Antiviral effects of natural small molecules on aquatic rhabdovirus by interfering with early viral replication

Spring viremia of carp virus(SVCV)is globally widespread and poses a serious threat to aquatic ecology and aquaculture due to its broad host range.To develop effective agents to control SVCV infection,we selected 16 naturally active small molecules to assess their anti-SVCV activity.Notably,dihydroartemisinin(DHA)(100μmol/L)and(S,S)-(+)-tetrandrine(TET)(16μmol/L)exhibited high antiviral effects in epithelioma papulosum cyprinid(EPC)cells,with inhibitory rates of 70.11%and 73.54%,respectively.The possible antiviral mechanisms were determined as follows:1.Preincubation with DHA and TET decreased viral particle infectivity in fish cells,suggesting that horizontal transmission of SVCV in the aquatic environment was disrupted;2.Although neither had an effect on viral adhesion,TET(but not DHA)interfered with SVCV entry into host cells(>80%),suggesting that TET may have an antiviral function in early viral replication.For in vivo study,both agents enhanced the survival rate of SVCV-infected zebrafish by 53.3%,significantly decreased viral load,and modulated the expression of antiviralrelated genes,indicating that DHA and TET may stimulate the host innate immune response to prevent viral infection.Overall,our findings indicated that DHA and TET had positive effects on suppressing SVCV infection by affecting early-stage viral replication,thus holding great potential as immunostimulants to reduce the risk of aquatic rhabdovirus disease outbreaks.

Photosensitive pro-drug nanoassemblies harboring a chemotherapeutic dormancy function potentiates cancer immunotherapy

Immunotherapy combined with effective therapeutics such as chemotherapy and photodynamic therapy have been shown to be a successful strategy to activate anti-tumor immune responses for improved anticancer treatment.However,developing multifunctional biodegradable,biocompatible,low-toxic but highly efficient,and clinically available transformed nano-immunostimulants remains a challenge and is in great demand.Herein,we report and design of a novel carrier-free photo-chemotherapeutic nano-prodrug COS-BA/Ce6 NPs by combining three multifunctional components-a self-assembled natural small molecule betulinic acid(BA),a water-soluble chitosan oligosaccharide(COS),and a low toxic photosensitizer chlorin e6(Ce6)-to augment the antitumor efficacy of the immune adjuvant anti-PD-L1-mediated cancer immunotherapy.We show that the designed nanodrugs harbored a smart and distinctive“dormancy”characteristic in chemotherapeutic effect with desired lower cytotoxicity,and multiple favorable therapeutic features including improved^(1)O_(2)generation induced by the reduced energy gap of Ce6,pH-responsiveness,good biodegradability,and biocompatibility,ensuring a highly efficient,synergistic photochemotherapy.Moreover,when combined with anti-PD-L1 therapy,both nano-coassembly based chemotherapy and chemotherapy/photodynamic therapy(PDT)could effectively activate antitumor immunity when treating primary or distant tumors,opening up potentially attractive possibilities for clinical immunotherapy.