PGH1, the Precursor for the Anti-Inflammatory Prostaglandins of the 1-series, Is a Potent Activator of the Pro-Inflammatory Receptor CRTH2/DP2

Prostaglandin H1 (PGH1) is the cyclo-oxygenase metabolite of dihomo-γ-linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as “anti-inflammatory”. Herein we present evidence that PGH1 is a potent activator of the pro-inflammatory PGD2 receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca2+ flux studies reveal that PGH1 activates CRTH2 as PGH2, PGD2 or PGD1 do. The PGH1 precursor DGLA and the other PGH1 metabolites did not display such effect. PGH1 specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH1 is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH1 mediates migration of and Ca2+ flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH1 as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase

Unilateral Cryptorchidism in Mice Mutant for Ptgds

International audienc

Prostaglandin D2 acts through the Dp2 receptor to influence male germ cell differentiation in the foetal mouse testis

International audienceThrough intercellular signalling, the somatic compartment of the foetal testis is able to program primordial germ cells to undergo spermatogenesis.Fibroblastgrowthfactor9 and several members of the transforming growth factorβ superfamily are involved in this process in the foetal testis, counteracting the induction of meiosis byretinoic acid and activating germinal mitotic arrest. Here, using in vitro and in vivo approaches, we show that prostaglandin D2(PGD2), which is produced through both L-Pgds and H-Pgds enzymatic activities in the somatic and germ cell compartments of the foetal testis, plays a role in mitotic arrest in male germ cells by activating the expression and nuclear localization of the CDK inhibitor p21 Cip1 and by repressing pluripotency markers. We show that PGD2 acts through its Dp2 receptor, at least in part through direct effects in germ cells, and contributes to the proper differentiation of male germ cells through the upregulation of the master gene Nanos2. Our data identify PGD2 signalling as an early pathway that acts in both paracrine and autocrine manners, and contributes to thedifferentiation of germ cells in the foetal testis

Increased cerebral blood flow in the right frontal lobe area during sleep precedes self-awakening in humans

<p>Abstract</p> <p>Background</p> <p>Some people can subconsciously wake up naturally (self-awakening) at a desired/planned time without external time stimuli. However, the underlying mechanism regulating this ability remains to be elucidated. This study sought to examine the relationship between hemodynamic changes in oxyhemoglobin (oxy-Hb) level in the prefrontal cortex and sleep structures during sleep in subjects instructed to self-awaken.</p> <p>Results</p> <p>Fifteen healthy right-handed male volunteers with regular sleep habits participated in a consecutive two-night crossover study. The subjects were instructed to wake up at a specified time (“request” condition) or instructed to sleep until the morning but forced to wake up at 03:00 without prior notice (“surprise” condition). Those who awoke within ± 30 min of the planned waking time were defined as those who succeeded in self-awakening (“success” group). Seven subjects succeeded in self-awakening and eight failed.</p> <p>No significant differences were observed in the amounts of sleep in each stage between conditions or between groups. On the “request” night, an increase in oxy-Hb level in the right prefrontal cortex and a decrease in δ power were observed in the “success” group around 30 min before self-awakening, whereas no such changes were observed in the “failure” group. On the “surprise” night, no significant changes were observed in oxy-Hb level or δ power in either group.</p> <p>Conclusions</p> <p>These findings demonstrate a correlation between self-awakening and a pre-awakening increase in hemodynamic activation in the right prefrontal cortex, suggesting the structure’s contribution to time estimation ability.</p

Prostagladin D2 is a mast cell-derived antiangiogenic factor in lung carcinoma

It is well established that prostaglandins (PGs) are involved in tumor angiogenesis and growth, yet the role of prostaglandin D2 (PGD2) remains virtually unknown. Here, we show that host hematopoietic PGD2 synthase (H-PGDS) deficiency enhances Lewis lung carcinoma (LLC) progression, accompanied by increased vascular leakage, angiogenesis, and monocyte/mast cell infiltration. This deficiency can be rescued by hematopoietic reconstitution with bone marrow from H-PGDS–naive (WT) mice. In tumors on WT mice, c-kit+ mast cells highly express H-PGDS. Host H-PGDS deficiency markedly up-regulated the expression of proangiogenic factors, including TNF-α in the tumor. In mast cell-null KitW-sh/W-sh mice, adoptive transfer of H-PGDS–deficient mast cells causes stronger acceleration in tumor angiogenesis and growth than in WT mast cells. In response to LLC growth, H-PGDS–deficient mast cells produce TNF-α excessively. This response is suppressed by the administration of a synthetic PGD2 receptor agonist or a degradation product of PGD2, 15-deoxy-Δ12,14-PGJ2. Additional TNF-α deficiency partially counteracts the tumorigenic properties seen in H-PGDS–deficient mast cells. These observations identify PGD2 as a mast cell-derived antiangiogenic factor in expanding solid tumors. Mast cell-derived PGD2 governs the tumor microenvironment by restricting excessive responses to vascular permeability and TNF-α production