Chemical Composition of Rubus pirifolius Smith

[Objectives]This paper aimed to study the chemical composition of Rubus pirifolius Smith[Methods]A preliminary experiment was carried out using the qualitative reactions of various chemical constituents,in order to roughly detect the types of chemical constituents that may be contained in R.pirifolius Smith The ethanol extract of R.pirifolius Smith were separated and purified using silica gel column chromatography,silica gel thin-layer chromatography and recrystallization,and the chemicals obtained were identified using mass spectrometry,nuclear magnetic resonance and literature reference.[Results]The main constituents of R.pirifolius Smith are saponins,tannins,flavonoids,phytosterols,triterpenes and anthraquinones.A total of five compounds were isolated from the ethanol extract of R.pirifolius Smith,and they were identified asβ-sitosterol(1),arjunolic acid(2),stigmasterol-3-O-β-D-glucopyranoside(3),euscaphic acid(4)and 3,3′,4-trimethyle llegic acid(5).[Conclusions]Compounds 1,2,3,4 and 5 were isolated from R.pirifolius Smith for the first time.

Gp350-anchored extracellular vesicles: promising vehicles for delivering therapeutic drugs of B cell malignancies

Although chimeric antigen receptor-modified(CAR)T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia,its effect on Burkitt lymphoma(BL)and chronic B lymphocytic leukemia(B-CLL)is unsatisfactory.Moreover,fatal side effects greatly impede CAR T cell application.Extracellular vesicles(EVs)are excellent carriers of therapeutic agents.Nevertheless,EVs mainly accumulate in the liver when administered without modification.As an envelope glycoprotein of Epstein–Barr viruses,gp350 can efficiently bind CD21 on B cells.Here,gp350 was directly anchored onto red blood cell EVs(RBC-EVs)via its transmembrane region combined with low-voltage electroporation.The results showed that gp350 could anchor to RBC-EVs with high efficiency and that the resulting gp350-anchored RBC-EVs(RBC-EVs/gp350^(Etp))exhibited increased targeting to CD21+BL and B-CLL relative to RBC-EVs.After the loading of doxorubicin or fludarabine,RBC-EVs/gp350^(Etp) had powerful cytotoxicity and therapeutic efficacy on CD21+BL or B-CLL,respectively.Moreover,RBC-EVs/gp350^(Etp) loaded with a drug did not exhibit any apparent systemic toxicity and specifically induced the apoptosis of tumor B cells but not normal Bcells.Therefore,our findings indicate that drug-loaded RBC-EVs/gp350^(Etp) may be adopted in the treatment of CD21+B cell malignancies.

Tumor extracellular vesicles mediate anti-PD-L1 therapyresistance by decoying anti-PD-L1

PD-L1+tumor-derived extracellular vesicles(TEVs)cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody(αPD-L1)blockade.However,whether and how PD-L1+TEVs mediateαPD-L1 therapy resistance is unknown.Here,we show that PD-L1+TEVs substantially decoyαPD-L1 and that TEV-boundαPD-L1 is more rapidly cleared by macrophages,causing insufficient blockade of tumor PD-L1 and subsequentαPD-L1 therapy resistance.Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reversesαPD-L1 therapy resistance.Either an increasedαPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishesαPD-L1 therapy resistance.Moreover,in the treatment cycle with the same total treatment dose ofαPD-L1,high-dose and low-frequency treatment had better antitumor effects than low-dose and highfrequency treatment,induced stronger antitumor immune memory,and eliminatedαPD-L1 therapy resistance.Notably,in humanized immune system mice with human xenograft tumors,both increasedαPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects ofαPD-L1.Furthermore,increased doses ofαPD-L1 andαPD-1 had comparable antitumor effects,butαPD-L1 amplified fewer PD-1+Treg cells,which are responsible for tumor hyperprogression.Altogether,our results reveal a TEV-mediated mechanism ofαPD-L1-specific therapy resistance,thus providing promising strategies to improveαPD-L1 efficacy.