Disease relevance of Ptgds

• L-PGDS mRNA is expressed in B16 mouse melanoma cells, but undetectable in human melanoma cell lines [1].
• The distribution of L-PGDS-positive OLs was inversely related to the severity of demyelination, as assessed by accumulation of scavenger macrophages [2].
• We conclude that L-PGDS plays an important role regulating insulin sensitivity and atherosclerosis in type 2 diabetes and may represent a novel model of insulin resistance, atherosclerosis, and diabetic nephropathy [3].
• Pronounced eosinophilic lung inflammation and Th2 cytokine release in human lipocalin-type prostaglandin D synthase transgenic mice [4].
• Orally administered HQL-79 (30 mg/kg body weight) inhibited antigen-induced production of PGD2, without affecting the production of PGE2 and PGF2alpha, and ameliorated airway inflammation in wild-type and human H-PGDS-overexpressing mice [5].

Psychiatry related information on Ptgds

• The three PGs, i.e. PGD2, PGE1 and PGI2 which showed anti-hypoxic effects decreased locomotor activity and potentiated hexobarbital-induced sleep [6].
• These results were not consistent with a role of PGD2 as a sleep-promoting substance as, if that was the case, it would be increased during the REM sleep deprivation [7].
• PGD2 did not prevent convulsions induced in response to electroshock or pentylenetetrazol [8].

High impact information on Ptgds

• Activated mast cells release various chemical mediators, including prostaglandin D2 (PGD2), whose role in allergic asthma has now been investigated by the generation of mice deficient in the PGD receptor (DP) [9].
• In response to PGD2, CRTH2 induces intracellular Ca2+mobilization and chemotaxis in Th2 cells in a Galphai-dependent manner [10].
• In addition, CRTH2, but not DP, mediates PGD2-dependent cell migration of blood eosinophils and basophils [10].
• Taken together, we propose that the inhibition of LC migration could represent an additional stratagem for the schistosomes to escape the host immune system and that PGD2 may play a key role in the control of cutaneous immune responses [11].
• KL at concentrations of 10 ng/ml elicited half-maximal eicosanoid generation and at concentrations of > 50 ng/ml elicited a maximal generation of approximately 15 ng LTC4 and 1 ng PGD2 per 10(6) cells, with 20% net beta-hexosaminidase release 10 min after stimulation [12].

Chemical compound and disease context of Ptgds

• L-PGDS is expressed in oligodendrocytes (OLs) in the central nervous system and is up-regulated in OLs of the twitcher mouse, a model of globoid cell leukodystrophy (Krabbe's disease) [13].
• We investigated whether up-regulation of L-PGDS is either unique to Krabbe's disease or is a more generalized phenomenon in lysosomal storage disorders (LSDs), using LSD mouse models of Tay-Sachs disease, Sandhoff disease, GM(1) gangliosidosis and Niemann-Pick type C1 disease [13].
• To examine whether PGHS-2 is induced by phorbol ester in mast cells, we studied mRNA expression of PGHS-2 and also measured prostaglandin D2 (PGD2) production when canine mastocytoma cells were incubated with phorbol myristate acetate (PMA) [14].
• Urinary L-PGDS excretion was significantly increased in patients with diabetic nephropathy, IgA nephropathy, and chronic glomerulonephritis even when serum creatinine was not increased [15].
• On the other hand, PGD2 dose-dependently blocked the allodynia induced by a maximal dose (10 ng/mouse) of PGE2, with an IC50 of 93.2 pg/mouse, but did not affect the PGE2 (10 ng)-induced hyperalgesia at doses up to 10 ng [16].

Biological context of Ptgds

• This compound also found inhibited the COX-2-dependent conversion of the exogenous arachidonic acid to PGD2 in a dose-dependent manner with an IC50 values of 19.0 microM, using a COX enzyme assay kit [17].
• The upregulation of L-PGDS was more remarkable in perineuronal OLs than in interfascicular OLs [2].
• Perineuronal oligodendrocytes protect against neuronal apoptosis through the production of lipocalin-type prostaglandin D synthase in a genetic demyelinating model [2].
• We thus propose a new step in the sex-determining cascade where PGD2 acts as an autocrine factor inducing SOX9 nuclear translocation and subsequent Sertoli cell differentiation [18].
• Surprisingly, L-PGDS gene expression is reduced 2-fold after E(2) treatment in the ventrolateral preoptic area (VLPO), the suspected site of action for the sleep-promoting effects of PGD(2) [19].

Anatomical context of Ptgds

• In contrast, prostaglandin-D-synthase (Ptgds) and lipocalin 2 (Lcn2) mRNA increase in basal forebrain of both strains after influenza infection [20].
• Immunohistochemical analysis of wild-type mice identified the specific expression of L-PGDS in follicular melanocytes [1].
• Methyl gallate (MG) is a medicinal herbal product that is isolated from Paeonia lactiflora that inhibits cyclooxygenase-2 (COX-2) dependent phases of prostaglandin D2 (PGD2) generation in bone marrow-derived mast cells (BMMC) in a concentration-dependent manner with an IC50 values of 17.0 microM [17].
• Finally, we showed by employing specific inhibitors that the causative signaling molecule is prostaglandin D2 (PGD2) and that PGD2 can induce Sox9 transcription in cultured XX gonads [21].
• We examined the effect of injection of 15d-PGJ(2) (30 ng twice a day) or PGDS expressing-retrovirally transfected fibroblast on BLM-induced dermal sclerosis [22].

Associations of Ptgds with chemical compounds

• MITF may modulate the production of prostaglandin D(2) by activating the L-PGDS gene in melanocytes [1].
• Mechanical scratching increased PGD2, PGE2, PGI2 and PGF(2 alpha) [23].
• In the normal skin of COX-1-deficient mice, skin PGD2 level was lower than that of wild-type mice, although PGE2, PGI2 and PGF(2 alpha) levels were almost equal to those of wild type [23].
• 15-d PGJ(2) and PGDS-expressing cells also suppressed degranulation of cultured mast cells and histamine release by these cells [22].
• We evaluated the effect of treatment with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or the injection of prostaglandin D(2) synthase (PGDS) cDNA expressing-retrovirally transfected fibroblasts on bleomycin (BLM)-induced scleroderma-like skin sclerosis [22].
• These results indicated that the two binding sites for PGH(2) and retinoic acid in the large cavity of L-PGDS were responsible for the broad ligand specificity of L-PGDS and the non-competitive inhibition of L-PGDS activity by retinoic acid [24].

Physical interactions of Ptgds

• The results of electrophoretic mobility shift assay and chromatin immunoprecipitation assay revealed that LRH-1 and SREBP-1c bound to their respective binding elements in the promoter of L-PGDS gene [25].

Regulatory relationships of Ptgds

• Delayed PGD2 generation was suppressed by approximately 80% by an antibody raised against recombinant murine type II sPLA2 [26].
• Northern blot analysis, using estrogen receptor (ER)-disrupted mice, suggests that L-PGDS is specifically induced by ERbeta in vivo [27].

Other interactions of Ptgds

• By cDNA microarray analysis, we have identified lipocalin-type prostaglandin D synthase (L-PGDS), whose mRNA is undetectable in the homozygous Mitf(mi-bw) skin [1].
• These lines of evidence suggest that L-PGDS is an anti-apoptotic molecule protecting neurons and OLs from apoptosis in the twitcher mouse [2].
• Hematopoietic prostaglandin D synthase (PGDS) is a key enzyme involved in production of the PGD and J series, which have various role in inflammation and immunity [22].
• Overexpression of sPLA2 receptors caused a marked increase in AA and PGD2 release after stimulation of BMMC, implicating sPLA2 receptors in this process [28].
• Thus, kinetic, pharmacologic, and genetic analyses suggest that an inducible, heparin-sensitive PLA2, rather than cPLA2, provides arachidonic acid to concomitantly induced PGHS-2 for delayed-phase PGD2 biosynthesis in activated BMMC [29].

Analytical, diagnostic and therapeutic context of Ptgds

• In situ hybridization revealed significant increases in L-PGDS expression in the arcuate and ventromedial nucleus of the medial basal hypothalamus compared with vehicle controls [19].
• METHODS: Expression of endogenous PGDS in a murine air-pouch model of MSU crystal-induced acute inflammation was determined by real-time polymerase chain reaction [30].
• Cell culture data revealed significant differences between insulin-stimulated mitogen-activated protein kinase phosphatase-2, protein-tyrosine phosphatase-1D, and phosphorylated focal adhesion kinase expression levels in L-PGDS KO vascular smooth muscle cells and controls [3].
• Quantitative RT-PCR revealed that L-PGDS mRNA was up-regulated in the brains of all these mouse models [13].
• Moreover, surface plasmon resonance analyses revealed that L-PGDS binds GM(1) and GM(2) gangliosides, accumulated in neurons in the course of LSD, with high affinities (K(D) = 65 and 210 nm, respectively) [13].

References