过氧化物酶体增殖物激活受体
一氧化氮合酶
受体
核受体
STAT蛋白
炎症
内科学
肿瘤坏死因子α
兴奋剂
内分泌学
激活剂(遗传学)
信号转导
化学
癌症研究
药理学
一氧化氮
生物
转录因子
医学
车站3
生物化学
基因
作者
Christine Linard,Olivier Grémy,Marc Benderitter
标识
DOI:10.1124/jpet.107.129122
摘要
Radiation-induced intestinal injuries, including inflammation and immune response, remain a limiting factor in the effectiveness of pelvic radiotherapy and in the patient's quality of life during and after treatment. Peroxisome proliferation-activated receptor (PPAR) agonists are now emerging as therapeutic drugs for various inflammatory diseases that are characterized by impaired PPAR expression. The purpose of this study was to investigate the profile of PPAR expression in rat colonic mucosa 3 and 7 days after abdominal gamma-irradiation (10 Gy). We tested whether irradiation-induced acute inflammatory response could be modulated pharmacologically with the antiinflammatory properties of 5-aminosalicylic acid (5-ASA) (250 mg/kg/day), which is a PPAR activator. Irradiation drastically reduced mRNA and protein levels of PPARalpha and -gamma and of the heterodimer retinoid X receptor (RXR)alpha at 3 days postirradiation. 5-ASA treatment normalized both PPARgamma and RXRalpha expression at 3 days postirradiation and PPARalpha at 7 days. By promoting PPAR expression and its nuclear translocation, 5-ASA interfered with the nuclear factor (NF)-kappaB pathway, both by reducing irradiation-induced NF-kappaB p65 translocation/activation and increasing the expression of nuclear factor-kappaB inhibitor (IkappaB) mRNA and protein. Therefore, 5-ASA prevents irradiation-induced inflammatory processes as well as expression of tumor necrosis factor alpha, monocyte chemotactic protein-1, inducible nitric-oxide synthase, and macrophage infiltration. In addition, 5-ASA restores the interferon gamma/signal transducer and activator of transcription (STAT)-1 and STAT-3 concentrations that were impaired at 3 and 7 days postirradiation and are correlated with suppressor of cytokine signaling-3 repression. Collectively, these results indicate that PPAR agonists may be effective in the prevention of inflammatory processes and immune responses during and after pelvic radiotherapy.
科研通智能强力驱动
Strongly Powered by AbleSci AI