integrated-uhplc-msms-hrms-strategy-for-screening-potentially

Integrated UHPLC-MS/MS and HRMS Strategy for Screening Potentially Hepatotoxic Furan-Containing Compounds in <em>Dioscorea bulbifera</em> L.

Dioscorea bulbifera L. (DBL), a traditional herbal medicine used to treat thyroid disorders and tumors, has raised considerable safety concerns due to its ...

Guizhou Medical University

 L. (DBL) is a common traditional Chinese medicine, with diosbulbin B (DSB) as its main toxic component. DSB-derived cis-enedial (DDE), an electrophilic intermediate produced during the metabolic activation of DSB, reacts with cysteine (Cys) and lysine (Lys) residues to form the corresponding pyrrole derivative in proteins. Cys-modified proteins were identified using tandem mass tagging-activity-based protein profiling (TMT-ABPP). The modification of hepatic acetyl-CoA acyltransferase 2 (ACAA2) was detected by TMT-ABPP, immunoprecipitation, and LC-MS/MS in mice treated with DSB or DBL, as well as in incubation of recombinant human ACAA2 with DDE. Molecular docking analysis further revealed that Cys128 and Lys143 likely participated in the formation of the pyrrole derivative. The protein adduction resulted in concentration- and dose-dependent inhibition of ACAA2 in vitro and in vivo. Accumulation of upstream triglycerides was observed in mice given higher doses of DSB, accompanied by a decrease of downstream acetyl coenzyme A levels, possibly resulting from the adduction of ACAA2.

Disruption of Acetyl-CoA Acyltransferase 2 Resulting from Exposure to Diosbulbin B.

Methyleugenol (MTL) and safrole (SFL) are hepatotoxic flavorants with distinct IARC classifications (Group 2A versus 2B), and yet the structural reason for this differential toxicity is unclear. Results showed that MTL was more hepatotoxic than SFL, owing to its more efficient metabolic activation. This was evidenced by greater glutathione (GSH) depletion, GSH conjugate formation, and protein adduction. CYP3A4 was identified as the key enzyme mediating this difference. Molecular simulations demonstrated that although SFL binds CYP3A4 with higher affinity, its rigid 3,4-methylenedioxy group displaces the allylic moiety from heme iron, resulting in suboptimal catalytic positioning. In contrast, MTL's 3-methoxy substituent enables stable orientation near the catalytic site, facilitating reactive metabolite formation. Thus, minor structural differences critically dictate the CYP3A4-mediated metabolic activation and subsequent hepatotoxic risk of allylbenzenes. This work provides a mechanistic basis for understanding structure-toxicity relationships and improving the safety assessment of flavor compounds in spices.

Mechanistic Insight into Difference in Hepatotoxicity of Methyleugenol and Safrole.

1.  Buch.-Ham. (SBH) is widely used in traditional Chinese medicine, yet its clinical application is constrained by hepatotoxic pyrrolizidine alkaloids (PAs). The relative toxic contributions of individual PAs in SBH and their  metabolic consequences remain unclear.

Exploring the components of hepatotoxicity induced by  Buch.-Ham. based on integrated network toxicology, metabolomics, and  experiments.

Colorectal cancer (CRC) is strongly associated with aberrant activation of the PI3K/Akt/mTOR pathway, in which PI3Kα represents a clinically validated therapeutic target. Herein, we report the rational design, synthesis, and biological evaluation of quinoxaline derivatives as potent PI3Kα selective inhibitors derived from the lead compound 18a, which was developed in our previous study and suffered from poor drug-like properties. Structure-guided modification led to the identification of compound 8b, which exhibited remarkably improved solubility and oral bioavailability, and it showed nano-mol level inhibitory activity against PI3Kα. In HCT-116 cells, 8b effectively suppressed proliferation, migration, and colony formation, induced apoptosis, and selectively triggered G2/M-phase arrest via downregulation of Cyclin B1 and CDK1. Mechanistic studies further confirmed robust inhibition of PI3K/Akt/mTOR signaling pathway and associated transcriptional reprogramming. Collectively, 8b represents a promising orally active PI3Kα inhibitor for CRC targeted therapy.

Article	Year
Disruption of Acetyl-CoA Acyltransferase 2 Resulting from Exposure to Diosbulbin B. Chemical research in toxicology\| PubMed ID: 40213991	2025
Mechanistic Insight into Difference in Hepatotoxicity of Methyleugenol and Safrole. Journal of agricultural and food chemistry\| PubMed ID: 41605223	2026
Exploring the components of hepatotoxicity induced by Buch.-Ham. based on integrated network toxicology, metabolomics, and experiments. Xenobiotica; the fate of foreign compounds in biological systems\| PubMed ID: 42091236	2026
Design, synthesis, and anti-colorectal cancer activity of quinoxalines with improved drug-like properties. Bioorganic chemistry\| PubMed ID: 42119204	2026

Yunfang Jiang

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