Title: Natural soluble epoxide hydrolase inhibitors from Inula britanica and their potential interactions with soluble epoxide hydrolase: Insight from inhibition kinetics and molecular dynamics Zhao WY, Yan JJ, Zhang M, Wang C, Feng L, Lv X, Huo XK, Sun CP, Chen LX, Ma XC Ref: Chemico-Biological Interactions, :109571, 2021 : PubMed
Soluble epoxide hydrolase (sEH) is a potential drug target to treat inammation and neurodegenerative diseases. In this study, we found that the extract of Inula britanica exhibited significantly inhibitory effects against sEH, therefore, we investigated its phytochemical constituents to obtain seven new compounds together with sixteen known ones (1-20), including two pairs of novel enantiomers, (2S,3S)-britanicafanin A (1a), (2R,3R)-britanicafanin A (1b), (2R,3S)-britanicafanin B (2a), and (2S,3R)-britanicafanin B (2b), and three new lignans britanicafanins C-E (3-5). Their structures were determined by HRESIMS, 1D and 2D NMR, and electronic circular dichroism (ECD) spectra as well as quantum chemical computations. All the isolates were evaluated for their inhibitory effects against sEH, compounds 1-3, 5-7, 9, 10, 13, 14, and 17-20 showed significant inhibitory effects against sEH with IC(50) values from 3.56 microM to 26.93 microM. The inhibition kinetics results indicated that compounds 9, 10, 13, and 19 were all uncompetitive inhibitors, and their inhibition constants (K(i)) values were 7.11, 1.99, 4.06, and 8.78 microM, respectively. Their potential interactions were analyzed by molecular docking and molecular dynamics (MD), which suggested that amino acid residues Asp335 and Asn359, especially Gln384, played an important role in the inhibition of compounds 10 and 13 on sEH, and compounds 10 and 13 could be considered as the potential candidates for the development of sEH inhibitors.
Title: A novel 15-spiro diterpenoid dimer from Andrographis paniculata with inhibitory potential against human carboxylesterase 2 Sun CP, Yang ZJ, Zhao WY, Zhang RY, Li H, Chen LX Ref: Bioorg Chem, 97:103680, 2020 : PubMed
The phytochemical investigation of Andrographis paniculata resulted in the isolation of a novel 15-spiro diterpenoid dimer bisandrographolide G (1). Its structure was determined by 1D and 2D NMR, HRESIMS, electronic circular dichroism (ECD), and TD DFT calculations of ECD spectra. It showed potent inhibitory activity against human carboxylesterase 2 (CES 2) with an IC50 value of 4.61 +/- 0.23 muM, and it was defined as a mixed-competitive type inhibitor with a Ki value of 8.88 muM based on the inhibition kinetics result. This finding gave us a hit to develop new generation of human CES 2 inhibitors.
Title: The Biosynthesis of Norsesquiterpene Aculenes Requires Three Cytochrome P450 Enzymes to Catalyze a Stepwise Demethylation Process Lee CF, Chen LX, Chiang CY, Lai CY, Lin HC Ref: Angew Chem Int Ed Engl, 58:18414, 2019 : PubMed
Aculenes are a unique class of norsequiterpenes (C(14) ) that are produced by Aspergillus aculeatus. The nordaucane skeleton in aculenes A-D may be derived from an ent-daucane precursor through demethylation, however, the enzymes involved remain unexplored. We identified the biosynthetic gene cluster and characterized the biosynthetic pathway based on gene inactivation, feeding experiments, and heterologous reconstitution in Saccharomyces cerevisiae and Aspergillus oryzae. We discovered that three cytochromeP450 monoxygenases are required to catalyze the stepwise demethylation process. AneF converts the 12-methyl group into a carboxylic acid and AneD installs the 10-hydroxy group for later tautomerization and stabilization. Finally, AneG installs an electron-withdrawing carbonyl group at the C-2 position, which triggers C-12 decarboxylation to yield the nordaucane skeleton. Additionally, a terpene cyclase (AneC) was found that forms a new product (dauca-4,7-diene).
The aim of this study was to investigate the relationship between the acetylcholine concentration in the blood and gelsenicine-induced death in mice. Kunming mice were given intraperitoneal injections of normal saline, gelsenicine or different doses of acetylcholine chloride. Atropine was given to the mice which received gelsenicine or medium dose acetylcholine chloride injection. The blood was sampled immediately when the mice died or survived for 20 min after injection. The acetylcholine concentration and acetylcholinesterase activity in the blood were measured by the testing kits, and the mortality was calculated and analyzed. The results showed that half lethal dose of gelsenicine (0.15 mg/kg) reduced the acetylcholinesterase activity and increased the blood acetylcholine concentration. The blood acetylcholine concentration of the dead mice in the gelsenicine group was increased to 43.0 mug/mL (from 31.1 mug/mL in the control), which was lower than that (53.9 mug/mL) of the dead mice in the medium dose acetylcholine chloride group, but almost equal to that (42.7 mug/mL) of the survival mice in the medium dose acetylcholine chloride group. Atropine could successfully rescue the mice from acetylcholine poisoning, but its efficiency of rescuing the mice from gelsenicine intoxication was weak. These results suggest that gelsenicine can inhibit acetylcholinesterase activity and increase blood acetylcholine concentration, but the accumulation of acetylcholine may not be the only or main cause of the death induced by gelsenicine in mice.
The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. We have determined the nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map. Efforts are under way to close the remaining gaps; however, the sequence is of sufficient accuracy and contiguity to be declared substantially complete and to support an initial analysis of genome structure and preliminary gene annotation and interpretation. The genome encodes approximately 13,600 genes, somewhat fewer than the smaller Caenorhabditis elegans genome, but with comparable functional diversity.
