查看更多>>摘要：Previously,we proposed a new perspective of triptolide (TP)-associated hepatotoxicity: liver hypersensitivity upon lipopolysaccharide (LPS) stimulation.However,the mechanisms for TP/LPS-induced hepatotoxicity remained elusive.The present study aimed to clarify the role of LPS in TP/LPS-induced hepatotoxicity and the mechanism by which TP induces liver hypersensitivity upon LPS stimulation.TNF-α inhibitor,etanercept,was injected intraperitoneally into mice to investigate whether induction of TNF-α by LPS participated in the liver injury induced by TP/LPS co-treatment.Mice and hepatocytes pretreated with TP were stimulated with recombinant TNF-α to assess the function of TNF-α in TP/LPS co-treatment.Additionally,time-dependent NF-κB activation and NF-κB-mediated pro-survival signals were measured in vivo and in vitro.Finally,overexpression of cellular FLICE-inhibitory protein (FLIP),the most potent NF-κB-mediated pro-survival protein,was measured in vivo and in vitro to assess its function in TP/LPS-induced hepatotoxicity.Etanercept counteracted the toxic reactions induced by TP/LPS.TP-treatment sensitized mice and hepatocytes to TNF-α,revealing the role of TNF-α in TP/LPS-induced hepatotoxicity.Mechanistic studies revealed that TP inhibited NF-κB dependent pro-survival signals,especially FLIP,induced by LPS/TNF-α.Moreover,overexpression of FLIP alleviated TP/LPS-induced hepatotoxicity in vivo and TP/TNF-α-induced apoptosis in vitro.Mice and hepatocytes treated with TP were sensitive to TNF-α,which was released from LPS-stimulated immune cells.These and other results show that the TP-induced inhibition of NF-κB-dependent transcriptional activity and FLIP production are responsible for liver hypersensitivity.
查看更多>>摘要：In this report,a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2.The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT).Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations.Especially,compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I,K103N,Y181C,Y188L and E138K) with an EC50 ranging from 6.02 to 23.9 nmol/L,which were comparable to those of etravirine (ETR).Moreover,the RT inhibition activity,preliminary structure-activity relationship and molecular docking were also investigated.Furthermore,26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8％.Taken together,the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.
查看更多>>摘要：Seven indole alkaloid glycosides containing a 1'-(4"-hydroxy-3",5"-dimethoxyphenyl)ethyl unit (1-7) were isolated from an aqueous extract of Isatis indigotica leaves (da qing ye).Their structures were determined by spectroscopic data analysis combined with enzymatic hydrolysis as well as comparison of their experimental CD (circular dichroism) and calculated ECD (electrostatic circular dichroism) spectra.Based on analysis of[α]D20 and/or Cotton effect (CE) data of 1-7,two simple roles to assign location and/or configuration of β-glycopyranosyloxy and 1'-(phenyl)ethyl units in the indole alkaloid glycosides are proposed.Stereoselectivity in plausible biosynthetic pathways of 1-7 is discussed.Compounds 3 and 4 and their mixture in a 3∶2 ratio showed activity against KCNQ2 in CHO cells.The mixture of 5 and 6 (3:2) exhibited antiviral activity against influenza virus H1N1 PR8 with IC50 64.7 μmol/L (ribavirin,IC5o 54.3 μmol/L),however,the individual 5 or 6 was inactive.Preliminary structure-activity relationships were observed.
查看更多>>摘要：Due to numerous obstacles such as complex matrices,real-time monitoring of complex reaction systems (e.g.,medicinal herb stewing system) has always been a challenge though great values for safe and rational use of drugs.Herein,facilitated by the potential ability on the tolerance of complex matrices of extractive electrospray ionization mass spectrometry,a device was established to realize continuous sampling and real-time quantitative analysis of herb stewing system for the first time.A complete analytical strategy,including data acquisition,data mining,and data evaluation was proposed and implemented with overcoming the usual difficulties in real-time mass spectrometry quantification.The complex Fuzi (the lateral root of Aconitum)-meat stewing systems were real-timely monitored in 150 min by qualitative and quantitative analysis of the nine key alkaloids accurately.The results showed that the strategy worked perfectly and the toxicity of the systems were evaluated and predicated accordingly.Stewing with trotters effectively accelerated the detoxification of Fuzi soup and reduced the overall toxicity to 68％,which was recommended to be used practically for treating rheumatic arthritis and enhancing immunity.The established strategy was versatile,simple,and accurate,which would have a wide application prospect in real-time analysis and evaluation of various complex reaction systems.
查看更多>>摘要：Natural products,as a gift of nature to humanity,have long been used as drugs or pharmacological actives to help people cure various diseases.Yet we still know comparatively little about their ability to be materials.In recent years,some small molecule natural products isolated from traditional Chinese medicines have been found to have new features,namely,self-assembly to form gels (i.e.,natural product gels,NPG).However,the application development of these natural products is seriously lacking,which greatly weakens their practical value and delays the maturity of the field.Here,a series of self-assembled triterpenoid natural products are used as materials (gel scaffolds) to construct drug delivery systems.Surprisingly,these NPG not only exhibit the excellent self-healing,controlled gelation,good safety and sustained release,but also achieve synergistic treatment of tumors through bioactive natural products.Compared with non-bioactive gel scaffolds,NPG scaffolds show great advantages in tumor therapy,including optimal tumor inhibition,preferable health,better body recovery,stronger immune function,less toxic side effects and longer survival.The successful construction of NPG scaffolds not only takes full advantage of the self-assembled natural products,but also takes an important step in the development of new applications for natural products.
查看更多>>摘要：Background: Hydrogen bonding interaction was considered to play a critical role in controlling drug release from transdermal patch.However,the quantitative evaluation of hydrogen bonding strength between drug and polar functional group was rarely reported,and the relationship between hydrogen bonding strength and controlled release capacity of pressure sensitive adhesive (PSA) was not well understood.The present study shed light on this relationship.Methods: Acrylate PSAs with amide group were synthesized by a free radical-initiated solution polymerization.Six drugs,i.e.,etodolac,ketoprofen,gemfibrozil,zolmitriptan,propranolol and lidocaine,were selected as model drugs.In vitro drug release and skin permeation experiments and in vivo pharmacokinetic experiment were performed.Partial correlation analysis,fourier-transform infrared spectroscopy and molecular simulation were conducted to provide molecular details of drug-PSA interactions.Mechanical test,rheology study,and modulated differential scanning calorimetry study were performed to scrutinize the free volume and molecular mobility of PSAs.Results: Release rate of all six drugs from amide PSAs decreased with the increase of amide group concentrations;however,only zolmitriptan and propranolol showed decreased skin permeation rate.It was found that drug release was controlled by amide group through hydrogen bonding,and controlled release extent was positively correlated with hydrogen bonding strength.Conclusion: From these results,we concluded that drugs with strong hydrogen bond forming ability and high skin permeation were suitable to use amide PSAs to regulate their release rate from patch.
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