Isolation and Biological Evaluation of Alfa-Mangostin as Potential Therapeutic Agents against Liver Fibrosis

Yi-Jen Liao; Chun-Ya Lee; Yuh-Ching Twu; Fat-Moon Suk; Tzu-Chieh Lai; Ya-Ching Chang; Yi-Cheng Lai; Jing-Wei Yuan; Hong-Ming Jhuang; Huei-Ruei Jian; Li-Chia Huang; Kuang-Po Chen; Ming-Hua Hsu

doi:10.3390/bioengineering10091075

Isolation and Biological Evaluation of Alfa-Mangostin as Potential Therapeutic Agents against Liver Fibrosis

Bioengineering (Basel). 2023 Sep 11;10(9):1075. doi: 10.3390/bioengineering10091075.

Authors

Yi-Jen Liao¹, Chun-Ya Lee¹, Yuh-Ching Twu², Fat-Moon Suk^{3

4}, Tzu-Chieh Lai⁵, Ya-Ching Chang⁵, Yi-Cheng Lai⁵, Jing-Wei Yuan⁵, Hong-Ming Jhuang⁵, Huei-Ruei Jian⁵, Li-Chia Huang⁵, Kuang-Po Chen⁶, Ming-Hua Hsu⁵

Affiliations

¹ School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
² Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
³ Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
⁴ Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
⁵ Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan.
⁶ Department of Chemistry, Chinese Culture University, Taipei 111, Taiwan.

Abstract

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 (CCl₄) 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 CCl₄-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.

Keywords: alfa-mangostin; liver fibrosis; mangostin.

Abstract

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