Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Institute of Agricultural Biology and Biotechnology, CNR, Pisa, Italy.
PLoS One. 2018 Sep 25;13(9):e0204336. doi: 10.1371/journal.pone.0204336. eCollection 2018.
Glucocorticoids (GCs) are currently used for the therapeutic management of cholestatic diseases, but their use and molecular mechanism remain controversial. The aims of this study were 1) to assess the therapeutic effect of a 2-week treatment with the GC dexamethasone on hepatic damage in bile duct-ligated rats; 2) to investigate its effect on the activation of the nuclear receptors (NRs) pregnane X receptor (PXR), constitutive androstane receptor (CAR) and GC receptor (GR), and NF-kB, as well as on oxidative stress and bile acid (BA) hepatic composition. Cholestasis was induced by ligation of bile duct (BDL animals) in 16 male Wistar-Kyoto rats, and eight of them were daily treated by oral gavage with 0.125 mg/ml/kg DEX for 14 days. Eight Sham-operated rats were used as controls. Severity of cholestasis was assessed histologically and on plasma biochemical parameters. The nuclear expression of NF-kB (p65), GR, PXR and CAR was measured in hepatic tissue by Western Blot. Oxidative stress was evaluated by measuring malondialdehyde, carbonylated proteins, GHS and ROS content in rat livers. LC-MS was used to measure the plasma and liver concentration of 7 BAs. Histological findings and a significant drop in several markers of inflammation (p65 nuclear translocation, mRNA expressions of TNF-α, IL-1β, IL-6) showed that DEX treatment reversed cholestasis-induced inflammation, and similar results have been obtained with oxidative stress markers. The nuclear expression of p65 and CAR were inversely correlated, with the latter increasing significantly after DEX treatment (p<0.01 vs vehicle). Hepatic BA levels tended to drop in the untreated cholestatic rats, whereas they were similar to those of healthy rats in DEX-treated animals. Plasma BAs decreased significantly in DEX-treated animals with respect to untreated cholestatic rats. In conclusion, DEX reduces inflammation and oxidative stress in BDL rats, and probably CAR is responsible for this effect. Therefore, this NR represents a promising pharmacological target for managing cholestatic and inflammatory liver diseases.
糖皮质激素（GCs）目前被用于治疗胆汁淤积性疾病，但它们的使用和分子机制仍存在争议。本研究的目的是：1）评估 2 周治疗用 GC 地塞米松对胆管结扎大鼠肝损伤的治疗效果；2）研究其对核受体（NRs）孕烷 X 受体（PXR）、组成型雄烷受体（CAR）和 GC 受体（GR）以及 NF-kB 的激活作用，以及对氧化应激和胆汁酸（BA）肝组成的影响。通过结扎胆管（BDL 动物）诱导胆汁淤积，16 只雄性 Wistar-Kyoto 大鼠中 8 只每天通过口服灌胃接受 0.125mg/ml/kg DEX 治疗 14 天。8 只假手术对照大鼠作为对照组。通过组织学和血浆生化参数评估胆汁淤积的严重程度。通过 Western Blot 测量肝组织中 NF-kB（p65）、GR、PXR 和 CAR 的核表达。通过测量大鼠肝脏中丙二醛、羰基蛋白、GSH 和 ROS 含量来评估氧化应激。LC-MS 用于测量血浆和肝脏中 7 种 BA 的浓度。组织学发现和几种炎症标志物（p65 核易位、TNF-α、IL-1β、IL-6mRNA 表达）显著下降表明，DEX 治疗逆转了胆汁淤积诱导的炎症，并且氧化应激标志物也得到了类似的结果。p65 和 CAR 的核表达呈负相关，DEX 治疗后后者显著增加（p<0.01 与载体相比）。未经治疗的胆汁淤积大鼠肝 BA 水平趋于下降，而 DEX 治疗动物的 BA 水平与健康大鼠相似。与未经治疗的胆汁淤积大鼠相比，DEX 治疗动物的血浆 BA 水平显著下降。总之，DEX 可减轻 BDL 大鼠的炎症和氧化应激，可能是 CAR 介导了这种作用。因此，这种 NR 可能是治疗胆汁淤积性和炎症性肝病的有前途的药理靶点。
