Expression of Prostaglandin E2 Receptors in Acquired Middle Ear Cholesteatoma

OBJECTIVES: To investigate the expression of prostaglandin E2 receptor subtypes, E-prostanoid (EP) 1–4 receptors, in acquired cholesteatoma and its possible role in the pathologic process of this disorder. METHODS: Specimens of human acquired cholesteatoma were obtained from 29 patients and 19 skin biopsies of normal external auditory canal were as controls. The mRNA and protein expression of EP receptors was assessed by quantitative real-time polymerase chain reaction, immunohistochemistry and Western blot. RESULTS: In acquired cholesteatoma, EP1–EP4 receptors were mainly expressed on squamous epithelium and subepithelial infiltrated inflammatory cells. In external auditory canal skin, EP1–EP4 receptors were mainly expressed on squamous epithelium and glandular epithelium. The expression of EP4 receptor on mRNA and protein levels were significant lower in acquired cholesteatoma compared with controls. EP1–EP3 receptors had no significant difference between the experimental and control group. CONCLUSION: Low expression of EP4 may play a crucial role in the pathologic process of inflammation reaction and bone destruction in acquired cholesteatoma, but not EP1, EP2, or EP3 receptors.

Paricalcitol attenuates lipopolysaccharide-induced inflammation and apoptosis in proximal tubular cells through the prostaglandin E₂ receptor EP4

BACKGROUND: Vitamin D is considered to exert a protective effect on various renal diseases but its underlying molecular mechanism remains poorly understood. This study aimed to determine whether paricalcitol attenuates inflammation and apoptosis during lipopolysaccharide (LPS)-induced renal proximal tubular cell injury through the prostaglandin E₂ (PGE₂) receptor EP4. METHODS: Human renal tubular epithelial (HK-2) cells were pretreated with paricalcitol (2 ng/mL) for 1 hour and exposed to LPS (1 μg/mL). The effects of paricalcitol pretreatment in relation to an EP4 blockade using AH-23848 or EP4 small interfering RNA (siRNA) were investigated. RESULTS: The expression of cyclooxygenase-2, PGE₂, and EP4 were significantly increased in LPS-exposed HK-2 cells treated with paricalcitol compared with cells exposed to LPS only. Paricalcitol prevented cell death induced by LPS exposure, and the cotreatment of AH-23848 or EP4 siRNA offset these cell-protective effects. The phosphorylation and nuclear translocation of p65 nuclear factor-kappaB (NF-κB) were decreased and the phosphorylation of Akt was increased in LPS-exposed cells with paricalcitol treatment. AH-23848 or EP4 siRNA inhibited the suppressive effects of paricalcitol on p65 NF-κB nuclear translocation and the activation of Akt. The production of proinflammatory cytokines and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were attenuated by paricalcitol in LPS exposed HK-2 cells. The cotreatment with an EP4 antagonist abolished these anti-inflammatory and antiapoptotic effects. CONCLUSION: EP4 plays a pivotal role in anti-inflammatory and antiapoptotic effects through Akt and NF-κB signaling after paricalcitol pretreatment in LPS-induced renal proximal tubule cell injury.

Inhibitory effect of EP4 antagonist on bone metastasis of prostate cancer / 医学研究生学报

Objective The purpose of this study was to examine the inhibitory effect of ONO-AE3-208, an EP4 antagonist, on prostate cancer with bone metastasis in an animal model . Methods A PC3/LUC cell line was constructed by stably transfecting luciferin to prostate cancer PC 3 cells and inoculated into the left ventricle of nude mice to establish an animal model of prostate cancer with bone metastasis .After modeling , the animals in the experimental group and control groups were intraperitoneally given ONO -AE3-208 and double-distilled water, respectively, followed by examination of the metastasis loci and tumor burden by bioluminescence ima -ging and statistical analysis with survival curves . Results At 60 days after modeling , the animals in the control group exhibited sig-nificantly increased metastases and fluorescence burdens as compared with the experimental group (P<0.01), and the increase was in a time-dependent manner (P<0.01).At 60 days, the controls began to die while the experimental animals remained well alive , and at 180 days, the mice of the control group all died .The survival rate of the animals was significantly higher in the experimental group than in the control ( 13.3% vs 0%, P <0.01 ) and the median survival time remarkably longer in the former than in the latter group (162 d vs 116 d, P <0.01). Conclusion The EP4 antagonist ONO-AE3-208 inhibited the bone metastasis of prostate cancer and prolonged the survival time in the model mice .