Liao Yi-Jen, Lee Chun-Ya, Twu Yuh-Ching, Suk Fat-Moon, Lai Tzu-Chieh, Chang Ya-Ching, Lai Yi-Cheng, Yuan Jing-Wei, Jhuang Hong-Ming, Jian Huei-Ruei, Huang Li-Chia, Chen Kuang-Po, Hsu Ming-Hua
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
Bioengineering (Basel). 2023 Sep 11;10(9):1075. doi: 10.3390/bioengineering10091075.
The increased proliferation and activation of hepatic stellate cells (HSCs) are associated with liver fibrosis development. To date, there are no FDA-approved drugs for the treatment of liver cirrhosis. Augmentation of HSCs apoptosis is one of the resolutions for liver fibrosis. In this study, we extracted α-mangostin (1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methyl-2-butenyl)-9H-xanthen-9-one) from the fruit waste components of mangosteen pericarp. The isolated α-mangostin structure was determined and characterized with nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) and compared with those known compounds. The intracellular signaling pathway activities of α-mangostin on Transforming growth factors-beta 1 (TGF-β1) or Platelet-derived growth factor subunit B (PDGF-BB) induced HSCs activation and were analyzed via Western blot and Real-time Quantitative Polymerase Chain Reaction (Q-PCR). α-Mangostin-induced mitochondrial dysfunction and apoptosis in HSCs were measured by seahorse assay and caspase-dependent cleavage. The in vivo anti-fibrotic effect of α-mangostin was assessed by carbon tetrachloride (CCl) treatment mouse model. The data showed that α-mangostin treatment inhibited TGF-β1-induced Smad2/3 phosphorylation and alpha-smooth muscle actin (α-SMA) expression in HSCs in a dose-dependent manner. Regarding the PDGF-BB-induced HSCs proliferation signaling pathways, α-mangostin pretreatment suppressed the phosphorylation of extracellular-signal-regulated kinase (ERK) and p38. The activation of caspase-dependent apoptosis and dysfunction of mitochondrial respiration (such as oxygen consumption rate, ATP production, and maximal respiratory capacity) were observed in α-mangostin-treated HSCs. The CCl-induced liver fibrosis mouse model showed that the administration of α-mangostin significantly decreased the expression of the fibrosis markers (α-SMA, collagen-a2 (col1a2), desmin and matrix metalloproteinase-2 (MMP-2)) as well as attenuated hepatic collagen deposition and liver damage. In conclusion, this study demonstrates that α-mangostin attenuates the progression of liver fibrosis through inhibiting the proliferation of HSCs and triggering apoptosis signals. Thus, α-mangostin may be used as a potential novel therapeutic agent against liver fibrosis.
肝星状细胞（HSCs）增殖和激活的增加与肝纤维化的发展相关。迄今为止，尚无美国食品药品监督管理局（FDA）批准的用于治疗肝硬化的药物。增强肝星状细胞凋亡是解决肝纤维化的方法之一。在本研究中，我们从山竹果皮的果渣成分中提取了α-倒捻子素（1,3,6-三羟基-7-甲氧基-2,8-双（3-甲基-2-丁烯基）-9H-呫吨-9-酮）。通过核磁共振（NMR）和高分辨率质谱（HRMS）确定并表征了分离出的α-倒捻子素结构，并与那些已知化合物进行比较。通过蛋白质免疫印迹法（Western blot）和实时定量聚合酶链反应（Q-PCR）分析了α-倒捻子素对转化生长因子-β1（TGF-β1）或血小板衍生生长因子亚基B（PDGF-BB）诱导的肝星状细胞激活的细胞内信号通路活性。通过海马实验和半胱天冬酶依赖性切割来测定α-倒捻子素诱导的肝星状细胞线粒体功能障碍和凋亡。通过四氯化碳（CCl）处理的小鼠模型评估α-倒捻子素的体内抗纤维化作用。数据显示，α-倒捻子素处理以剂量依赖性方式抑制TGF-β1诱导的肝星状细胞中Smad2/3磷酸化和α-平滑肌肌动蛋白（α-SMA）表达。关于PDGF-BB诱导的肝星状细胞增殖信号通路，α-倒捻子素预处理抑制了细胞外信号调节激酶（ERK）和p38的磷酸化。在α-倒捻子素处理的肝星状细胞中观察到半胱天冬酶依赖性凋亡的激活和线粒体呼吸功能障碍（如氧消耗率、ATP产生和最大呼吸能力）。CCl诱导的肝纤维化小鼠模型显示，给予α-倒捻子素可显著降低纤维化标志物（α-SMA、胶原蛋白α2（col1a2）、结蛋白和基质金属蛋白酶-2（MMP-2））的表达，并减轻肝脏胶原沉积和肝损伤。总之，本研究表明α-倒捻子素通过抑制肝星状细胞增殖和触发凋亡信号来减轻肝纤维化的进展。因此，α-倒捻子素可能用作抗肝纤维化的潜在新型治疗剂。
