Dammarane-type triterpenoid saponins isolated from Gynostemma pentaphyllum ameliorate liver fibrosis via agonizing PP2Cαand inhibiting deposition of extracellular matrix

Gypenosides,structurally analogous to ginsenosides and derived from a sustainable source,are recognized as the principal active compounds found in Gynostemma pentaphyllum,a Chinese medicinal plant used in the treatment of the metabolic syndrome.By bioactive tracking isolation of the plants collected from different regions across China,we obtained four new gypenosides(1−4),together with nine known gypenosides(5−13),from the methanol extract of the plant.The structures of new gypenosides were elucidated by one-dimensional(1D)and two-dimensional(2D)nuclear magnetic resonance(NMR)spectra,complemented by chemical degradation experiments.Through comprehensive evaluation involving COL1A1 promoter assays and PP2Cαactivity assays,we established a definitive structure-activity relationship for these dammarane-type triterpenoids,affirming the indispensability of the C-3 saccharide chain and C-17 lactone ring in effectively impeding extracellular matrix(ECM)deposition within hepatic stellate cells.Further in vivo study on the CCl4-induced liver damage mouse model corroborated that compound 5 significantly ameliorated the process of hepatic fibrosis by oral administration.These results underscore the potential of dammarane-type triterpenoids as prospective antifibrotic leads and highlight their prevalence as key molecular frameworks in the therapeutic intervention of chronic hepatic disorders.

Simultaneous Determination of Eleven Bioactive Constituents in Honey-Processed Licorice by High-Performance Liquid Chromatography-Diode Array Detector and Its Application from the Perspective of Processing Influence under Orthogonal Design

Objective:The aim of this study was to develop a reliable approach to simultaneously quantify 11 markers and explore the quality variation in honey-processed licorice.Materials and Methods:A high-performance liquid chromatography-diode array detector method was developed for the simultaneous determination of 11 markers(nine flavonoids and two triterpenoid saponins)in honey-processed licorice.The changes to the 11 markers in honey-processed licorice were investigated using an orthogonal design with three input factors.Results:The established method was precise,accurate,and sensitive enough for the simultaneous quantitative evaluation of 11 markers in honey-processed licorice.Intuitive analysis and variance analysis revealed that(1)the soaking time of crude licorice,stir-frying temperature,and stir-frying time remarkably influenced the content of liquiritin apioside,signifying the decomposition of liquiritin apioside to liquiritin or transformation of liquiritin apioside to isoliquiritin apioside,(2)stir-frying temperature significantly influenced licorice-saponin G2,(3)stir-frying temperature was the most important factor of the three input factors,(4)in terms of composition,honey fried licorice had significant effects on two components,namely liquiritin apioside and licorice-saponin G2.Conclusions:Honey processing influenced the content of the 11 licorice analytes differently.This paper highlights the first report on how the quality of honey-processed licorice varies under different processing conditions and suggests the optimal levels of the investigated three factors as A2B2C3 according to the degrees of influence of these factors on the 11 components.Specifically,the soaking time of crude licorice with honey solution,stir-frying temperature,and stir-frying time were 40 min,100°C,and 20 min,respectively.

Transition-metal-catalyzed switchable divergent cycloaddition of para-quinone methides and vinylethylene carbonates:Access to different sized medium-sized heterocycles

Divergent synthesis of medium-sized rings with controllable ring sizes represents a longstanding challenge in organic synthesis.Herein,we developed a transition-metal-catalyzed switchable divergent cycloaddition of para-quinone methides and vinylethylene carbonates by controlling the steric hindrance of substituent.Different from reported alkoxide-triggered annulations,this process undergoes a regiodivergent allylation of para-quinone methides followed by 1,6-addition reaction,providing a new route to selectively synthesize seven-to ten-membered nitrogen-containing heterocycles in high yields with excellent regioselectivities.This protocol features a broad substrate scope,wide functional group tolerance as well as operational simplicity.The reaction mechanism was investigated by conducting a series of control experiments as well as DFT calculations and the origins of the regioselectivities of the cycloaddition process were rationalized.

Lonicerin targets EZH2 to alleviate ulcerative colitis by autophagy-mediated NLRP3 inflammasome inactivation

Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis.Although targeting NLRP3 inflammasome has been considered to be a potential therapy,the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial.By focusing on the flavonoid lonicerin,one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb Lonicera japonica Thunb.,here we report its therapeutic effect on intestinal inflammation by binding directly to enhancer of zeste homolog 2(EZH2)histone methyltransferase.EZH2-mediated modification of H3 K27 me3 promotes the expression of autophagy-related protein 5,which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation.Mutations of EZH2 residues(His 129 and Arg685)indicated by the dynamic simulation study have found to greatly diminish the protective effect of lonicerin.More importantly,in vivo studies verify that lonicerin dose-dependently disrupts the NLRP3-ASC-pro-caspase-1 complex assembly and alleviates colitis,which is compromised by administration of EZH2 overexpression plasmid.Thus,these findings together put forth the stage for further considering lonicerin as an anti-inflammatory epigenetic agent and suggesting EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases.