BACKGROUND: Cytochrome P450 (CYP) 46A1 enzyme is a neuro-specific metabolic enzyme that converts cholesterol to 24-hydroxycholesterol. Inhibition of CYP46A1 activity is of great significance to improve neurodegenerative disorder. OBJECTIVE: The present study aimed to investigate the inhibitory effect of wolfberry di caffeoyl spermidine derivatives on CYP46A1. METHODS: The inhibitory effect of six wolfberry dicaffeoylspermidine derivatives on CYP46A1 activity was investigated using cholesterol as a substrate in vitro. Molecular docking was used to simulate the interactions between wolfberry dicaffeoylspermidine derivatives and CYP46A1. RESULTS: Of these spermidines, lycibarbarspermidines D (1) and A (2) showed highly-selective and strong inhibitory effects on CYP46A1 but not on other human CYP isoforms. Both 1 and 2 exhibit mixed partial competitive inhibition of CYP46A1, with Ki values of 106 nM and 258 nM, respectively. Notably, 1 and 2 had excellent orientations within the active cavity of CYP46A1, and both formed three water-hydrogen bonds with W732 and W765, located near the heme of CYP46A1. CONCLUSION: Compounds 1 and 2 showed a highly-selective and nanomolar affinity for CYP46A1 in vitro. These findings suggested that compounds 1 and 2 could be used as potent inhibitors of CYP46A1 in vitro.

Osteoarthritis (OA) involves lesions of the entire joint and remains one of the health problems plaguing the world. The pathological mechanism of OA is complex and involves multiple signaling pathways. Over 300 million people worldwide are living with OA, which imposes a huge burden on society. Nucleic acid nanomaterials are of interest to the biomedical field due to their small dimension, ideal biocompatibility, and structure editability. Various nucleic acids have been used as therapeutic drugs to regulate the pathogenesis and development of OA. Among them, some can enter the cell by themselves and others with the aid of vectors. Apart from high therapeutic efficiency, nucleic acid nanomaterials also act as carriers for transporting drugs. This paper reviews recent advances in nucleic acid nanomaterials in OA therapy, suggesting that nucleic acid nanomaterials-based therapy has good prospects for development.

BACKGROUND: Cycloastragenol (CAG) is a sapogenin derived from the main bioactive constituents of Astragali Radix (AR). However, the current research on CAG metabolism in vivo and in vitro is still inadequate, and the metabolite cluster is incomplete due to incomplete analysis strategy. OBJECTIVE: The objective of this study was to screen and identify the metabolic behavior of CAG in vivo and in vitro. METHODS: A simple and rapid analysis strategy based on UHPLC-Q-Exactive Orbitrap mass spectrometry combined with data-mining processing technology was developed and used to screen and identify CAG metabolites in rat body fluids and tissues after oral administration. RESULTS: As a result, a total of 82 metabolites were fully or partially characterized based on their accurate mass, characteristic fragment ions, retention times, corresponding Clog P values, and so on. Among the metabolites, 61 were not reported in previous reports. These metabolites (6 metabolites in vitro and 91 in vivo) were generated through reactions of hydroxylation, glucuronidation, sulfation, hydrogenation, hydroxylation, demethylation, disopropylation, dehydroxylation, ring cleavage, and carboxyl substitution and their composite reactions, and the hydroxylation might be the main metabolic reaction of CAG. In addition, the characteristic fragmentation pathways of CAG were summarized for the subsequent metabolite identification. CONCLUSION: The current study not only clarifies the metabolite cluster-based and metabolic regularity of CAG in vivo and in vitro, but also provides ideas for metabolism of other saponin compounds.

BACKGROUND: Filifolium sibiricum flavonoids dropping pill (FSFp), a unique Chinese Filifolii sibirici herba extract preparation, has the potential as an alternative therapy against S. aureus infection (SA) and anti-infection. However, its chemical composition and in vivo metabolism characteristics remain unknown, which limits its clinical application. METHODS: Here, we aimed to understand the in vitro and in vivo material basis of FSFp. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to identify chemicals in FSFp as well as its phase I and phase II reaction metabolites in plasma, urine and feces. RESULTS: A total of 38 chemicals were characterized in FSFp, including 22 flavonoids, 10 organic acids, 3 chromones, 1 aromatic ketone, 1 coumarin, and 1 ligan. After analysis of the drugged bio-samples, a total of 21 compounds were found in urine, and 16 of them were found in feces, but only one was found in plasma. In addition, 56 FSFp-related metabolites were characterized, of which 56 were in urine, 4 in feces, and 8 in plasma. CONCLUSION: This is the first comprehensive research of FSFp on chemical constituents and metabolic profiles. It was expected that this study would offer reliable support for further investigation of FSFp.