Prostaglandin J2 (PGJ2) and its metabolites ⌬ 12 -PGJ2 and 15-deoxy-⌬ 12,14 -PGJ2 (15d-PGJ2) are naturally occurring derivatives of prostaglandin D2 that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ 2 is a high-affinity ligand for the peroxisome proliferator-activated receptor ␥ (PPAR␥) and has been demonstrated to inhibit the induction of inflammatory response genes, including inducible NO synthase and tumor necrosis factor ␣, in a PPAR␥-dependent manner. We report here that 15d-PGJ2 potently inhibits NF-B-dependent transcription by two additional PPAR␥-independent mechanisms. Several lines of evidence suggest that 15d-PGJ2 directly inhibits NF-B-dependent gene expression through covalent modifications of critical cysteine residues in IB kinase and the DNA-binding domains of NF-B subunits. These mechanisms act in combination to inhibit transactivation of the NF-B target gene cyclooxygenase 2. Direct inhibition of NF-B signaling by 15d-PGJ 2 may contribute to negative regulation of prostaglandin biosynthesis and inflammation, suggesting additional approaches to the development of antiinflammatory drugs. P rostaglandin J 2 (PGJ 2 ) and its metabolites are naturally occurring derivatives of prostaglandin D 2 (PGD 2 ). The pathway for formation of these compounds involves sequential conversion of PGD 2 to PGJ 2 , ⌬ 12 -PGJ 2 , and 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ) (1). The last of these metabolites, 15d-PGJ 2 , is a high-affinity ligand for peroxisome proliferator-activated receptor ␥ (PPAR␥) (2, 3). 15d-PGJ 2 represses several genes in activated macrophages, including the inducible NO synthase (iNOS) and tumor necrosis factor ␣ (TNF␣) genes, and this repression is at least partly dependent on PPAR␥ expression (4-6). 15d-PGJ 2 is present in vivo during the resolution phase of inflammation, suggesting that it may function as a feedback regulator of the inflammatory response (7).Previous studies evaluating PPAR␥-dependent inhibition of iNOS expression indicated that 15d-PGJ 2 was significantly more effective than synthetic PPAR␥ ligands, despite binding to PPAR␥ with lower affinity (4). PGJ 2 and its metabolites are characterized by the presence of a cyclopentenone ring system that contains an electrophilic carbon that can react covalently by means of the Michael addition reaction with nucleophiles such as the free sulfhydryls of glutathione and cysteine residues in cellular proteins (1,8,9). This reactive center is not present in the synthetic PPAR␥ ligands and has been proposed to account for some of the receptor-independent biological actions of PGJ 2 , its metabolites, and the related cyclopentenone prostaglandins PGA 2 and PGA 1 (8, 9).The transcription factor NF-B plays a key role in the activation of inflammatory response genes (10). In resting cells, NF-B is sequestered in the cytoplasm by association with an inhibitory protein IB. In response to signaling by inflammatory cytokines, IB kinase (IKK) is activated and phosphorylates IB on two serine residues. IB is then ubiquitinated...

We have detected deletions of portions of the Y chromosome long arm in 12 of 89 men with azoospermia (no sperm in semen). No Y deletions were detected in their male relatives or in 90 other fertile males. The 12 deletions overlap, defining a region likely to contain one or more genes required for spermatogenesis (the Azoospermia Factor, AZF). Deletion of the AZF region is associated with highly variable testicular defects, ranging from complete absence of germ cells to spermatogenic arrest with occasional production of condensed spermatids. We find no evidence of YRRM genes, recently proposed as AZF candidates, in the AZF region. The region contains a single-copy gene, DAZ (Deleted in AZoospermia), which is transcribed in the adult testis and appears to encode an RNA binding protein. The possibility that DAZ is AZF should now be explored.

No abstract

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.

No abstract

Abstract:The cyclopentenone prostaglandins PGA 2 , PGA 1 , and PGJ 2 are formed by dehydration within the cyclopentane ring of PGE 2 , PGE 1 , and PGD 2 . PGJ 2 is metabolized further to yield D 12 -PGJ 2 and 15-deoxy-D 12,14 -PGJ 2 (15d-PGJ 2 ). Various compounds within the cyclopentenone prostaglandin family possess potent anti-in¯ammatory, 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-D 12,14 -PGJ 2 is a high af®nity ligand for the nuclear receptor PPARg and modulates gene transcription by binding to this receptor. Other activities of the cyclopentenone prostaglandins are mediated by the reactive a,b-unsaturated carbonyl group located in the cyclopentenone ring. The transcription factor NF-kB and its activating kinase are key targets for the anti-in¯ammatory activity of 15d-PGJ 2 , which inhibits NF-kB-mediated transcriptional activation by PPARg-dependent and independent molecular mechanisms. Other cyclopentenone prostaglandins, such as D 7 -PGA 1 and D 12-PGJ 2 , 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.

PURPOSE The retinoid response is mediated by nuclear receptors, including retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). All-trans retinoic acid (RA) binds only RARs, while 9-cis RA is an agonist for both RARs and RXRs. Recently, LGD1069 was identified as a highly selective RXR agonist with low affinity for RARs. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of LGD1069 in patients with advanced cancer. PATIENTS AND METHODS Fifty-two patients received. LGD1069 administered orally once daily at doses that ranged from 5 to 500 mg/m2 for 1 to 41 weeks. Treatment proceeded from a starting dose of 5 mg/m2. Pharmacokinetic sampling was performed on selected patients on days 1, 15, and 29. RESULTS Reversible, asymptomatic increases in liver biochemical tests were the most common dose-limiting adverse effect. Less prominent reactions included leukopenia, hypertriglyceridemia, and hypercalcemia. Characteristic retinoid toxicities, such as cheilitis, headache, and myalgias/arthralgias, were mild or absent. Two patients with cutaneous T-cell lymphoma experienced major antitumor responses. Pharmacokinetic studies obtained in 27 patients at eight dose levels showed that the day 1 area under the plasma concentration-times-time curves (AUCs) were proportional to dose. At all doses studied, the day 1 AUCs were similar to those on days 15 and 29, indicating a lack of induced metabolism. CONCLUSION LGD1069 is a unique compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor-cell proliferation and apoptosis. Further investigation of this drug is warranted. Based on the results of this study, a dose of 300 mg/m2 is recommended for single-agent trials.

No abstract