Prostaglandin D2 Metabolite Research Articles

Effects of mPGES-1 deletion on eicosanoid and fatty acid profiles in mice

mPGES-1 is considered an alternative target for anti-inflammatory treatment with improved selectivity and safety compared to NSAIDs. mPGES-1 depletion not only suppresses inflammation via absence of inducible PGE2 but might also cause an activation of anti-inflammatory pathways. We studied effects of mPGES-1 deletion on the eicosanoid and fatty acid (FA) profiles in mice. In LPS-induced peritoneal macrophages from mPGES-1 knock-out (mPGES-1−/−, KO) mice PGE2 production was markedly attenuated, whereas levels of PGD2 metabolites (15-deoxy-Δ12,14 PGJ2 and 15-deoxy-Δ12,14 PGD2) were increased compared to wild type mice. The levels of oxidized fatty acid 13-HODE were also significantly up-regulated in KO macrophages. Significant differences in the total lipid FA composition (decrease in monounsaturated FA and increase in eicosadienoic acid) were detected in spleen of KO and WT mice. These effects of mPGES-1 deletion on eicosanoid and fatty acid metabolism have important implications for future mPGES-1 inhibitors and deserve further investigation.

Quantification of major urinary metabolites of PGE2 and PGD2 in cystic fibrosis: Correlation with disease severity

Cystic fibrosis transmembrane conductance (CFTR) alterations are involved in the overproduction of prostaglandins (PG) in CF in vitro. We assessed the relationship between PGE-M and PGD-M urinary metabolites of PGE2 and PGD2 and CF severity. Twenty-four controls and 35 CF patients were recruited. PGE-M and PGD-M levels were measured by liquid chromatography/mass spectrometry and results were expressed as median and 25th–75th interquartile of ng/mg creatinine (Cr). PGE-M (15.63; 9.07–43.35ng/mg Cr) and PGD-M (2.16; 1.43–3.53ng/mg Cr) concentrations were higher in CF than in controls: PGE-M, (6.63; 4.35–8.60ng/mg Cr); PGD-M (1.23; 0.96–1.54ng/mg Cr). There was no correlation between metabolite levels and spirometric values. Patients with pancreatic insufficiency (n=29) had higher PGE-M levels (19.09; 9.36–52.69ng/mg Cr) than those with conserved function (n=6) (9.61; 5.78–14.34ng/mg Cr). PGE-M levels were associated with genotype severity: mild (7.14; 5.76–8.76, n=8), moderate (16.67; 13.67–28.62ng/mg Cr, n=5) and severe (22.82; 10.67–84.13ng/mg Cr). Our study confirms the key role of CFTR in the regulation of the cyclooxygenase pathway of arachidonic acid metabolism found in in vitro studies.

AB0042 Deletion of mpges-1 affects fatty acid composition and eicosanoid profiles in mice

BackgroundmPGES-1 is considered an attractive alternative target for anti-inflammatory treatment with improved selectivity and safety compared to NSAIDs. Genetic deletion or pharmacological inhibition of mPGES-1 activity or expression down-regulate inflammation...

Identification of 15d-PGJ2 as an antagonist of farnesoid X receptor: Molecular modeling with biological evaluation

15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2) is one of the major metabolites from prostaglandin D2 in arachidonic acid (AA) metabolic pathway. It was determined as a ligand of peroxisome proliferator-activated receptor γ (PPARγ) functioning potently in adipocyte development. However, the fact that 15d-PGJ2 exerts also PPARγ-independent biological actions has highly addressed its multi-target behavior. Here, we identified that 15d-PGJ2 was an antagonist of farnesoid X receptor (FXR), as investigated by surface plasmon resonance, fluorescence quenching and homo time-resolved fluorescence based analyses, and the coactivator-recruitment and luciferase-reporter related investigation. Assay of 15d-PGJ2 regulation on hFXRα target genes revealed that treatment of HepG2 cells with 15d-PGJ2 resulted in the stimulation of mRNA expressions of bile-salt export pump (BSEP), and the decrease of cholesterol 7a-hydroxylase (CYP7a1). In addition, functional assays indicated that 15d-PGJ2 promoted the conversion of cholesterol to bile acids in HepG2 cells. Moreover, molecular docking combined with molecular dynamics simulation was applied to develop the possible model of 15d-PGJ2 binding to hFXRα ligand binding domain (LBD) at atomic level, and the responsible residues for 15d-PGJ2/hFXRα-LBD interaction were thereby determined, which were further confirmed by SPR assays against hFXRα-LBD site-directed mutations. Given that hFXRα functions potently in the regulation of hepatic bile acid metabolism and lipid/glucose homeostasis, our current work is expected to help better understand the multi-target features of this PGD2 metabolite in biological pathways, and 15d-PGJ2 as a new discovered FXR antagonist might find its potential application in further anti-hypercholesterol research.

Suppressive effects of antimycotics on thymic stromal lymphopoietin production in human keratinocytes

BackgroundThymic stromal lymphopoietin (TSLP) is produced by epidermal keratinocytes, and it induces Th2-mediated inflammation. TSLP expression is enhanced in lesions with atopic dermatitis, and is a therapeutic target. Antimycotic agents improve the symptoms of atopic dermatitis. ObjectiveThe objective of this study was to examine whether antimycotics suppress TSLP expression in human keratinocytes. MethodsNormal human keratinocytes were incubated with polyinosinic–polycytidylic acid (poly I:C) plus IL-4 in the presence of antimycotics. TSLP expression was analyzed by ELISA and real time PCR. Luciferase assays were performed to analyze NF-κB activity. IκBα degradation was analyzed by Western blot analysis. ResultsPoly I:C plus IL-4 increased the secretion and mRNA levels of TSLP, which was suppressed by an NF-κB inhibitor, and also enhanced NF-κB transcriptional activities and induced the degradation of IκBα in keratinocytes. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine suppressed the secretion and mRNA expression of TSLP, NF-κB activity, and IκBα degradation induced by poly I:C plus IL-4. These suppressive effects were similarly manifested by 15-deoxy-Δ-12,14-PGJ2 (15d-PGJ2), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes and decreased the release of thromboxane B2, a thromboxane A2 metabolite. Antimycotic-induced suppression of TSLP production and NF-κB activity was counteracted by an inhibitor of lipocalin type-prostaglandin D synthase. ConclusionsAntimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine may suppress poly I:C plus IL-4-induced production of TSLP by inhibiting NF-κB via increasing 15d-PGJ2 production in keratinocytes. These antimycotics may block the overexpression of TSLP in lesions with atopic dermatitis.

A prostaglandin D2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old

BackgroundDuchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by muscle dystrophin deficiency. Downstream of the primary dystrophin deficiency is not well elucidated. Here, the hypothesis that prostaglandin D2 (PGD2)-mediated inflammation is involved in the pathology of DMD was examined by measuring tetranor PGDM, a major PGD2 metabolite, in urine of DMD patients. MethodsWe measured tetranor PGDM in urine using LC–MS/MS. First morning urine samples were collected from genetically confirmed DMD patients and age-matched healthy controls aged 4 to 15y. ResultsThe urinary tetranor PGDM concentration was 3.08±0.15 and 6.90±0.35ng/mg creatinine (mean±SE) in 79 control and 191 DMD samples, respectively. The mean concentration was approximately 2.2-times higher in DMD patients than in controls (p<0.05). Remarkably, urinary tetranor PGDM concentrations in DMD patients showed chronological changes: it stayed nearly 1.5 times higher than in controls until 7y but surged at the age of 8y to a significantly higher concentration. ConclusionUrinary tetranor PGDM concentrations were shown to be increased in DMD patients and became higher with advancing age. It was indicated that PGD2-mediated inflammation plays a role in the pathology of DMD.

Abstract 3995: Antitumor effect of prostaglandin D2 by peroxisome proliferator-activated receptor gamma (PPARγ)-dependent pathway in gastric carcinoma.

Abstract Introduction: Prostaglandin D2 (PGD2) has been demonstrated to have not only physiological responses but also anti-tumor effects against some types of cancer cells such as a lung cancer. PGD2 act through two major receptors, DP1 and DP2 of chemoattractant receptor-like molecule on the Th2 cell. Recently, some papers reported that PGD2 may act through PPARγ, suggesting that the effects of PGD2 are involved in either PGD2 dependent or independent pathway. PGD2 metabolite, 15-deoxy-Δ12 14-PGJ2, activates peroxisome proliferator-activated receptor γ (PPARγ) which induces growth inhibition of various cells. PPARγ is expressed in various types of cancers including gastric cancer. Since the role of PGD2 on gastric cancer cells is still unknown, this study is aimed to investigate the effect of PGD2 signalings on the proliferation of gastric cancer cells. Materials and Methods: Three human gastric cancer cell lines, OCUM-2M, OCUM-12, and MKN-74, were used. Effect of PGD2 or PPARγ antagonist on the proliferation of cancer cells was examined by MTT assay. The expression level of PGD2 receptor, DP1 and DP2, and PPARγ of gastric cancer cells was examined by RT-PCR. The effect of PGD2 on cell cycle was examined with PI staining by flowcytometry. Results: PGD2 significantly decreased the proliferation of OCUM-2M and MKN-74 cells at a dose-dependent manner, but not that of OCUM-12. PGD2 receptors, DP1 and DP2, were not expressed in 3 gastric cancer cell lines while PPARγ was expressed in OCUM-2M and MKN-74. BADGE, a PPARγ antagonist, significantly suppressed the growth-inhibitory effects of PGD2 on OCUM-2M and MKN-74 cells. PGD2 increased G0/G1 phase of cancer and decereased G2/M phase. Conclusion: PGD2 decreased the proliferation of gastric cancer cells through PPARγ dependent pathway. PGD2 might be a promising therapeutic agent for gastric cancer with PPARγ expression. Citation Format: Tatsunari Fukuoka, Masakazu Yashiro, Hiroshi Takeda, Takayuki Maruyama, Haruhito Kinoshita, Tamammi Morisaki, Tsuyoshi Hasegawa, Toshiki Hirakawa, Naoki Aomatsu, Katsunobu Sakurai, Kenjiro Kimura, Hisashi Nagahara, Takahiro Toyokawa, Ryosuke Amano, Eiji Noda, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Hiroshi Otani, Kiyoshi Maeda, Masaichi Ohira, Kosei Hirakawa. Antitumor effect of prostaglandin D2 by peroxisome proliferator-activated receptor gamma (PPARγ)-dependent pathway in gastric carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3995. doi:10.1158/1538-7445.AM2013-3995

Type 1 Regulatory T Cells and Regulatory B Cells Induced by Tolerogenic Dendritic Cells

Dendritic cells (DC) are professional antigen-presenting cells that are capable of both activating immune responses and inducing tolerance. Several studies have revealed efficiency of therapeutic vaccination with tolerogenic DC (tolDC) in inhibition of experimental autoimmunity. The purpose of this study was to compare four different protocols for generation of tolDC - the antidiabetic drug troglitazone (TGZ DC), NF-κB inhibitor BAY 11-7082 (BAY DC), prostaglandin D2 metabolite 15d-PGJ2 (PGJ DC) and a combination of dexamethasone and 1α,25-dihydroxyvitamin D3 (DexVD3 DC) regarding phenotype, cytokine production and T cell stimulatory capacity. TGZ DC and BAY DC had a phenotype comparable to immature DC, while DexVD3 DC were more macrophage like. Analysis of cytokine production using cell culture supernatants from all DC populations revealed that DexVD3 DC were efficient producers of IL-10 and produced less pro-inflammatory cytokines. T cells primed with DexVD3 DC showed reduced proliferation, and further analyses of these T cells revealed that functionally effective type 1 regulatory T cells (Tr1) but not FoxP3(+) Treg were induced. Furthermore, DexVD3 DC promoted the induction of regulatory B cells (Breg). Together, these results indicate that DexVD3 DC have the best potential to be used in a tolerogenic antigen-presenting cell-based immunotherapy setting.

Peroxisome Proliferator-activated Receptor γ Agonists Induce Cell Cycle Arrest through Transcriptional Regulation of Krüppel-like Factor 4 (KLF4)

Peroxisome proliferator-activated receptor γ (PPARγ), a subgroup of ligand-activated nuclear receptors, plays critical roles in cell cycle regulation, differentiation, apoptosis, and invasion. PPARγ is involved in tumorigenesis and is a potent target for cancer therapy. PPARγ transactivation of KLF4 has been demonstrated in various studies; however, how PPARγ regulates KLF4 expression is not clear. In this study, we reveal that PPARγ regulates the expression of KLF4 by binding directly to the PPAR response element (PPRE) within the KLF4 promoter. The PPRE resides at -1657 to -1669 bp upstream of the KLF4 ATG codon, which is essential for the transactivation of troglitazone-induced KLF4 expression. Furthermore, we found that stable silencing of KLF4 obviously suppressed the G(1)/S arrest and anti-proliferation effects induced by PPARγ ligands. Taken together, our data indicate that up-regulation of KLF4 upon PPARγ activation is mediated through the PPRE in the KLF4 promoter, thus providing further insights into the PPARγ signal transduction pathway as well as a novel cancer therapeutic strategy.

Increased Generation of Cyclopentenone Prostaglandins after Brain Ischemia and Their Role in Aggregation of Ubiquitinated Proteins in Neurons

The cyclopentenone prostaglandin (CyPG) J₂ series, including prostaglandin J₂ (PGJ₂), Δ¹²-PGJ₂, and 15-deoxy-∆¹²,¹⁴-prostaglandin J₂ (15d-PGJ₂), are active metabolites of PGD₂, exerting multiple effects on neuronal function. However, the physiologic relevance of these effects remains uncertain as brain concentrations of CyPGs have not been precisely determined. In this study, we found that free PGD₂ and the J₂ series CyPGs (PGJ₂, Δ¹²-PGJ₂, and 15d-PGJ₂) were increased in post-ischemic rat brain as detected by UPLC-MS/MS with 15d-PGJ₂ being the most abundant CyPG. These increases were attenuated by pre-treating with the cyclooxygenase (COX) inhibitor piroxicam. Next, effects of chronic exposure to 15d-PGJ₂ were examined by treating primary neurons with 15d-PGJ₂, CAY10410 (a 15d-PGJ₂ analog lacking the cyclopentenone ring structure), or vehicle for 24 to 96 h. Because we found that the concentration of free 15d-PGJ₂ decreased rapidly in cell culture medium, freshly prepared medium containing 15d-PGJ₂, CAY10410, or vehicle was changed twice daily to maintain steady extracellular concentrations. Incubation with 2.5 μM 15d-PGJ₂, but not CAY10410, increased the neuronal cell death without the induction of caspase-3 or PARP cleavage, consistent with a primarily necrotic mechanism for 15d-PGJ₂-induced cell death which was further supported by TUNEL assay results. Ubiquitinated protein accumulation and aggregation was observed after 96 h 15d-PGJ₂ incubation, accompanied by compromised 20S proteasome activity. Unlike another proteasome inhibitor, MG132, 15d-PGJ₂ treatment did not activate autophagy or induce aggresome formation. Therefore, the cumulative cytotoxic effects of increased generation of CyPGs after stroke may contribute to delayed post-ischemic neuronal injury.

Adult urticaria pigmentosa with transitory disappearance of lesions during enoxaparinum treatment

Lab A complete blood count, basic metabolic profile, hepatic and lipid panels were within normal limits and we excluded systemic involvement. A bone density study showed osteoporosis. Serum tryptase levels, 24 hour urinary N-methylhistamine, N-methylimidazoleacetic acid and prostaglandin D2 metabolites excretion werewithin normal limits. Skin biopsy cofirmed the diagnosis of generalized cutaneous mastocytosis (Urticaria pigmentosa) (Fig. 2A-D). The patient left the Dermatology Unit with no medication, but she called us, a few weeks later for a new appointment. She described and we confirmed the dissapearance of the cutaneous lesions during the last weeks, while she was hospitalised for a hip fracture and treated with Enoxaparinum 40mg s.c/daily for 14 days. The patient refused a new biopsy and we saw her again three months later, she again showed the characteristic brownishred skin lesions of Urticaria pigmentosa, exactly as at the first appointment. The lesions had begun to appear very soon after she had stopped taking Enoxaparinum (Fig. 3). ADULT URTICARIA PIGMENTOSA WITH TRANSITORY DISAPPEARANCE OF LESIONS DURING ENOXAPARINUM TREATMENT

PGJ2 Provides Prolonged CNS Stroke Protection by Reducing White Matter Edema

Few clinically effective approaches reduce CNS-white matter injury. After early in-vivo white matter infarct, NFκB-driven pro-inflammatory signals can amplify a relatively small amount of vascular damage, resulting in progressive endothelial dysfunction to create a severe ischemic lesion. This process can be minimized by 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), an analog of the metabolically active PGD2 metabolite. We evaluated PGJ2's effects and mechanisms using rodent anterior ischemic optic neuropathy (rAION); an in vivo white matter ischemia model. PGJ2 administration systemically administered either acutely or 5 hours post-insult results in significant neuroprotection, with stereologic evaluation showing improved neuronal survival 30 days post-infarct. Quantitative capillary vascular analysis reveals that PGJ2 improves perfusion at 1 day post-infarct by reducing tissue edema. Our results suggest that PGJ2 acts by reducing NFκB signaling through preventing p65 nuclear localization and inhibiting inflammatory gene expression. Importantly, PGJ2 showed no in vivo toxicity structurally as measured by optic nerve (ON) myelin thickness, functionally by ON-compound action potentials, on a cellular basis by oligodendrocyte precursor survival or changes in ON-myelin gene expression. PGJ2 may be a clinically useful neuroprotective agent for ON and other CNS infarcts involving white matter, with mechanisms of action enabling effective treatment beyond the currently considered maximal time for intervention.

Systemic reactions to allergen immunotherapy: A role for measuring a PGD2 metabolite?

Systemic reactions to allergen immunotherapy: A role for measuring a PGD2 metabolite?

Activation of adipogenesis by lipocalin-type prostaglandin D synthase-generated Δ12-PGJ2 acting through PPARγ-dependent and independent pathways

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS)-produced PGD2 accelerates adipogenesis. In this study, we investigated the molecular mechanism of PGD2-mediated activation of adipogenesis in mouse adipocytic 3T3-L1 cells. LC/MS analysis showed that Δ12-PGJ2, one of the PGD2 metabolites, was predominantly produced in the differentiated 3T3-L1 cells. Δ12-PGJ2 enhanced the expression of adipogenic genes in a Δ12-PGJ2-concentration-dependent manner. Suppression of the expression of the adipogenic genes by L-PGDS siRNA or AT-56, an L-PGDS inhibitor, was cleared by the addition of Δ12-PGJ2. Moreover, the production of adiponectin and leptin was increased by treatment with Δ12-PGJ2. Furthermore, the results of a mammalian two-hybrid assay demonstrated that Δ12-PGJ2 enhanced the PPARγ-mediated transcription activity. However, Δ12-PGJ2-activated expression of adipogenic genes such as fatty acid binding protein 4 (aP2) and stearoyl-CoA desaturase was inhibited only at 38% and 42%, respectively, by treatment with GW9662, a PPARγ antagonist in 3T3-L1 cells, although Troglitazone-mediated activation of the expression of these adipogenic genes was completely suppressed by GW9662, suggesting the existence of a PPARγ-independent mechanism for Δ12-PGJ2-activated adipogenesis. These results, taken together, indicate that Δ12-PGJ2 is a dominant metabolite of L-PGDS-produced PGD2 during adipogenesis and acts as an activator for adipogenesis through both PPARγ-dependent and -independent mechanisms in 3T3-L1 cells.

Long-term CFTR inhibition modulates 15d-prostaglandin J2 in human pulmonary cells

Prostaglandins, the products of arachidonic acid release and oxidation by phospholipase A2 and cyclooxygenases (COX) 1 and 2 respectively, are known as important inflammation mediators. However, their diversity in structure, properties and cell specificity make their physiological function difficult to define. In the lung, the prostaglandin D2 (PGD2) metabolite 15d-PGJ2 is known to modulate the properties of a large number of intracellular compounds, leading to both pro- and anti-inflammatory effects. In the lung, the serous sub-mucosal glands, that strongly express CFTR (cystic fibrosis transmembrane conductance regulator), play an important role in the defence against inflammation, and their derivatives Calu-3 cells are largely used in in vitro experiments. The present study was undertaken to determine whether the PGD synthase-PGD2-15d-PGJ2 pathway is active in Calu-3 cells, and whether its activity requires a functional CFTR. Both cellular and released PGD2 and 15d-PGJ2 were measured in cells treated with CFTR inhibitors and stimulated or not with inflammatory IL-1β. Pretreatment with either CFTRinh172 or GlyH101 inhibitors decreased the basal cell content of both prostaglandins, and so did acute stimulation with IL-1β, but the latter was dramatically reversed in CFTRinh172-treated cells. CFTRinh172 also altered the release of inflammation mediators PGE2 and IL-8, and this effect was blunted by exogenous 15d-PGJ2. CFTRinh172-induced modulation of 15d-PGJ2 cellular content was not detected in CFTR-silenced Calu-3 cells, but it was reproduced in pulmonary CFBE41o-cells, which express F508del-CFTR. These results show that cellular 15d-PGJ2 production, which controls PGE2 and IL-8 release, is disturbed by CFTR dysfunction. In Calu-3 cells, 15d-PGJ2 production resulted from COX-2-regulated COX-1 activation, while CFTRinh172-induced alteration of 15d-PGJ2 synthesis involved both decreased expression of PGD synthase and disturbed relationships between both COXs. CFTR-mediated regulation of PGD synthase-PGD2-15d-PGJ2 pathway and cellular 15d-PGJ2 effects may involve a large number of molecular reactive pathways. Their exploration should help understand the development of CF inflammation and might bring new perspectives in its treatment.

Measurement of Bronchoconstrictive Eicosanoids in Chronic Obstructive Pulmonary Disease

The aim of the study was the evaluation of the concentration of 9α11β prostaglandin F(2) - a stable metabolite of prostaglandin D(2) (PGD(2)) and leukotriene E(4) (LTE(4)) in stable and exacerbated COPD patients. 29 COPD patients aged 73 ± 8.34, mean FEV1 = 48.64 ± 15.75% of predictive value and 29 healthy controls aged 57.48 ± 10.86, mean FEV1 = 97.17 ± 13.81% of predictive value participated in this study. Samples of urine and blood were taken from COPD patients during exacerbation and in stable state of the disease; LTE(4) was determined in urine using commercial enzyme immunoassay (EIA) and 9α11β prostaglandin F(2) (9α11βPGF(2)) - stable metabolite of PGD(2) was evaluated in blood and urine using GC/MS. LTE(4) concentration in urine (677.15 vs. 436.4 pg/mg of creatinine; p = 0.035) and 9α11βPGF(2) in blood serum (5.35 vs. 3.07 pg/ml; p = 0.007) were significantly higher in exacerbated COPD patients than in control group. There was no difference in LTE(4) level in urine and 9α11βPGF2 in blood serum between exacerbated and stable COPD. The urinary 9α11βPGF(2) concentration did not differ between all studied groups. We found a positive correlation between smoking history and the urine LTE(4) level (r = 0.395; p = 0.002) as well as blood 9α11βPGF(2) concentration (r = 0.603; p = 0.001) in COPD patients. 9α11βPGF(2) and LTE(4) level in urine did not differ between the stable COPD group and the control group. We also did not find any difference between LTE4 level in urine and 9α11βPGF(2) in blood and urine between exacerbated and stable COPD. Finally, LTE(4) concentration in urine and 9α11βPGF(2) in blood occurred to be significantly higher in exacerbated COPD patients than in control group.

Urinary tetranor-PGDM concentrations in aspirin-intolerant asthma and anaphylaxis

Urinary tetranor-PGDM concentrations in aspirin-intolerant asthma and anaphylaxis

Tetranor PGDM analyses for the amyotrophic lateral sclerosis: Positive and simple diagnosis and evaluation of drug effect

Amyotrophic lateral sclerosis (ALS) is a late-onset, progressive motor neuronal degenerative disease occurring as sporadically and as a familial disorder. The patients with ALS typically become progressively paralyzed and develop respiratory failure that eventually leads to death within 3–5 years. For this disease, there is no effective diagnostic method and also drug. This report describes a simple and useful diagnostic biomarker for ALS. Our findings suggest that the combination analysis of a metabolite of prostaglandin D2, 11,15-dioxo-9-hydroxy-,2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM and tPGDM) with creatinine is the diagnostic approach for ALS with high accuracy. tPGDM has the potential to be an important diagnostic tool in the pre-symptomatic stages and progression evaluation of ALS, and also to be a biomarker for the evaluation of drug effect.

Induction of apoptosis in non-small cell lung carcinoma A549 cells by PGD2metabolite, 15d-PGJ2

PGD2 (prostaglandin D2) is a mediator in various pathophysiological processes, including inflammation and tumorigenesis. PGD2 can be converted into active metabolites and is known to activate two distinct receptors, DP (PGD2 receptor) and CRTH2/DP2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). In the past, PGD2 was thought to be involved principally in the process of inflammation. However, in recent years, several studies have shown that PGD2 has anti-proliferative ability against tumorigenesis and can induce cellular apoptosis via activation of the caspase-dependent pathway in human colorectal cancer cells, leukaemia cells and eosinophils. In the lung, where PGD2 is highly released when sensitized mast cells are challenged with allergen, the mechanism of PGD2-induced apoptosis is unclear. In the present study, A549 cells, a type of NSCLC (non-small cell lung carcinoma), were treated with PGD2 under various conditions, including while blocking DP and CRTH2/DP2 with the selective antagonists BWA868C and ramatroban respectively. We report here that PGD2 induces A549 cell death through the intrinsic apoptotic pathway, although the process does not appear to involve either DP or CRTH2/DP2. Similar results were also found with H2199 cells, another type of NSCLC. We found that PGD2 metabolites induce apoptosis effectively and that 15d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2) is a likely candidate for the principal apoptotic inducer in PGD2-induced apoptosis in NSCLC A549 cells.

Induction of apoptosis in non-small cell lung carcinoma A549 cells by PGD2metabolite, 15d-PGJ2

PGD2 (prostaglandin D2) is a mediator in various pathophysiological processes, including inflammation and tumorigenesis. PGD2 can be converted into active metabolites and is known to activate two distinct receptors, DP (PGD2 receptor) and CRTH2/DP2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). In the past, PGD2 was thought to be involved principally in the process of inflammation. However, in recent years, several studies have shown that PGD2 has anti-proliferative ability against tumorigenesis and can induce cellular apoptosis via activation of the caspase-dependent pathway in human colorectal cancer cells, leukaemia cells and eosinophils. In the lung, where PGD2 is highly released when sensitized mast cells are challenged with allergen, the mechanism of PGD2-induced apoptosis is unclear. In the present study, A549 cells, a type of NSCLC (non-small cell lung carcinoma), were treated with PGD2 under various conditions, including while blocking DP and CRTH2/DP2 with the selective antagonists BWA868C and ramatroban respectively. We report here that PGD2 induces A549 cell death through the intrinsic apoptotic pathway, although the process does not appear to involve either DP or CRTH2/DP2. Similar results were also found with H2199 cells, another type of NSCLC. We found that PGD2 metabolites induce apoptosis effectively and that 15d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2) is a likely candidate for the principal apoptotic inducer in PGD2-induced apoptosis in NSCLC A549 cells.