PDF(Pubmed)
Abstract：
Oxidative stress and epigenetic alterations, including the overexpression of all class I and II histone deacetylases (HDACs), particularly HDAC2 and HDAC4, have been identified as key molecular mechanisms driving pulmonary fibrosis. Treatment with piceatannol (PIC) or vitamin D (Vit D) has previously exhibited mitigating impacts in pulmonary fibrosis models. The present study investigated the effects of PIC, Vit D, or a combination (PIC-Vit D) on the expression of HDAC2, HDAC4, and transforming growth factor-beta (TGF-β) in the lungs; the phosphatidylinositide-3-kinase (PI3K)/AKT signaling pathway; and the antioxidant status of the lungs. The objective was to determine if the treatments had protective mechanisms against pulmonary fibrosis caused by bleomycin (BLM) in rats. Adult male albino rats were given a single intratracheal dosage of BLM (10 mg/kg) to induce pulmonary fibrosis. PIC (15 mg/kg/day, oral (p.o.)), Vit D (0.5 μg/kg/day, intraperitoneal (i.p.)), or PIC-Vit D (15 mg/kg/day, p.o. plus 0.5 μg/kg/day, i.p.) were given the day following BLM instillation and maintained for 14 days. The results showed that PIC, Vit D, and PIC-Vit D significantly improved the histopathological sections; downregulated the expression of HDAC2, HDAC4, and TGF-β in the lungs; inhibited the PI3K/AKT signaling pathway; decreased extracellular matrix (ECM) deposition including collagen type I and alpha smooth muscle actin (α-SMA); and increased the antioxidant capacity of the lungs by increasing the levels of glutathione (GSH) that had been reduced and decreasing the levels of malondialdehyde (MDA) compared with the BLM group at a p-value less than 0.05. The concomitant administration of PIC and Vit D had a synergistic impact that was greater than the impact of monotherapy with either PIC or Vit D. PIC, Vit D, and PIC-Vit D exhibited a notable protective effect through their antioxidant effects, modulation of the expression of HDAC2, HDAC4, and TGF-β in the lungs, and suppression of the PI3K/AKT signaling pathway.
摘要：
氧化应激和表观遗传改变，包括所有I类和II类组蛋白脱乙酰酶（HDACs）的过表达，特别是HDAC2和HDAC4，已被确定为驱动肺纤维化的关键分子机制。piceatannol（PIC）或维生素D（VitD）的治疗先前已在肺纤维化模型中表现出缓解作用。本研究调查了PIC的影响，维生素D,或组合（PIC-VitD）对肺中HDAC2，HDAC4和转化生长因子-β（TGF-β）的表达；磷脂酰肌醇-3-激酶（PI3K）/AKT信号通路；和肺的抗氧化状态。目的是确定治疗是否具有针对大鼠博来霉素（BLM）引起的肺纤维化的保护机制。成年雄性白化病大鼠给予单次气管内剂量的BLM（10mg/kg）以诱导肺纤维化。PIC（15mg/kg/天，口服（p.o.），维生素D(0.5μg/kg/天，腹膜内（i.p.）），或PIC-VitD(15毫克/千克/天，p.o.加0.5μg/kg/天，在BLM滴注后的第二天给予i.p.），并维持14天。结果表明,PIC,维生素D,和PIC-VitD显着改善了组织病理学切片；下调了肺中HDAC2，HDAC4和TGF-β的表达；抑制了PI3K/AKT信号通路；减少了包括I型胶原和α平滑肌肌动蛋白（α-SMA）在内的细胞外基质（ECM）沉积；通过增加谷胱甘肽（GSH）的水平而增加了肺的抗氧化能力，与丙二醛（丙二醛）的水平相比减少了0.05PIC和VitD的伴随给药具有比PIC或VitD的单一疗法的影响更大的协同影响。维生素D,PIC-VitD通过其抗氧化作用表现出显著的保护作用，调节HDAC2，HDAC4和TGF-β在肺中的表达，和抑制PI3K/AKT信号通路。
