Role of prostaglandin E receptor subtypes EP2 and EP4 in autocrine and paracrine functions of vascular endothelial growth factor in the inner ear

<p>Abstract</p> <p>Background</p> <p>The physiological effects of prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) are mediated by the prostaglandin E receptor subtypes EP1, EP2, EP3, and EP4, and the respective agonists have been purified. PGE1 and PGE2 can increase the production of vascular endothelial growth factor (VEGF), particularly through EP2 and EP4. The biological effects of VEGF are mediated by the phosphotyrosine kinase receptors fms-related tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1). Here we examined the effects of EP2 and EP4 agonists on the production of VEGF proteins and <it>VEGF </it>messenger RNAs (mRNAs) in the inner ear, using an enzyme-linked immunosorbent assay and the real-time quantitative reverse transcription-polymerase chain reaction, respectively. We also examined the localization of EP2, VEGF, Flt-1, and Flk-1 in the cochlea by immunohistochemistry.</p> <p>Results</p> <p>The expression of EP2 occurred in the cochlea, and the local application of an EP2 or EP4 agonist increased VEGF protein and <it>VEGF </it>mRNA levels in the inner ear. Furthermore, the intensity of the VEGF immunoreactivity in the spiral ganglion appeared to be increased by the local EP2 or EP4 agonist treatment. Immunoreactivity for Flt-1, and Flk-1 was found in the cochlear sensory epithelium, spiral ganglion, spiral ligament, and stria vascularis.</p> <p>Conclusions</p> <p>These findings demonstrate that EP2 and EP4 agonists stimulate VEGF production in the inner ear, particularly in the spiral ganglions. Moreover, the Flt-1 and Flk-1 expression observed in the present study suggests that VEGF has autocrine and paracrine actions in the cochlea. Thus, EP2 and EP4 might be involved in the mechanisms underlying the therapeutic effects of PGE1 on acute sensorineural hearing loss via VEGF production.</p

Методика використання фізичних задач в курсі охорона праці

(uk) У статті розкривається важливість розв’язання фізичних задач в курсі охорона праці. Використання фізичних задач забезпечить повноцінне засвоєння навчального матеріалу з курсу.(en) In the article importance of of physicaltasks opens up in a course labour protection. The use of physical tasks will provide the valuable mastering of educational material from a course

プロスタグランディンＥ受容体サブタイプEP4作動薬は音響外傷に対し蝸牛を保護する

京都大学0048新制・課程博士博士(医学)甲第15206号医博第3406号新制||医||979(附属図書館)27684京都大学大学院医学研究科医学専攻(主査)教授 大森 治紀, 教授 成宮 周, 教授 河野 憲二学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Prostaglandin E receptor subtype EP4 agonist serves better to protect cochlea than prostaglandin E1.

[Objective]The present study aimed to examine whether an E-prostanoid receptor 4 (EP4) agonist has superior protective effects to those of prostaglandin E1 (PGE1) in a guinea pig model of noise trauma. [Methods]Drugs were locally applied on the round window membrane of guinea pig cochleae, followed by exposure of the test animals to intense noise. Protective effects mediated by an EP4 agonist were compared with those mediated by PGE1. Auditory function was monitored by measurements of the auditory brainstem response (ABR), and histological damage was assessed by immunohistochemical analysis of cochlear specimens. [Results]Animals treated with an EP4 agonist exhibited significantly better hearing recovery than those pretreated with PGE1. Histologically, the numbers of remaining outer hair cells in cochleae treated with the EP4 agonist were significantly higher than in those treated with PGE1. [Conclusion]The selective activation of EP4 has a stronger protective effect on cochleae against noise trauma than does the broad activation of EPs by PGE1

Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress.

Excessive reactive oxygen species (ROS) induce apoptosis and are associated with various diseases and with aging. SIRT1 (sirtuin-1), an NAD+-dependent protein deacetylase, decreases ROS levels and participates in cell survival under oxidative stress conditions. SIRT1 modulates the transcription factors p53, a tumor suppressor and inducer of apoptosis, and the forkhead O (FOXO) family, both of which play roles for cell survival and cell death. In this study, we aimed to know which is working greatly among p53 and FOXOs transcription factors in SIRT1's cell protective functions under oxidative stress conditions. The antimycin A-induced increase in ROS levels and apoptosis was enhanced by SIRT1 inhibitors nicotinamide and splitomicin, whereas it was suppressed by a SIRT1 activator, resveratrol, and a SIRT1 cofactor, NAD+. SIRT1-siRNA abolished the effects of splitomicin and resveratrol. p53-knockdown experiment in C2C12 cells and experiment using p53-deficient HCT116 cells showed that splitomicin and resveratrol modulated apoptosis by p53-dependent and p53-independent pathways. In p53-independent cell protective pathway, we found that FOXO1, FOXO3a, and FOXO4 were involved in SOD2's upregulation by resveratrol. The knockdown of these three FOXOs by siRNAs completely abolished the SOD2 induction, ROS reduction, and anti-apoptotic function of resveratrol. Our results indicate that FOXO1, FOXO3a and FOXO4, are indispensable for SIRT1-dependent cell survival against oxidative stress, although deacetylation of p53 has also some role for cell protective function of SIRT1

Numerical Analysis on the Contribution of the Singular Perturbation by the Hall Term to the Spectrum of MHD Turbulence using a Shell Model

We have developed a new shell model for the Hall magnetohydrodynamic (MHD) system to investigate the spectral properties of the plasma turbulence. Through the numerical simulation of the shell model, in the Hall MHD case, we find that the energy spectra