Publications

• Cyclopentenone prostaglandins: new insights on biological activities and cellular targets.

  Straus D.S., Glass C.K.

  The cyclopentenone prostaglandins PGA2, PGA1, and PGJ2 are formed by dehydration within the cyclopentane ring of PGE2, PGE1, and PGD2. PGJ2 is metabolized further to yield Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). Various compounds within the cyclopentenone prostaglandin fami ... >> More

  The cyclopentenone prostaglandins PGA2, PGA1, and PGJ2 are formed by dehydration within the cyclopentane ring of PGE2, PGE1, and PGD2. PGJ2 is metabolized further to yield Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). Various compounds within the cyclopentenone prostaglandin family possess potent anti-inflammatory, anti-neoplastic, and anti-viral activity. Most actions of the cyclopentenone prostaglandins do not appear to be mediated by binding to G-protein coupled prostanoid receptors. Rather, the bioactivity of these compounds results from their interaction with other cellular target proteins. 15-deoxy-Delta(12,14)-PGJ(2) is a high affinity ligand for the nuclear receptor PPARgamma and modulates gene transcription by binding to this receptor. Other activities of the cyclopentenone prostaglandins are mediated by the reactive alpha,beta-unsaturated carbonyl group located in the cyclopentenone ring. The transcription factor NF-kappaB and its activating kinase are key targets for the anti-inflammatory activity of 15d-PGJ2, which inhibits NF-kappaB-mediated transcriptional activation by PPARgamma-dependent and independent molecular mechanisms. Other cyclopentenone prostaglandins, such as Delta(7)-PGA1 and Delta(12)-PGJ2, have strong anti-tumor activity. These compounds induce cell cycle arrest or apoptosis of tumor cells depending on the cell type and treatment conditions. We review here recent progress in understanding the mechanisms of action of the cyclopentenone prostaglandins and their possible use as therapeutic agents. << Less

  Med Res Rev 21:185-210(2001) [PubMed] [EuropePMC]

• Delta12-prostaglandin J2 as a product and ligand of human serum albumin: formation of an unusual covalent adduct at His146.

  Yamaguchi S., Aldini G., Ito S., Morishita N., Shibata T., Vistoli G., Carini M., Uchida K.

  Human serum albumin (HSA), the most abundant protein in plasma, has a very unique function, catalyzing the conversion of prostaglandin J(2) (PGJ(2)), a dehydration product of PGD(2), to yield Delta(12)-PGJ(2). These PGD(2) metabolites are actively transported into cells and accumulated in the nucl ... >> More

  Human serum albumin (HSA), the most abundant protein in plasma, has a very unique function, catalyzing the conversion of prostaglandin J(2) (PGJ(2)), a dehydration product of PGD(2), to yield Delta(12)-PGJ(2). These PGD(2) metabolites are actively transported into cells and accumulated in the nuclei, where they act as potent inducers of cell growth inhibition and cell differentiation, and exhibit their own unique spectrum of biological effects. The facts that (i) arachidonic acid metabolites bind to human serum albumin (HSA) and the metabolism of these molecules is altered as a result of binding, (ii) HSA catalyzes the transformation of PGJ(2) into Delta(12)-PGJ(2), and (iii) Delta(12)-PGJ(2) is stable in serum suggest that HSA may bind and stabilize Delta(12)-PGJ(2) in a specific manner. A molecular interaction analysis using surface plasmon resonance (Biacore) indeed suggested the presence of a specific Delta(12)-PGJ(2)-binding site in HSA. To investigate the molecular details of the binding of this PGD(2) metabolite to albumin, we analyzed the cocrystal structure of the HSA-Delta(12)-PGJ(2)-myristate complex by X-ray crystallography and found that two Delta(12)-PGJ(2) molecules bind to a primary site in subdomain IB of the protein. The electron density results suggested that one of the two Delta(12)-PGJ(2) molecules that specifically bind to the site covalently interacted with a histidine residue (His146). Using nano-LC-MS/MS analysis of the HSA-Delta(12)-PGJ(2) complex, the formation of an unusual Delta(12)-PGJ(2)-histidine adduct at His146 was confirmed. Thus, our crystallographic and mass spectrometric analyses of the HSA-Delta(12)-PGJ(2) complex provided intriguing new insights into the molecular details of how this electrophilic ligand interacts with its primary producer and transporter. << Less

  J Am Chem Soc 132:824-832(2010) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites.

  Liu H., Li W., Rose M.E., Pascoe J.L., Miller T.M., Ahmad M., Poloyac S.M., Hickey R.W., Graham S.H.

  Prostaglandin D2 (PGD2) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD2 may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ2, Δ(12)-PGJ2 a ... >> More

  Prostaglandin D2 (PGD2) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD2 may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ2, Δ(12)-PGJ2 and 15-deoxy-Δ(12,14)-PGJ2, inducing cell death independently of prostaglandin receptors. This study aims to elucidate the effect of PGD2 on neuronal cell death and its underlying mechanisms. PGD2 dose-dependently induced cell death in rat primary neuron-enriched cultures in concentrations of ≥10μM, and this effect was not reversed by treatment with either DP1 or DP2 receptor antagonists. Antioxidants N-acetylcysteine (NAC) and glutathione which contain sulfhydryl groups that can bind to CyPGs, but not ascorbate or tocopherol, attenuated PGD2-induced cell death. Conversion of PGD2 to CyPGs was detected in neuronal culture medium; treatment with these CyPG metabolites alone exhibited effects similar to those of PGD2, including apoptotic neuronal cell death and accumulation of ubiquitinated proteins. Disruption of lipocalin-type prostaglandin D synthase (L-PGDS) protected neurons against hypoxia. These results support the hypothesis that PGD2 elicits its cytotoxic effects through its bioactive CyPG metabolites rather than DP receptor activation in primary neuronal culture. << Less

  Neurotoxicology 39:35-44(2013) [PubMed] [EuropePMC]

• 15-Deoxy-delta12,14-PGJ2: endogenous PPARgamma ligand or minor eicosanoid degradation product?

  Powell W.S.

  15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) affects gene transcription by activating PPARgamma and by covalent addition to transcription factors and signaling molecules, However, it is not known whether the high concentrations of 15d-PGJ2 required for these responses are consistent with physio ... >> More

  15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) affects gene transcription by activating PPARgamma and by covalent addition to transcription factors and signaling molecules, However, it is not known whether the high concentrations of 15d-PGJ2 required for these responses are consistent with physiological levels. A new study suggests that in vivo 15d-PGJ2 levels are actually several orders of magnitude below the levels required to induce many of the biological effects attributed to this molecule. << Less

  J Clin Invest 112:828-830(2003) [PubMed] [EuropePMC]

• 15-deoxy-delta 12,14-prostaglandin J2. A prostaglandin D2 metabolite generated during inflammatory processes.

  Shibata T., Kondo M., Osawa T., Shibata N., Kobayashi M., Uchida K.

  Prostaglandin D(2) (PGD(2)), a major cyclooxygenase product in a variety of tissues, readily undergoes dehydration to yield the cyclopentenone-type PGs of the J(2) series, such as 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), which have been suggested to exert anti-inflammatory effects in vivo. Meanw ... >> More

  Prostaglandin D(2) (PGD(2)), a major cyclooxygenase product in a variety of tissues, readily undergoes dehydration to yield the cyclopentenone-type PGs of the J(2) series, such as 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), which have been suggested to exert anti-inflammatory effects in vivo. Meanwhile, the mechanism of these effects is not well understood and the natural site and the extent of its production in vivo remain unclear. In the present study, we raised a monoclonal antibody specific to 15d-PGJ(2) and determined its production in inflammation-related events. The monoclonal antibody (mAb11G2) was raised against the 15d-PGJ(2)-keyhole limpet hemocyanin conjugate and was found to recognize free 15d-PGJ(2) specifically. The presence of 15d-PGJ(2) in vivo was immunohistochemically verified in the cytoplasm of most of the foamy macrophages in human atherosclerotic plaques. In addition, the immunostaining of lipopolysaccharide-stimulated RAW264.7 macrophages with mAb11G2 demonstrated an enhanced intracellular accumulation of 15d-PGJ(2), suggesting that the PGD(2) metabolic pathway, generating the anti-inflammatory PGs, is indeed utilized in the cells during inflammation. The activation of macrophages also resulted in the extracellular production of PGD(2), which was associated with a significant increase in the extracellular 15d-PGJ(2) levels, and the extracellular 15d-PGJ(2) production was reproduced by incubating PGD(2) in a cell-free medium and in phosphate-buffered saline. Moreover, using a chiral high performance liquid chromatography method for separation of PGD(2) metabolites, we established a novel metabolic pathway, in which PGD(2) is converted to 15d-PGJ(2) via an albumin-independent mechanism. << Less

  J Biol Chem 277:10459-10466(2002) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.