Cucurbitacin I

Ganoderma lucidum (G. lucidum), a medicinal fungus, exhibits diverse pharmacological effects against many diseases. Studies have shown that the ethanol extract of G. lucidum (GLEE), which is rich in triterpenoids, possesses significant anti-carcinogenic effects. Early research focused solely on the pharmacokinetics and metabolism of individual triterpenoids in normal rodents. However, no research has examined the distribution of prototype compounds and metabolites of GLEE in multiple tissues, plasma, or tumor tissue. In this study, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), combined with the Global Natural Products Social Molecular Networking (GNPS) platform and UNIFI software, was employed to identify and quantify the chemical composition of GLEE. A total of 105 compounds were identified, including 100 triterpenoids and 5 fatty acids, with 18 high-content monomers quantitatively analyzed. Following six weeks of GLEE administration in tumor-bearing nude mice, 42 prototype compounds and 24 metabolites were identified across plasma, tumors, and eight tissues, including small intestine, stomach, liver, heart, lung, kidney, spleen, and colon. Notably, ganoderic acids A, B, C1, F, and H were the most widely distributed compounds across these tissues. The metabolism of GLEE involves both phase I and phase II reactions. This study is the first to provide a comprehensive profile of GLEE's chemical composition, distribution, and metabolism, revealing the potential active triterpenoids responsible for its anti-cancer effects. Our findings provide a foundation for future studies focused on the pharmacological mechanisms of these compounds, offering new insights into the therapeutic potential of G. lucidum in cancer treatment.

Glioblastoma multiforme (GBM) is the most aggressive and prevalent central nervous system (CNS) malignancy, characterized by tumor heterogeneity and poor prognosis.In GBM, tumor-induced inflammation, hypoxia, and cellular damage release damage-associated mol. patterns (DAMPs) like High Mobility Group Box 1 (HMGB1).HMGB1 exerts both tumor-promoting and tumor-suppressive effects, its functional outcome is regulated by its subcellular localization, redox state, and the immune cell infiltrate within the tumor microenvironment (TME).In our study, we focus on confirming the protumorigenic role of HMGB1 using bioinformatic tools to further validate its contribution to tumor progression.Therefore, targeted inhibition of HMGB1 seems to be a promising therapeutic strategy.Glycyrrhizin, a triterpenoid, is a known HMGB1 inhibitor.We aimed to create a more effective inhibitor by utilizing structural insights of glycyrrhizin.We used computational screening to evaluate the bioactivity of other potential triterpenoids as HMGB1 inhibitors in the context of GBM.Mol. docking and MD simulation were performed to screen the triterpenoid library.We found that triterpenoids like cucurbitacin E, F, I, and K have a higher potential to bind at the TLR4 and RAGE binding domains of HMGB1 compared to glycyrrhizin.These domains are crucial for HMGB1-receptor interactions, which enhance GBM malignancy.Moreover, drug-likeness and pharmacokinetic analyses of cucurbitacins indicated favorable therapeutic profiles.Our findings advance the discovery of novel HMGB1 inhibitors, improve GBM treatment, and establish a foundation for further validation and clin. applications.