Psoraleae Fructus (Bu Gu Zhi, BGZ) is extensively utilized for dermatological and osseous disorders in China. BGZ-induced liver injury has become one of the major concerns, which predominantly cause cholestasis, with the pathogenesis not being fully elucidated. Currently, studies on hepatotoxic mechanisms of BGZ have mainly been conducted on 2D cell culture systems or rodent models, which may not fully encapsulate human pathophysiology. Therefore, we generated human liver organoids (HLOs) from healthy donor(s) for living-related liver transplantation to explore the hepatotoxic mechanism. We identified bavachinin (BVC) as the most hepatotoxic component for cholestasis. After validating by CLF tests, we identified BVC caused cholestasis by down-regulating BAAT, which catalyzes the amidation of bile acids. We also found that up-regulating BAAT with harmaline could mitigate cholestasis and enhance cell viabilities in HLOs. We further demonstrated that glycocholic acid (GCA) levels decreased in BVC-treated HLOs. Supplementation of GCA to BVC-treated HLOs significantly improved cell viabilities. Collectively, our data suggested that BVC impaired the GCA synthesis by down-regulating the expression of BAAT, thereby inducing cholestasis.

18 Apr 2025·ACS Chemical Biology

Formation of the i-motif Structures by Human Telomeric c-Rich Sequences d(CCCTAA)n and Its Recognition by Bisbenzylisoquinoline Alkaloids

Article

Author: Lin, Zexuan ; Cui, Xiaojie ; Luo, Feixian ; Tang, Huining ; Yang, Jishun ; Tang, Yi ; Huang, Junliu ; Wang, Wenshu ; Yang, Yang

The human telomeric repeat CCCTAA has been reported to form a higher-order structure called an intercalated motif (i-motif) that plays important roles in telomere function and telomerase activity regulation, and small molecule ligands targeting human telomeric i-motif (hTelo-iM) is a promising therapeutic strategy for cancer treatment, yet the i-motif folding pattern of long CCCTAA repeats and the hTelo-iM ligand screening have not been studied extensively. In this study, we systematically investigated the i-motif structures formed by four and eight telomeric C-rich repeats d(CCCTAA)₄ (hTeloC-24mer) and d(CCCTAA)₈ (hTeloC-48mer) under varied conditions and found that the long hTeloC-48mer probably forms unstacked tandem i-motif consisting of two hTeloC-24mer i-motif monomers under near physiological conditions. Moreover, natural bisbenzylisoquinoline (BBI) alkaloids, isofangchinoline, fangchinoline, cepharanthine, and tetrandrine, were screened from 33 natural small molecules to effectively disrupt and destabilize the hTelo-iM structures mainly through major groove hydrogen bonding and van der Waals interactions. Further, telomerase repeated amplification protocol (TRAP) assay suggested that the selected BBI alkaloids can inhibit the telomere extension by telomerase. These findings provide a theoretical basis for further telomere structure research as well as a novel class of natural small molecule compounds regulating the hTelo-iM structure and telomerase activity, which may contribute to the anticancer drug design and strategy development taking the hTelo-iM as a target.

01 Apr 2025·Bioorganic & Medicinal Chemistry Letters

Synthesis of harmaline N-9 derivatives and investigation of in vitro anticancer activity

Article

Author: Liu, Yongjian ; Li, Shuqi ; Ge, Jinling ; Liu, Hao ; Chen, Heng ; Yu, Shaojun ; Liu, Yonggang

Harmaline as a natural compound possessed a wide range of pharmacological activities. In this study, 22 novel harmaline-based derivatives were synthesized and screened for in vitro anti-proliferation activity against three cancer cell lines, HCT116, MCF7, and MGC803. The modification site was at the position N-9 of harmaline. The 24-hour IC₅₀ of compound HL22 against HCT116, MGC803, and MCF7 was 3.84 ± 0.11 μM, 5.26 ± 0.46 μM, and 8.67 ± 0.13 μM, respectively. Compound HL22 significantly reduced the migratory ability of MGC803 cells. The monoclonal formation of MGC803 cells was also inhibited by HL22. The ¹H NMR metabolomics analysis suggested that the antiproliferative mechanism could be associated for the metabolism of glycine, serine and threonine, the metabolism of taurine and hypotaurine, glutathione metabolism, and the metabolism of nicotinic acid and nicotinamide. The significance of this study is that the anti-cancer activity of the modified N-9 derivatives of harmaline has been explored for the first time.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Preclinical	Saudi Arabia	University of Hail	01 Oct 2022

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