Lung adenocarcinoma (LUADC) belongs to the most prevalent and lethal cancer types. As 15-deoxy-Δ12,14-prostaglandin J₂ (15d-PGJ₂) displays anti-oxidative, -inflammatory, and -cancer properties, we investigated whether this cyclopentenone PG, a stable degradation end-product of cyclooxygenase-generated PGD₂, exerts beneficial effects in three LUADC cell lines (A549, H1299, H23). We here report that 15d-PGJ₂ had substantial cytotoxic effects in all three LUADC cell lines by promoting early apoptosis and inhibiting the cell cycle, proliferation, and migration. As indicators of cell malignancy, scratch closure and colony formation were significantly inhibited by 15d-PGJ₂. 15d-PGJ₂ induced generation of ROS and subsequent activation of MAPKs. Expression of Nrf-2, a well-known tumor driver, was markedly diminished by 15d-PGJ₂ treatment. Although PPARγ, DP1, and DP2 are expressed in LUADC cells, blocking these receptors with specific inhibitors (SR16832 and BW245C) did not reverse 15d-PGJ₂-mediated cytotoxicity, suggesting receptor-independent effects. 15d-PGJ₂ decreased SIRT1 expression in LUADC cells and the knockdown of SIRT1 diminished the cytotoxic effects of 15d-PGJ₂. Importantly, 15d-PGJ₂ significantly reduced tumor growth using the chorioallantoic membrane (CAM) assay. The structural analog of 15d- PGJ₂, 9,10-dihydro-15d-PGJ₂ (lacking the α,β-unsaturated ketone structural element), did not show any toxic effects in LUADC cells. Altogether, our findings suggest that 15d-PGJ₂ led to significantly reduced tumor growth and cell proliferation in three LUADC cell lines. The CAM assay results suggest that 15d-PGJ₂ is a suitable endogenous compound to interfere with LUADC tumor progression. We show that SIRT1 modulates the effects of 15d-PGJ₂ and may be used as a therapeutic target for LUADC.

2023-01-01·Frontiers in immunology

Enhancement of prostaglandin D₂-D prostanoid 1 signaling reduces intestinal permeability by stimulating mucus secretion.

Article

作者: Sakamoto, Naoaki ; Hayashi, Akane ; Kobayashi, Koji ; Murata, Takahisa

IntroductionThe intestinal barrier plays a crucial role in distinguishing foods from toxins. Prostaglandin D₂ (PGD₂) is one of the lipid-derived autacoids synthesized from cell membrane-derived arachidonic acid. We previously reported that pharmacological stimulation of PGD₂ receptor, D prostanoid 1 (DP1) attenuated the symptoms of azoxymethane/dextran sodium sulfate-induced colitis and ovalbumin-induced food allergy in mouse models. These observations suggested that DP1 stimulation protects the intestinal barrier. The present study aimed to uncover the effects of DP1 stimulation on intestinal barrier function and elucidate the underlying mechanisms.Materials and methodsIntestinal permeability was assessed in mice by measuring the transfer of orally administered fluorescein isothiocyanate-dextran (40 kDa) into the blood. The DP1 agonist BW245C (1 mg/kg) was administered 10 min prior to dextran administration. The intestinal permeability was confirmed using the ex vivo everted sac method. Tight junction integrity was evaluated in vitro by measuring the transepithelial electrical resistance (TER) in the human intestinal epithelial cell line Caco-2. Mucus secretion was assessed by observing Alcian Blue-stained intestinal sections.ResultsPharmacological DP1 stimulation reduced intestinal permeability both in vivo and ex vivo. Immunohistochemical staining showed that DP1 was strongly expressed on the apical side of the epithelial cells. DP1 stimulation did not affect TER in vitro but induced mucus secretion from goblet cells. Mucus removal by a mucolytic agent N-acetyl-l-cysteine canceled the inhibition of intestinal permeability by DP1 stimulation.ConclusionThese observations suggest that pharmacological DP1 stimulation decreases intestinal permeability by stimulating mucus secretion.

2021-07-01·Mucosal Immunology1区 · 医学

DP1 prostanoid receptor activation increases the severity of an acute lower respiratory viral infection in mice via TNF-α-induced immunopathology

1区 · 医学

Article

作者: Li, Jia ; Rittchen, Sonja ; Hasnain, Sumaira Z ; Ullah, Md Ashik ; Phipps, Simon

Respiratory syncytial virus (RSV) bronchiolitis is a leading cause of infant hospitalization and mortality. We previously identified that prostaglandin D2 (PGD2), released following RSV infection of primary human airway epithelial cells or pneumonia virus of mice (PVM) infection of neonatal mice, elicits pro- or antiviral innate immune responses as a consequence of D-type prostanoid receptor 2 (DP2) or DP1 activation, respectively. Here, we sought to determine whether treatment with the DP1 agonist BW245c decreases the severity of bronchiolitis in PVM-infected neonatal mice. Consistent with previous findings, BW245c treatment increased IFN-λ production and decreased viral load in week 1 of the infection. However, unexpectedly, BW245c treatment increased mortality in week 2 of the infection. This increased morbidity was associated with viral spread to the parenchyma, an increased cellular infiltrate of TNF-α-producing cells (neutrophils, monocytes, and CD4⁺ T cells), and the heightened production of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. These phenotypes, as well as the increased mortality, were significantly attenuated following the administration of anti-TNF-α to PVM-infected, BW245c-treated mice. In summary, pharmacological activation of the DP1 receptor in PVM-infected neonatal mice boosts antiviral innate and adaptive immunity, however, this is ultimately detrimental, as a consequence of increased TNF-α-induced morbidity and mortality.

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适应症	最高研发状态	国家/地区	公司	日期
冠心病	临床1期	-	GSK Plc	-
冠状动脉疾病	临床1期	英国	GSK Plc	-
血栓形成	临床1期	英国	GSK Plc	-
脑卒中	临床前	美国	University of Florida	2014-02-01
高眼压症	临床前	-	Alcon AG	2002-06-01