College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China.
Intelligent Synthetic Biology Center , Daejeon 34141 , Republic of Korea.
J Agric Food Chem. 2019 Feb 6;67(5):1392-1401. doi: 10.1021/acs.jafc.8b05943. Epub 2019 Jan 24.
Our previous study has confirmed that maltol can attenuate alcohol-induced acute hepatic damage and prevent oxidative stress in mice. Therefore, maltol might have the capacity to improve thioacetamide (TAA)-induced liver fibrosis. The purpose of this work was to explore the antifibrotic efficacy and underlying mechanisms of maltol for TAA-treated mice. Progressive liver fibrosis was established with a dose-escalating protocol in which the mice received TAA intraperitoneal three times a week for a total duration of 9 weeks. The injection doses of TAA were 50 mg/kg for the first week, 100 mg/kg for the second and third weeks, and 150 mg/kg for the rest of the injections. Maltol with doses of 50 and 100 mg/kg was given by gavage after 4 weeks of intraperitoneal injection of TAA, respectively, once daily for 5 weeks. Results indicated that TAA intraperitoneal injection significantly increased serum activities of alanine aminotransferase (ALT) (52.93 ± 13.21 U/L vs 10.22 ± 3.36 U/L) and aspartate aminotransferase (AST) (67.58 ± 25.84 U/L vs 39.34 ± 3.89 U/L); these elevations were significantly diminished by pretreatment with maltol. Additionally, maltol ameliorated TAA-induced oxidative stress with attenuation in MDA ( p < 0.05 or p < 0.01) content; evident elevation in the GSH levels, GSH/GSSG ratio ( p < 0.05 or p < 0.01), and superoxide dismutase (SOD) ( p < 0.01); and restored liver histology accompanied by a decrease of α-smooth muscle actin (α-SMA) expression. Furthermore, maltol significantly suppressed the transforming growth factor-β1 (TGF-β1) expression and the PI3K/Akt pathway. This study suggested that maltol alleviated experimental liver fibrosis by suppressing the activation of HSCs and inducing apoptosis of activated HSCs through TGF-β1-mediated PI3K/Akt signaling pathway. These findings further clearly suggested that maltol is a potent therapeutic candidate for the alleviation of liver fibrosis.
我们之前的研究证实了麦芽酚可以减轻酒精引起的急性肝损伤并预防小鼠的氧化应激。因此，麦芽酚可能有能力改善硫代乙酰胺（TAA）诱导的肝纤维化。本工作的目的是探讨麦芽酚对 TAA 处理的小鼠的抗纤维化作用及其机制。通过递增剂量方案建立进行性肝纤维化，其中每周三次给小鼠腹腔注射 TAA，共 9 周。TAA 的注射剂量为第 1 周 50mg/kg，第 2 周和第 3 周 100mg/kg，其余注射剂量为 150mg/kg。在 TAA 腹腔注射 4 周后，分别给予麦芽酚 50 和 100mg/kg 剂量的灌胃，每日一次，持续 5 周。结果表明，TAA 腹腔注射显著增加血清丙氨酸氨基转移酶（ALT）（52.93±13.21U/L 比 10.22±3.36U/L）和天冬氨酸氨基转移酶（AST）（67.58±25.84U/L 比 39.34±3.89U/L）的活性；这些升高在麦芽酚预处理后明显降低。此外，麦芽酚改善了 TAA 诱导的氧化应激，降低了 MDA（p<0.05 或 p<0.01）含量；显著提高了 GSH 水平、GSH/GSSG 比值（p<0.05 或 p<0.01）和超氧化物歧化酶（SOD）（p<0.01）；并恢复了肝组织学，同时降低了α-平滑肌肌动蛋白（α-SMA）的表达。此外，麦芽酚显著抑制了转化生长因子-β1（TGF-β1）的表达和 PI3K/Akt 通路。本研究表明，麦芽酚通过抑制 TGF-β1 介导的 PI3K/Akt 信号通路抑制 HSCs 的激活和诱导活化的 HSCs 凋亡，减轻实验性肝纤维化。这些发现进一步清楚地表明，麦芽酚是一种有效的治疗肝纤维化的候选药物。
