Salvia miltiorrhiza Bunge is highly valued in traditional Chinese medicine for its roots and rhizomes. Its bioactive diterpenoid tanshinones have been reported to have many pharmaceutical activities, including antibacterial, anti-inflammatory, and anticancer properties. Previous studies found four different diterpenoid biosynthetic pathways from the universal diterpenoid precursor (E, E, E)-geranylgeranyl diphosphate (GGPP) in S. miltiorrhiza. Here, we describe the functional characterization of ent-copalyl diphosphate synthase (SmCPSent), kaurene synthase (SmKS) and kaurene oxidase (SmKO) in the gibberellin (GA) biosynthetic pathway. SmCPSent catalyzes the cyclization of GGPP to ent-copalyl diphosphate (ent-CPP), which is converted to ent-kaurene by SmKS. Then, SmKO catalyzes the three-step oxidation of ent-kaurene to ent-kaurenoic acid. Our results show that the fused enzyme SmKS-SmCPSent increases ent-kaurene production by several fold compared with separate expression of SmCPSent and SmKS in yeast strains. In this study, we clarify the GA biosynthetic pathway from GGPP to ent-kaurenoic acid and provide a foundation for further characterization of the subsequent enzymes involved in this pathway. These insights may allow for better growth and the improved accumulation of bioactive tanshinones in S. miltiorrhiza through the regulation of the expression of these genes during developmental processes.

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Functional characterization of ent-copalyl diphosphate synthase, kaurene synthase and kaurene oxidase in the Salvia miltiorrhiza gibberellin biosynthetic pathway.

Potential of herb-drug / herb interactions between substrates and inhibitors of UGTs derived from herbal medicines.

Research progress of meliaceous limonoids from 2011 to 2021.

Bavachalcone and corylin are two major bioactive compounds isolated from Psoralea corylifolia L., which has been widely used as traditional Chinese medicine for many years. As two antibiotic or anticancer drugs, bavachalcone and corylin are used in combination with other drugs; thus it is necessary to evaluate potential pharmacokinetic herb-drug interactions (HDI) of the two bioactive compounds. The aim of the present study was to compare the effects of liver UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT1A7, UGT1A8, UGT 1A10, and UGT2B4 inhibited by bavachalcone and corylin. 4-Methylumbelliferone (4-MU) was used as a nonspecific “probe” substrate. Bavachalcone had stronger inhibition on UGT1A1 and UGT1A7 than corylin which did not inhibit UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A10, and UGT2B4. Data fitting using Dixon and Lineweaver-Burk plots demonstrated the noncompetitive inhibition of bavachalcone against UGT1A1 and UGT1A7-mediated 4-MU glucuronidation reaction. The values of inhibition kinetic parameters (Ki) were 5.41 μM and 4.51 μM for UGT1A1 and UGT1A7, respectively. The results of present study suggested that there was a possibility of UGT1A1 and UGT1A7 inhibition-based herb-drug interaction associated with bavachalcone and provided the basis for further in vivo studies to investigate the HDI potential between bavachalcone and UGT substrates.

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Comparison of the Inhibitory Potential of Bavachalcone and Corylin against UDP-Glucuronosyltransferases.

Herb-drug interaction strongly limits the clinical utilization of herbs and drugs. Irinotecan-induced diarrhea is closely related with the UDP-glucuronosyltransferase 1A1-catalyzed glucuronidation of SN-38 which has been widely regarded to be the toxic substance basis of irinotecan. The present study aims to determine the influence of herbal component psoralidin toward the toxicity of irinotecan. In vitro inhibition potential of psoralidin toward the glucuronidation of SN-38 was firstly investigated using human intestinal microsomes incubation system. Dose-dependent inhibition of psoralidin toward SN-38 glucuronidation was observed. Furthermore, Dixon plot showed that the intersection point was located in the second quadrant, indicating the competitive inhibition of psoralidin toward the glucuronidation of SN-38. Through the data fitting using competitive inhibition fitting equation, the inhibition kinetic parameter (K
 i) was calculated to be 5.8 μM. The translation of these in vitro data into the in vivo situation showed that pre-treatment with psoralidin significantly increased the toxicity of irinotecan, as indicated by the increased body weight loss and more severe colon histology damage. All these data indicated the herb-drug interaction between irinotecan and psoralidin-containing herbs.

Herb-drug interaction between irinotecan and psoralidin-containing herbs

Sarglaromatics A-E (1-5, respectively), five unprecedented naphthalene-like architecture-fused norlindenane sesquiterpene dimers, were discovered from the roots of Sarcandra glabra. The unique naphthalene core skeleton was obtained from classical lindenane [4 + 2] dimers via a free-radical-mediated C11-C11' bond formation reaction and 12'-decarboxylation. The highly fused octonary ring skeleton was elucidated by HRMS, NMR, ECD, quantum chemical calculations, and biogenetic inspiration. Compounds 1 and 2 showed significant anti-nonalcoholic steatohepatitis (NASH) activity by inhibiting lipid deposition in L02 cells.

Jun-Sheng Luo

Papers

Research progress of meliaceous limonoids from 2011 to 2021.

Sarglaromatics A-E: A Class of Naphthalene-Like Architecture Fused Norlindenane Sesquiterpene Dimers from Sarcandra glabra.

A/D-rings-seco limonoids from the fruits of Aglaia edulis and their bioactivities

Cryptotanshinone and dihydrotanshinone I exhibit strong inhibition towards human liver microsome (HLM)-catalyzed propofol glucuronidation.

Chlospicenes A and B, cyclopropane cracked lindenane sesquiterpenoid dimers with anti-nonalcoholic steatohepatitis activity from Chloranthus henryi