Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 10 to 12 per 100 000 people worldwide.^1,2 Currently, 5 tyrosine kinase inhibitors (TKIs) targeting the activated BCR-ABL1 oncoprotein have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with CML.

In this study, daphnetin 1 was chosen as the lead compound, and C-3 or C-4-substituted daphnetins were designed and synthesized to explore the potential relationship between the antioxidant activities and the chemical structures of daphnetin derivatives. The antioxidant activities of the generated compounds were evaluated utilizing the free radical scavenging effect on 2,2′-diphenyl-1-picrylhydrazyl, 2,2′-azinobis-(3-ethylbenzthiazoline-6-sulfonate) cation, and the ferric reducing power assays, and were then compared with those of the standard antioxidant Trolox. The results showed that the catechol group was the key pharmacophore for the antioxidant activity of the daphnetins. The introduction of an electron-withdrawing hydrophilic group at the C-4 position of daphnetin enhanced the antioxidative capacity, but this trend was not observed for C-3 substitution. In addition, introduction of a a hydrophobic phenyl group exerted negative effects on the antioxidant activity in both the C-3 and C-4 substitutions. Among all of the derivatives tested, the most powerful antioxidant was 4-carboxymethyl daphnetin (compound 9), for which the strongest antioxidant activity was observed in all of the assays. In addition, compound 9 also displayed strong pharmaceutical properties in the form of metabolic stability. To summarize, compound 9 holds great potential to be developed as an antioxidant agent with excellent antioxidant activity and proper pharmacokinetic behavior.

Aims To reveal the consistency and discrepancy in the gut microbial structure and function in inflammatory bowel disease (IBD) patients from different regions. Methods and Results Gut microbes, antibiotic resistance genes (ARGs) and virulence factors genes (VFGs) were analysed using metagenome data from three cohorts. The abundance of Escherichia coli extensively increased in IBD patients, whereas Subdoligranulum unclassified decreased dramatically in IBD patients from three countries. Escherichia coli showed a positive correlation with multiple ARGs and VFGs in cohorts from China and the United States, including multidrug-related resistance genes and Capsule and LOS-related virulence factors genes. Escherichia coli biofilm synthesis pathways significantly enriched in IBD patients from three different regions. Notably, Subdoligranulum unclassified and Eubacterium hallii were negatively related to ARGs and VFGs. Conclusions Consistent changes of microbiome structure and function were observed in IBD patients from three different regions. As pathogenic bacteria, E. coli may accelerate IBD progression through encapsulation in biofilms by upregulating antibiotic resistance in Crohn's disease patients. Subdoligranulum unclassified and E. hallii may be beneficial for IBD patients and could serve as potential probiotics for IBD treatment. Significance and Impact of the Study This work dispels worries about the regional differences in gut microbial changes in IBD patients and provides useful guidance for more rational microbiome-based therapies.

Mammalian catechol-O-methyltransferases (COMT) are an important class of conjugative enzymes, which play a key role in the metabolism and inactivation of catechol neurotransmitters, catechol estrogens and a wide range of endobiotics and xenobiotics that bear the catechol group. Currently, COMT inhibitors are used in combination with levodopa for the treatment of Parkinson’s disease in clinical practice. The crucial role of COMT in human health has raised great interest in the development of more practical assays for highly selective and sensitive detection of COMT activity in real samples, as well as for rapid screening and characterization of COMT inhibitors as drug candidates. This review summarizes recent advances in analytical methodologies for sensing COMT activity and their applications. Several lists of biochemical assays for measuring COMT activity, including the probe substrates, along with their analytical conditions and kinetic parameters, are presented. Finally, the challenges and future perspectives in the field, such as visualization of COMT activity in vivo and in situ, are highlighted. Collectively, this review article overviews the practical assays for measuring COMT activities in complex biological samples, which will strongly facilitate the investigations on the relevance of COMT to human diseases and promote the discovery of COMT inhibitors via high-throughput screening.

Human catechol-O-methyltransferase (hCOMT) is considered a therapeutic target due to its crucial roles in the metabolic inactivation of endogenous neurotransmitters and xenobiotic drugs. There are nevertheless few safe and effective COMT inhibitors and there lacks a diversity in structure. To discover novel safe and effective hCOMT inhibitors from herbal products, in this study, 53 herbal products were collected and their inhibitory effects against hCOMT were investigated. Among them, Scutellariae radix (SR) displayed the most potent inhibitory effect on hCOMT with an IC₅₀ value of 0.75 μg mL⁻¹. To further determine specific chemicals as COMT inhibitors, an affinity ultrafiltration coupled with liquid chromatography-mass spectrometry method was developed and successfully applied to identify COMT inhibitors from SR extract. The results demonstrated that scutellarein 2, baicalein 9 and oroxylin A 12 were potent COMT inhibitors, showing a high binding index (>3) and very low IC₅₀ values (32.9 ± 3.43 nM, 37.3 ± 4.32 nM and 18.3 ± 2.96 nM). The results of inhibition kinetics assays and docking simulations showed that compounds 2, 9 and 12 were potent competitive inhibitors against COMT-mediated 3-BTD methylation, and they could stably bind to the active site of COMT. These findings suggested that affinity ultrafiltration allows a rapid identification of natural COMT inhibitors from a complex plant extract matrix. Furthermore, scutellarein 2, baicalein 9 and oroxylin A 12 are potent inhibitors of hCOMT in SR, which could be used as promising lead compounds to develop more efficacious non-nitrocatechol COMT inhibitors for biomedical applications.