College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
Toxicol Appl Pharmacol. 2012 Jul 1;262(1):91-8. doi: 10.1016/j.taap.2012.04.025. Epub 2012 Apr 27.
Withaferin A (WFA), an active compound from Withania somnifera, is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In this study, we first investigated the possible barrier protective effects of WFA against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice induced by high mobility group box 1 protein (HMGB1) and the associated signaling pathways. The barrier protective activities of WFA were determined by measuring permeability, leukocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs. We found that WFA inhibited lipopolysaccharide (LPS)-induced HMGB1 release and HMGB1-mediated barrier disruption, expression of cell adhesion molecules (CAMs) and adhesion/transendothelial migration of leukocytes to human endothelial cells. WFA also suppressed acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocytes migration in vivo. Further studies revealed that WFA suppressed the production of interleukin 6, tumor necrosis factor-α (TNF-α) and activation of nuclear factor-κB (NF-κB) by HMGB1. Collectively, these results suggest that WFA protects vascular barrier integrity by inhibiting hyperpermeability, expression of CAMs, adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.
铁皮石斛中的活性化合物醉茄素 A（WFA）具有抗炎、心脏活性和中枢神经系统作用，因此被广泛研究。在这项研究中，我们首次研究了 WFA 对高迁移率族蛋白 B1（HMGB1）诱导的人脐静脉内皮细胞（HUVEC）和小鼠产生的促炎反应的可能屏障保护作用，以及相关的信号通路。通过测量 HMGB1 激活的 HUVEC 中通透性、白细胞黏附和迁移以及促炎蛋白的激活来确定 WFA 的屏障保护活性。结果发现，WFA 抑制了脂多糖（LPS）诱导的 HMGB1 释放和 HMGB1 介导的屏障破坏、细胞黏附分子（CAM）的表达以及白细胞向人内皮细胞的黏附和跨内皮迁移。WFA 还抑制了体内乙酸诱导的高通透性和羧甲基纤维素诱导的白细胞迁移。进一步的研究表明，WFA 抑制了 HMGB1 产生白细胞介素 6、肿瘤坏死因子-α（TNF-α）和核因子-κB（NF-κB）的激活。总之，这些结果表明，WFA 通过抑制通透性、CAM 的表达、白细胞的黏附和迁移来保护血管屏障的完整性，因此可将其作为治疗血管炎症性疾病的一种方法。
