Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.
Eur J Clin Invest. 2012 Jun;42(6):607-16. doi: 10.1111/j.1365-2362.2011.02625.x. Epub 2011 Nov 22.
We previously demonstrated that kaerophyllin, a lignan, isolated from a widely used traditional Chinese herb, Bupleurum scorzonerifolium, leading to the inhibition of hepatic stellate cells (HSCs) activation in vitro. This current study evaluated the in vivo role of kaerophyllin in protecting the liver against injury and fibrogenesis caused by thioacetamide (TAA) in rats and further explored the underlying mechanisms.
Liver fibrosis in Sprague-Dawley rats was induced by intraperitoneal injection of TAA (200 mg/kg) twice per week for 6 weeks. Animals were divided into five groups: vehicle control, TAA control, TAA + low dose kaerophyllin, TAA + high dose kaerophyllin and TAA + curcumin groups. Kaerophyllin (10 or 30 mg/kg) or curcumin (150 mg/mL) was given by gavage twice per day consecutively for 4 weeks starting 2 weeks after TAA injection. Rat HSCs were used to investigate the anti-inflammatory role of kaerophyllin against tumour necrosis factor α (TNF-α) in vitro. Peroxisome proliferator-activated receptor-γ (PPAR-γ) expression was knocked down in rat HSCs using PPAR-γ small interfering RNAs.
Kaerophyllin significantly protected liver from injury by reducing serum aspartate transaminase and alanine transaminase levels and by improving the histological architecture and fibrosis score. In addition, kaerophyllin suppressed inflammation by reducing the mRNA of TNF-α, interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) genes. In HSCs, kaerophyllin elevated PPAR-γ activity and reduced TNF-α-stimulated mRNA levels of intracellular adhesion molecule-1 (ICAM-1), MCP-1 and IL-1β genes, which were reversed by small interfering RNA knockdown of PPAR-γ gene.
Our results demonstrated that kaerophyllin protected the rat liver from TAA-caused injury and fibrogenesis by suppressing hepatic inflammation and inhibiting HSC activation, possibly through upregulation of PPAR-γ expression.
我们之前已经证明，从广泛使用的传统中药柴胡中分离出的木脂素，kaerophyllin，可抑制体外肝星状细胞（HSCs）的激活。本研究评估了 kaerophyllin 在保护大鼠肝脏免受硫代乙酰胺（TAA）引起的损伤和纤维化中的体内作用，并进一步探讨了其潜在机制。
通过每周两次腹腔注射 TAA（200mg/kg），诱导 Sprague-Dawley 大鼠肝纤维化，共 6 周。动物分为五组： vehicle 对照组、TAA 对照组、TAA+低剂量 kaerophyllin 组、TAA+高剂量 kaerophyllin 组和 TAA+姜黄素组。在 TAA 注射后 2 周开始，连续 4 周每天两次通过灌胃给予 kaerophyllin（10 或 30mg/kg）或姜黄素（150mg/mL）。在体外，使用肿瘤坏死因子-α（TNF-α）研究 kaerophyllin 对大鼠 HSCs 的抗炎作用。使用 PPAR-γ 小干扰 RNA 敲低大鼠 HSCs 中的过氧化物酶体增殖物激活受体-γ（PPAR-γ）表达。
kaerophyllin 通过降低血清天冬氨酸转氨酶和丙氨酸转氨酶水平以及改善组织学结构和纤维化评分，显著保护肝脏免受损伤。此外，kaerophyllin 通过降低 TNF-α、白细胞介素-1β（IL-1β）和单核细胞趋化蛋白-1（MCP-1）基因的 mRNA 来抑制炎症。在 HSCs 中，kaerophyllin 升高了 PPAR-γ 活性，并降低了 TNF-α 刺激的细胞间黏附分子-1（ICAM-1）、MCP-1 和 IL-1β 基因的 mRNA 水平，这些作用被 PPAR-γ 基因的小干扰 RNA 敲低所逆转。
我们的结果表明，kaerophyllin 通过抑制肝内炎症和抑制 HSC 激活来保护大鼠肝脏免受 TAA 引起的损伤和纤维化，这可能是通过上调 PPAR-γ 表达实现的。
