PGJ<sub>2</sub>and 2-Cyclopenten-1-one: Role of the Heat Shock Response

Ianaro, Angela; Ialenti, Armando; Maffia, Pasquale; Meglio, Paola Di; Rosa, Massimo Di; Santoro, M. Gabriella

doi:10.1124/mol.64.1.85

Cited by 49 publications

(28 citation statements)

References 34 publications

(42 reference statements)

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“…The ability of 15d-PGJ 2 and troglitazone to block cytokine-induced iNOS in macrophages and IL-1-induced IkBa degradation and JNK phosphorylation in islet cells were associated with expression of HSP70 (73). Similarly, Ianaro et al (74) have reported that in vivo treatment with 15d-PGJ 2 , its precursor PGD 2 , and the cyclopentenone ring induced HSF1 activation and HSP72 expression in inflamed tissue and that this effect was associated with the remission of the inflammatory reaction. One mechanism whereby HSPs may regulate inflammation is by altered activation of NF-kB through increased cytoplasmic binding to IkBa.…”

Section: Pparg-independent Effects Of Pparg Ligandsmentioning

confidence: 92%

Peroxisome Proliferator-Activated Receptor-?? Is a New Therapeutic Target in Sepsis and Inflammation

Zingarelli¹,

Cook²

2005

Shock

143

127

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Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily and a ligand-activated transcription factor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. PPARgamma forms a heterodimer with the retinoid X receptor and upon ligand-activation binds to the PPAR response element in the promoter of genes to allow transcription. The class of insulin-sensitizing drugs known as thiazolidinediones have been identified as specific PPARgamma agonists that have allowed the characterization of many genes regulated by PPARgamma. Thiazolidinediones include rosiglitazone, pioglitazone, troglitazone, and ciglitazone. In addition to these synthetic agonists, cyclopentenone prostaglandins of the J2 series have been identified as natural ligands for PPARgamma. Several in vitro and in vivo studies have demonstrated that pharmacological activation of PPARgamma by 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2) or thiazolidinediones has anti-inflammatory effects. This article provides an overview of the role of PPARgamma in regulating the inflammatory response and emphasizes the potential efficacy of PPARgamma ligands as novel therapeutic approaches beyond diabetes in sepsis, inflammation, and reperfusion injury.

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Section: Pparg-independent Effects Of Pparg Ligandsmentioning

confidence: 92%

Peroxisome Proliferator-Activated Receptor-?? Is a New Therapeutic Target in Sepsis and Inflammation

Zingarelli¹,

Cook²

2005

Shock

143

127

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“…15d-PGJ 2 is known to increase in the course of inflammatory processes [4]. 15d-PGJ 2 displays anti-inflammatory and protective effects against certain types of injury in cellular systems, animal models and humans [5][6][7]. In addition to these effects, 15d-PGJ 2 has been shown to induce cell growth arrest and apoptosis in several cancer cell types [8,9].…”

Section: Introductionmentioning

confidence: 99%

On the mechanism of inhibition of p27 degradation by 15-deoxy-Δ12,14-prostaglandin J 2 in lymphoblasts of Alzheimer’s disease patients

Muñoz

Esteras

Bermejo‐Pareja

et al. 2008

Cell. Mol. Life Sci.

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It has been proposed that neuroinflammation, among other factors, may trigger an aberrant neuronal cell cycle re-entry leading to neuronal death. Cell cycle disturbances are also detectable in peripheral cells from Alzheimer's disease (AD) patients. We previously reported that the anti-inflammatory 15- deoxy-Delta(12,14)-prostaglandin J (2) (15d-PGJ (2)) increased the cellular content of the cyclin-dependent kinase inhibitor p27, in lymphoblasts from AD patients. This work aimed at elucidating the mechanisms of 15d-PGJ (2)-induced p27 accumulation. Phosphorylation, half-life, and the nucleo-cytoplasmic traffic of p27 protein were altered by 15d-PGJ2 by mechanisms dependent on PI3K/Akt activity. 15d-PGJ (2) prevents the calmodulin-dependent Akt overactivation in AD lymphoblasts by blocking its binding to the 85-kDa regulatory subunit of PI3K. These effects of 15d-PGJ (2) were not mimicked by 9,10-dihydro-15-deoxy-Delta(12,14)- prostaglandin J (2), suggesting that 15d-PGJ (2) acts independently of peroxisome proliferator-activated receptor gamma activation and that the alpha,beta-unsaturated carbonyl group in the cyclopentenone ring of 15d-PGJ (2) is a requisite for the observed effects.

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“…matory response. Covalent protein modification is important for these effects (10,20). To substantiate the use of biotinylated 15d-PGJ 2 as a tool to identify potential targets for cyPG action, we assessed its ability to mimic the effects of 15d-PGJ 2 .…”

Section: Effects Of Biotinylated 15d-pgj 2 On the Stress And Inflammamentioning

confidence: 99%

Identification of Novel Protein Targets for Modification by 15-Deoxy-Δ12,14-Prostaglandin J2 in Mesangial Cells Reveals Multiple Interactions with the Cytoskeleton

Stamatakis¹,

Sánchez‐Gómez²

2006

Journal of the American Society of Nephrology

108

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The cyclopentenone prostaglandin 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ) has been shown to display protective effects against renal injury or inflammation. In cultured mesangial cells (MC), 15d-PGJ 2 inhibits the expression of proinflammatory genes and modulates cell proliferation. Therefore, cyclopentenone prostaglandins (cyPG) have been envisaged as a promise in the treatment of renal disease. The effects of 15d-PGJ 2 may be dependent on or independent from its role as a peroxisome proliferator-activated receptor agonist. It was shown recently that an important determinant for the peroxisome proliferatoractivated receptor-independent effects of 15d-PGJ 2 is the capacity to modify proteins covalently and alter their function. However, a limited number of protein targets have been identified to date. Herein is shown that a biotinylated derivative of 15d-PGJ 2 recapitulates the effects of 15d-PGJ 2 on the stress response and inhibition of inducible nitric oxide synthase levels and forms stable adducts with proteins in intact MC. Biotinylated 15d-PGJ 2 was then used to identify proteins that potentially are involved in cyPG biologic effects. Extracts from biotinylated 15d-PGJ 2 -treated MC were separated by two-dimensional electrophoresis, and the spots of interest were analyzed by mass spectrometry. Identified targets include proteins that are regulated by oxidative stress, such as heat-shock protein 90 and nucleoside diphosphate kinase, as well as proteins that are involved in cytoskeletal organization, such as actin, tubulin, vimentin, and tropomyosin. Biotinylated 15d-PGJ 2 binding to several targets was confirmed by avidin pull-down. Consistent with these findings, 15d-PGJ 2 induced early reorganization of vimentin and tubulin in MC. The cyclopentenone moiety and the presence of cysteine were important for vimentin rearrangement. These studies may contribute to the understanding of the mechanism of action and therapeutic potential of cyPG.

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Anti-Inflammatory Activity of 15-Deoxy-Δ^12,14-PGJ₂and 2-Cyclopenten-1-one: Role of the Heat Shock Response

Cited by 49 publications

References 34 publications

Peroxisome Proliferator-Activated Receptor-?? Is a New Therapeutic Target in Sepsis and Inflammation

Peroxisome Proliferator-Activated Receptor-?? Is a New Therapeutic Target in Sepsis and Inflammation

On the mechanism of inhibition of p27 degradation by 15-deoxy-Δ12,14-prostaglandin J 2 in lymphoblasts of Alzheimer’s disease patients

Identification of Novel Protein Targets for Modification by 15-Deoxy-Δ12,14-Prostaglandin J2 in Mesangial Cells Reveals Multiple Interactions with the Cytoskeleton

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Anti-Inflammatory Activity of 15-Deoxy-Δ12,14-PGJ2and 2-Cyclopenten-1-one: Role of the Heat Shock Response

Cited by 49 publications

References 34 publications

Peroxisome Proliferator-Activated Receptor-?? Is a New Therapeutic Target in Sepsis and Inflammation

Peroxisome Proliferator-Activated Receptor-?? Is a New Therapeutic Target in Sepsis and Inflammation

On the mechanism of inhibition of p27 degradation by 15-deoxy-Δ12,14-prostaglandin J 2 in lymphoblasts of Alzheimer’s disease patients

Identification of Novel Protein Targets for Modification by 15-Deoxy-Δ12,14-Prostaglandin J2 in Mesangial Cells Reveals Multiple Interactions with the Cytoskeleton

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Anti-Inflammatory Activity of 15-Deoxy-Δ^12,14-PGJ₂and 2-Cyclopenten-1-one: Role of the Heat Shock Response