BACKGROUND Inflammatory bowel disease（IBD） is characterized by chronic and non-specific inflammation of the intestinal mucosa and mainly includes ulcerative colitis and Crohn’s disease.AIM To explore the beneficial...BACKGROUND Inflammatory bowel disease（IBD） is characterized by chronic and non-specific inflammation of the intestinal mucosa and mainly includes ulcerative colitis and Crohn’s disease.AIM To explore the beneficial effect of Toxo ROP16Ⅰ/Ⅲ-induced M2 phynotype macrophages in homeostasis of IBDs through downregulation of M1 inflammatory cells.METHODS RAW264.7 macrophages stimulated by lipopolysaccharide（LPS）（M1 cells） were co-cultured with Caco-2 cells as an inflammatory model of IBD in vitro.The expression of Toxo ROP16Ⅰ/Ⅲ was observed in RAW264.7 macrophages that were transfected with p EGFP-rop16Ⅰ/Ⅲ.The phenotypes of M2 and M1 macrophage cells were assessed by quantitative real-time reverse transcriptase polymerase chain reaction and the expression of tumor necrosis factor（TNF）-α,interleukin（IL）-1β,IL-6,transforming growth factor（TGF）-β1,IL-10,inducible nitric oxide synthase（i NOS）,and arginase-1（Arg-1） was detected.The expression of i NOS,Arg-1,signal transducer and activator of transcription 3（Stat3）,p-Stat3,Stat6,pStat6,programmed death ligand-2（PD-L2）,caspase-3,-8,and-9 was analyzed by Western blotting,and Griess assays were performed to detect nitric oxide（NO）.TNF-α,IL-1β,IL-6,TGF-β1,and IL-10 expression in the supernatants was detected by enzyme-linked immunosorbent assay,and Caco-2 cell apoptosis was determined by flow cytometry after mixing M1 cells with M2 cells in a Caco-2 cell co-culture system.RESULTS M1 cells exhibited significantly increased production of i NOS,NO,TNF-α,IL-1β,and IL-6,while Toxo ROP16Ⅰ/Ⅲ induced macrophage bias to M2 cells in vitro,showing increased expression of Arg-1,IL-10 and TGF-β1 and elevated production of p-Stat3 and p-Stat6.The mixed M1 and M2 cell culture induced by Toxo ROP16 Ⅰ/Ⅲ exhibited decreased production of NO and i NOS and upregulated expression of Arg-1 and PD-L2.Accordingly,Caco-2 cells became apoptotic,and apoptosis-associated proteins such as caspase-3,-8 and-9 were dampened during co-culture of M1 and M2 cells.Flow cytometry analysis showed that co-culture of M1 cells with Caco-2 cells facilitated the apoptosis of Caco-2 cells,but co-culture of M1 and M2 cells alleviated Caco-2 cell apoptosis.CONCLUSION Toxo ROP16 Ⅰ/Ⅲ-induced M2 macrophages inhibited apoptosis of Caco-2 cells caused by M1 macrophages.This finding may help gain a better understanding of the underlying mechanism and represent a promising therapeutic strategy for IBDs.展开更多
The newly emerged Middle East respiratory syndrome coronavirus(MERS-CoV)is a highly pathogenic respira-tory virus with pathogenic mechanisms that may be driven by innate immune pathways.The goal of this study is to ch...The newly emerged Middle East respiratory syndrome coronavirus(MERS-CoV)is a highly pathogenic respira-tory virus with pathogenic mechanisms that may be driven by innate immune pathways.The goal of this study is to characterize the expression of the structural(S,E,M,N)and accessory(ORF 3,ORF 4a,ORF 4b,ORF 5)proteins of MERS-CoV and to determine whether any of these pro-teins acts as an interferon antagonist.Individual structural and accessory protein-coding plasmids with an N-terminal HA tag were constructed and transiently transfected into cells,and their native expression and subcellular localiza-tion were assessed using Wes tern blotting and indirect immunofl uorescence.While ORF 4b demonstrated majorly nuclear localization,all of the other proteins demonstrated cytoplasmic localization.In addition,for the fi rst time,our experiments revealed that the M,ORF 4a,ORF 4b,and ORF 5 proteins are potent interferon antagonists.Further exami-nation revealed that the ORF 4a protein of MERS-CoV has the most potential to counteract the antiviral effects of IFN via the inhibition of both the interferon production(IFN-βpromoter activity,IRF-3/7 and NF-κB activation)and ISRE promoter element signaling pathways.Together,our re-sults provide new insights into the function and pathogenic role of the structural and accessory proteins of MERS-CoV.展开更多
Toxoplasma gondii is a widespread parasite that may infect nearly all warm-blooded vertebrates.1 As an obligatory intracellular apicomplexan parasite,T.gondii has three different types of secretory organelles,includin...Toxoplasma gondii is a widespread parasite that may infect nearly all warm-blooded vertebrates.1 As an obligatory intracellular apicomplexan parasite,T.gondii has three different types of secretory organelles,including micronemes,rhoptries(ROP),and dense granules(GRAs),during invasion of host cells.2 Initially,the parasite replicates in a variety of host cell types as tachyzoites,especially in macrophages and dendritic cells(DCs).展开更多
Although the pathological findings of coronavirus disease 2019(COVID-19)associated with acute respiratory distress syndrome(ARDS)have been reported in previous studies,the data of histopatho-logical features of end-st...Although the pathological findings of coronavirus disease 2019(COVID-19)associated with acute respiratory distress syndrome(ARDS)have been reported in previous studies,the data of histopatho-logical features of end-stage COVID-19 lungs are still lacking.We have previously reported the clini-cal features and managements of three COVID-19 patients with irreversible deterioration of pulmonary function who received lung transplantation(LT)after being supported by extracorporeal membrane oxygenation(ECMO)[1].展开更多
Signal transducer and activator of transcription （STAT） proteins play an important role in cytokine signaling pathways and regulation of immune responses. The balance of the phosphorylated （activated） STAT1 （pST...Signal transducer and activator of transcription （STAT） proteins play an important role in cytokine signaling pathways and regulation of immune responses. The balance of the phosphorylated （activated） STAT1 （pSTAT1） and STAT3 （pSTAT3） has been documented in cancer immunology. In this study, we investigated the dynamic balance of pSTAT1 and pSTAT3 in C57BL/6 mice infected with either a nonlethal （Py17XNL） or lethal （Py17XL） strain of Plasmodium yoelii. Both Py17XNL and Py17XL infections induced a maximum activation of STAT1 and STAT3 on the first day after parasite inoculation. Additionally, the Py17XNL infection induced a pSTAT1- dominant response in mice during the early stage of infection, with the resolution of parasitemia. In contrast, Py17XL infection induced a pSTAT3-dominant response during the early phase of infection, with the death of the animals. Our results indicated that maximum activation of STAT1 and STAT3 occurred much earlier than the peak levels of cytokines induced by Plasmodium yoelii infection based on previous reports and that infection with Py17XNL and Py17XL induced different dynamic patterns of pSTAT1 and pSTAT3 balance.展开更多
Based on recent molecular data, it has been suggested that Sporothrix globosa is the main causal agent of sporotrichosis in China. The objective of this study was to compare the morphology, growth characteristics, pat...Based on recent molecular data, it has been suggested that Sporothrix globosa is the main causal agent of sporotrichosis in China. The objective of this study was to compare the morphology, growth characteristics, patterns of carbon source usage, and susceptibility to antifungal agents among Sporothrix strains. A total of 15 clinical strains confirmed to be S. globosa, from three different regions of China, and 11 ex-type strains from the CBS-KNAW biodiversity center were obtained. The elongated conidia of S. pal/ida, S. variecibatus, S. schenckii, and S. schenckii luriei were clearly different from the subglobose and globose conidia of S. globosa strains. S. schenckii is able to assimilate sucrose, raffinose, and ribitol. Susceptibility profiles of these Sporothrix species were evaluated by measuring minimum inhibitory concentrations （MICs）. Fluconazole, itraconazole, terbinafine, and amphotericin B showed good activity against most S. globosa clinical isolates from China. Potassium iodide also showed a low MIC against S. pal/ida, while fluconazole showed a high MIC for S. mexicana, S. humicola, S. g/obosa, S. schenckii, and S. inflata; these strains might be considered tolerant. The species showed differences in susceptibility to antifungal drugs and should therefore be properly identified during diagnosis prior to designing therapeutic strategies.展开更多
Metabolites of microorganisms have long been considered as potential sources for drug discovery.In this study,fve new depsidone derivatives,talaronins A-E(1-5)and three new xanthone derivatives,talaronins F-H(6-8),tog...Metabolites of microorganisms have long been considered as potential sources for drug discovery.In this study,fve new depsidone derivatives,talaronins A-E(1-5)and three new xanthone derivatives,talaronins F-H(6-8),together with 16 known compounds(9-24),were isolated from the ethyl acetate extract of the mangrove-derived fungus Talaromyces species WHUF0362.The structures were elucidated by analysis of spectroscopic data and chemical methods including alkaline hydrolysis and Mosher’s method.Compounds 1 and 2 each attached a dimethyl acetal group at the aromatic ring.A putative biogenetic relationship of the isolated metabolites was presented and suggested that the depsidones and the xanthones probably had the same biosynthetic precursors such as chrysophanol or rheochrysidin.The antimicrobial activity assay indicated that compounds 5,9,10,and 14 showed potent activity against Helicobacter pylori with minimum inhibitory concentration(MIC)values in the range of 2.42-36.04μmol/L.While secalonic acid D(19)demonstrated signifcant antimicrobial activity against four strains of H.pylori with MIC values in the range of 0.20 to 1.57μmol/L.Furthermore,secalonic acid D(19)exhibited cytotoxicity against cancer cell lines Bel-7402 and HCT-116 with IC_(50) values of 0.15 and 0.19μmol/L,respectively.The structure–activity relationship of depsidone derivatives revealed that the presence of the lactone ring and the hydroxyl at C-10 was crucial to the antimicrobial activity against H.pylori.The depsidone derivatives are promising leads to inhibit H.pylori and provide an avenue for further development of novel antibiotics.展开更多
Managing Editor:Peng Lyu.Chemotherapy-induced thrombocytopenia(CIT)is a common complication that increases bleeding risks and necessitates chemotherapy dose reduction or discontinuation,which decreases therapeutic ben...Managing Editor:Peng Lyu.Chemotherapy-induced thrombocytopenia(CIT)is a common complication that increases bleeding risks and necessitates chemotherapy dose reduction or discontinuation,which decreases therapeutic benefits and worsens the chances of survival.1 Current therapeutic options,such as platelet transfusion,administration of recombinant interleukin(IL)-11,and treatment with thrombopoietin receptor agonists,have potential drawbacks,including transfusion-related allergic reactions,fluid retention-induced heart disease,and the emergence of anti-thrombopoietin antibodies.展开更多
The development of a vaccine based on human immunodeficiency virus type 1(HIV-1) envelope glycoprotein(Env) that elicits potent protective antibodies against infection has been challenging. Recently, we compared the a...The development of a vaccine based on human immunodeficiency virus type 1(HIV-1) envelope glycoprotein(Env) that elicits potent protective antibodies against infection has been challenging. Recently, we compared the antibody production patterns of HIV-1 Env gp120 and hepatitis B virus surface antigen(HBsAg) to provide insights into how we may improve the protective efficacy of Env-based immunogens. Our previous study showed that HIV Env and HBsAg display different mechanisms of antibody elicitation and that T cells facilitate the responses to repeated immunizations. Here, to elucidate the detailed roles of primary immunization in immune memory response formation and antibody production, we immunized C57BL/6 mice with each antigen and evaluated the development of T follicular helper(Tfh) cells, germinal centers,and the memory responses involved in prime and boost immunizations. We found that after prime immunization, compared with HBsAg, gp120 induced higher frequencies of Tfh cells and programmed death(PD)-1^+T cells, greater major histocompatibility complex II expression on B cells, comparable activated B cells, but weaker germinal center(GC)reactions and memory B cell responses in the draining lymph nodes, accompanied by slower antibody recall responses and poor immune memory responses. The above results suggested that more PD-1^+T cells arising in primary immunization may serve as major contributors to the slow antibody recall response elicited by HIV-1 Env.展开更多
Recent studies indicated that type II Toxoplasma gondii(Tg)GRA15II favored the generation of classically activated macrophages(M1),whereas type I/III TgROP16I/III promoted the polarization of alternatively activated m...Recent studies indicated that type II Toxoplasma gondii(Tg)GRA15II favored the generation of classically activated macrophages(M1),whereas type I/III TgROP16I/III promoted the polarization of alternatively activated macrophages(M2).A number of studies have demonstrated that M2 cells are involved in the pathogenesis of the liver fibrogenesis caused by Schistosoma japonicum.The purpose of the present study was to explore the inhibitory effect of Toxoplasma-derived TgGRA15II on mouse hepatic fibrosis with schistosomiasis.The gra15II and rop16I/III genes were amplified from strains T.gondii PRU and Chinese 1 Wh3,respectively.Lentiviral vectors containing the gra15II or rop16I/III plasmid were constructed and used to infect the RAW264.7 cell line.The polarization of the transfected cells was evaluated,followed by co-culture of the biased macrophages with mouse hepatic stellate JS1 cells.Then,mice were injected with GRA15II-driven macrophages via the tail vein and infected with S.japonicum cercariae.TgGRA15II induced a M1-biased response,whereas TgROP16I/III drove the macrophages to a M2-like phenotype.The in vitro experiments indicated that JS1 cell proliferation and collagen synthesis were decreased following co-culture with TgGRA15II-activated macrophages.Furthermore,mice inoculated with TgGRA15II-biased macrophages displayed a notable alleviation of collagen deposition and granuloma formation in their liver tissues.Our results suggest that TgGRA15II-induced M1 cells may dampen the M2 dominant pathogenesis of hepatic fibrosis and granulomatosis.These results provide insights into the use of parasite-derived immunomodulators as potential anti-fibrosis agents and to re-balance the schistosomiasis-induced immune response.展开更多
The breakthrough development of induced pluripotent stem cells(iPSCs)raises the prospect of patient-specific treatment for many diseases through the replacement of affected cells.However,whether iPSC-derived functiona...The breakthrough development of induced pluripotent stem cells(iPSCs)raises the prospect of patient-specific treatment for many diseases through the replacement of affected cells.However,whether iPSC-derived functional cell lineages generate a deleterious immune response upon auto-transplantation remains unclear.In this study,we differentiated five human iPSC lines from skin fibroblasts and urine cells into neural progenitor cells(NPCs)and analyzed their immunogenicity.Through co-culture with autogenous peripheral blood mononuclear cells(PBMCs),we showed that both somatic cells and iPSC-derived NPCs do not stimulate significant autogenous PBMC proliferation.However,a significant immune reaction was detected when these cells were co-cultured with allogenous PBMCs.Furthermore,no significant expression of perforin or granzyme B was detected following stimulation of autogenous immune effector cells(CD3+CD8 T cells,CD3+CD8+T cells or CD3 CD56+NK cells)by NPCs in both PBMC and T cell co-culture systems.These results suggest that human iPSC-derived NPCs may not initiate an immune response in autogenous transplants,and thus set a base for further preclinical evaluation of human iPSCs.展开更多
Infectious microbes that spread easily in healthcare facilities remain as the severe threat for the public health,especially among immunocompromised populations.Given the intricate problem of dramatic increase in resi...Infectious microbes that spread easily in healthcare facilities remain as the severe threat for the public health,especially among immunocompromised populations.Given the intricate problem of dramatic increase in resistance to common biocides,the development of safe and efficient biocide formulated agents to alleviate drug resistance is highly demanding.In this study,Schiff-base ligands were successfully formed on natural biopolymer of epsilon-poly-L-lysine(ε-PL)decorated aldehyde functionalized mesoporous silica SBA-15(CHO-SBA-15)for the selective coordination of silver ions,which was affirmed by various physicochemical methods.Besides the identified broad-spectrum antibacterial activities,the as-prepared Schiff-base silver nanocomplex(CHO-SBA-15/ε-PL/Ag,CLA-1)exhibited an improved inhibitory effect on infectious pathogen growth typified by Escherichia coli and Staphylococcus aureus in comparison with two control silver complexes without Schiff-base conjugates,SBA-15/ε-PL/Ag and CHO-SBA-15/Ag,respectively.In addition,CLA-1 remarkably inhibited the growth of Mycobacterium tuberculosis due to the excellent antimicrobial activity of silver species.Significantly,CLA-1 kills Candida albicans cells,inhibits biofilm formation,and eliminates preformed biofilms,with no development of resistance during continuous serial passaging.The antifungal activity is connected to disruption of bacterial cell membranes and increased levels of intracellular reactive oxygen species.In mouse models of multidrug-resistant C.albicans infection,CLA-1 exhibited efficient in vivo fungicidal efficacy superior to two antifungal drugs,amphotericin B and fluconazole.Moreover,CLA-1 treatment induces negligible toxicity against normal tissues with safety.Therefore,this study reveals the pivotal role of the molecular design of Schiff-base silver nanocomplex formation on biopolymer surface-functionalized silica mesopores as a green and efficient nanoplatform to tackle infectious microbes.展开更多
Background:Zinc-finger nucleases(ZFNs)and transcription activator-like effector nucleases(TALENs)have been successfully used to knock out endogenous genes in stem cell research.However,the deficiencies of current gene...Background:Zinc-finger nucleases(ZFNs)and transcription activator-like effector nucleases(TALENs)have been successfully used to knock out endogenous genes in stem cell research.However,the deficiencies of current gene-based delivery systems may hamper the clinical application of these nucleases.A new delivery method that can improve the utility of these nucleases is needed.Results:In this study,we utilized a cell-penetrating peptide-based system for ZFN and TALEN delivery.Functional TAT-ZFN and TAT-TALEN proteins were generated by fusing the cell-penetrating TAT peptide to ZFN and TALEN,respectively.However,TAT-ZFN was difficult to purify in quantities sufficient for analysis in cell culture.Purified TAT-TALEN was able to penetrate cells and disrupt the gene encoding endogenous human chemokine(C-C motif)receptor 5(CCR5,a co-receptor for HIV-1 entry into cells).Hypothermic treatment greatly enhanced the TAT-TALENmediated gene disruption efficiency.A 5%modification rate was observed in human induced pluripotent stem cells(hiPSCs)treated with TAT-TALEN as measured by the Surveyor assay.Conclusions:TAT-TALEN protein-mediated gene disruption was applicable in hiPSCs and represents a promising technique for gene knockout in stem cells.This new technique may advance the clinical application of TALEN technology.展开更多
The dysbiosis of gut microbiota is associated with the pathogenesis of human diseases.However,observing shifts in the microbe abundance cannot fully reveal underlying perturbations.Examining the relationship alteratio...The dysbiosis of gut microbiota is associated with the pathogenesis of human diseases.However,observing shifts in the microbe abundance cannot fully reveal underlying perturbations.Examining the relationship alterations(RAs)in the microbiome between health and disease statuses provides additional hints about the pathogenesis of human diseases,but no methods were designed to detect and quantify the RAs between different conditions directly.Here,we present profile monitoring for microbial relationship alteration(PM2 RA),an analysis framework to identify and quantify the microbial RAs.The performance of PM2 RA was evaluated with synthetic data,and it showed higher specificity and sensitivity than the co-occurrence-based methods.Analyses of real microbial datasets showed that PM2 RA was robust for quantifying microbial RAs across different datasets in several diseases.By applying PM2 RA,we identified several novel or previously reported microbes implicated in multiple diseases.PM2 RA is now implemented as a web-based application available at http://www.pm2 ra-xingyinliulab.cn/.展开更多
基金Supported by the National Natural Science Foundation of China,No.81471983the Key Research and Development Plan Project of Anhui Province,Department of Science and Technology 2019,No.201904a07020043+1 种基金the Key Project of Natural Science Research in the Universities of Anhui Provence,No.KJ2017A202the Research Fund Project of Anhui Institute of Transforming Medicine,No.2017zhyx04
文摘BACKGROUND Inflammatory bowel disease（IBD） is characterized by chronic and non-specific inflammation of the intestinal mucosa and mainly includes ulcerative colitis and Crohn’s disease.AIM To explore the beneficial effect of Toxo ROP16Ⅰ/Ⅲ-induced M2 phynotype macrophages in homeostasis of IBDs through downregulation of M1 inflammatory cells.METHODS RAW264.7 macrophages stimulated by lipopolysaccharide（LPS）（M1 cells） were co-cultured with Caco-2 cells as an inflammatory model of IBD in vitro.The expression of Toxo ROP16Ⅰ/Ⅲ was observed in RAW264.7 macrophages that were transfected with p EGFP-rop16Ⅰ/Ⅲ.The phenotypes of M2 and M1 macrophage cells were assessed by quantitative real-time reverse transcriptase polymerase chain reaction and the expression of tumor necrosis factor（TNF）-α,interleukin（IL）-1β,IL-6,transforming growth factor（TGF）-β1,IL-10,inducible nitric oxide synthase（i NOS）,and arginase-1（Arg-1） was detected.The expression of i NOS,Arg-1,signal transducer and activator of transcription 3（Stat3）,p-Stat3,Stat6,pStat6,programmed death ligand-2（PD-L2）,caspase-3,-8,and-9 was analyzed by Western blotting,and Griess assays were performed to detect nitric oxide（NO）.TNF-α,IL-1β,IL-6,TGF-β1,and IL-10 expression in the supernatants was detected by enzyme-linked immunosorbent assay,and Caco-2 cell apoptosis was determined by flow cytometry after mixing M1 cells with M2 cells in a Caco-2 cell co-culture system.RESULTS M1 cells exhibited significantly increased production of i NOS,NO,TNF-α,IL-1β,and IL-6,while Toxo ROP16Ⅰ/Ⅲ induced macrophage bias to M2 cells in vitro,showing increased expression of Arg-1,IL-10 and TGF-β1 and elevated production of p-Stat3 and p-Stat6.The mixed M1 and M2 cell culture induced by Toxo ROP16 Ⅰ/Ⅲ exhibited decreased production of NO and i NOS and upregulated expression of Arg-1 and PD-L2.Accordingly,Caco-2 cells became apoptotic,and apoptosis-associated proteins such as caspase-3,-8 and-9 were dampened during co-culture of M1 and M2 cells.Flow cytometry analysis showed that co-culture of M1 cells with Caco-2 cells facilitated the apoptosis of Caco-2 cells,but co-culture of M1 and M2 cells alleviated Caco-2 cell apoptosis.CONCLUSION Toxo ROP16 Ⅰ/Ⅲ-induced M2 macrophages inhibited apoptosis of Caco-2 cells caused by M1 macrophages.This finding may help gain a better understanding of the underlying mechanism and represent a promising therapeutic strategy for IBDs.
基金This work was supported by the National Basic Research Program(973 Program)(No.2011CB504704)the Ministry of Health of China(2014ZX10004-001,2013ZX10004601).
文摘The newly emerged Middle East respiratory syndrome coronavirus(MERS-CoV)is a highly pathogenic respira-tory virus with pathogenic mechanisms that may be driven by innate immune pathways.The goal of this study is to characterize the expression of the structural(S,E,M,N)and accessory(ORF 3,ORF 4a,ORF 4b,ORF 5)proteins of MERS-CoV and to determine whether any of these pro-teins acts as an interferon antagonist.Individual structural and accessory protein-coding plasmids with an N-terminal HA tag were constructed and transiently transfected into cells,and their native expression and subcellular localiza-tion were assessed using Wes tern blotting and indirect immunofl uorescence.While ORF 4b demonstrated majorly nuclear localization,all of the other proteins demonstrated cytoplasmic localization.In addition,for the fi rst time,our experiments revealed that the M,ORF 4a,ORF 4b,and ORF 5 proteins are potent interferon antagonists.Further exami-nation revealed that the ORF 4a protein of MERS-CoV has the most potential to counteract the antiviral effects of IFN via the inhibition of both the interferon production(IFN-βpromoter activity,IRF-3/7 and NF-κB activation)and ISRE promoter element signaling pathways.Together,our re-sults provide new insights into the function and pathogenic role of the structural and accessory proteins of MERS-CoV.
基金The work was funded by the Natural Science Foundation of China(Y.C.,Grant no.81572801 and L.Y.,Grant no.81572022)the Postdoctoral Foundation of Anhui Province(Y.C.,Grant no.2017B160).
文摘Toxoplasma gondii is a widespread parasite that may infect nearly all warm-blooded vertebrates.1 As an obligatory intracellular apicomplexan parasite,T.gondii has three different types of secretory organelles,including micronemes,rhoptries(ROP),and dense granules(GRAs),during invasion of host cells.2 Initially,the parasite replicates in a variety of host cell types as tachyzoites,especially in macrophages and dendritic cells(DCs).
基金This research was supported by the National Natural Science Foundation of China[grant numbers 81922041 and 81772020]the Science and Technology of Jiangsu Province China[grant number BK20170048]and Natural Science Fund for Colleges and Universities in Jiangsu Province[grant number 19KJB340001].
文摘Although the pathological findings of coronavirus disease 2019(COVID-19)associated with acute respiratory distress syndrome(ARDS)have been reported in previous studies,the data of histopatho-logical features of end-stage COVID-19 lungs are still lacking.We have previously reported the clini-cal features and managements of three COVID-19 patients with irreversible deterioration of pulmonary function who received lung transplantation(LT)after being supported by extracorporeal membrane oxygenation(ECMO)[1].
基金for providing the Py17XNL strain and the Malaria Research and Reference Reagent Resource Center (MR4, MAL88851-01265293) for donating the Py17XL strain of Plasmodium yoelii.
文摘Signal transducer and activator of transcription （STAT） proteins play an important role in cytokine signaling pathways and regulation of immune responses. The balance of the phosphorylated （activated） STAT1 （pSTAT1） and STAT3 （pSTAT3） has been documented in cancer immunology. In this study, we investigated the dynamic balance of pSTAT1 and pSTAT3 in C57BL/6 mice infected with either a nonlethal （Py17XNL） or lethal （Py17XL） strain of Plasmodium yoelii. Both Py17XNL and Py17XL infections induced a maximum activation of STAT1 and STAT3 on the first day after parasite inoculation. Additionally, the Py17XNL infection induced a pSTAT1- dominant response in mice during the early stage of infection, with the resolution of parasitemia. In contrast, Py17XL infection induced a pSTAT3-dominant response during the early phase of infection, with the death of the animals. Our results indicated that maximum activation of STAT1 and STAT3 occurred much earlier than the peak levels of cytokines induced by Plasmodium yoelii infection based on previous reports and that infection with Py17XNL and Py17XL induced different dynamic patterns of pSTAT1 and pSTAT3 balance.
基金supported by the National Natural Science Foundation of China(No.31270062)
文摘Based on recent molecular data, it has been suggested that Sporothrix globosa is the main causal agent of sporotrichosis in China. The objective of this study was to compare the morphology, growth characteristics, patterns of carbon source usage, and susceptibility to antifungal agents among Sporothrix strains. A total of 15 clinical strains confirmed to be S. globosa, from three different regions of China, and 11 ex-type strains from the CBS-KNAW biodiversity center were obtained. The elongated conidia of S. pal/ida, S. variecibatus, S. schenckii, and S. schenckii luriei were clearly different from the subglobose and globose conidia of S. globosa strains. S. schenckii is able to assimilate sucrose, raffinose, and ribitol. Susceptibility profiles of these Sporothrix species were evaluated by measuring minimum inhibitory concentrations （MICs）. Fluconazole, itraconazole, terbinafine, and amphotericin B showed good activity against most S. globosa clinical isolates from China. Potassium iodide also showed a low MIC against S. pal/ida, while fluconazole showed a high MIC for S. mexicana, S. humicola, S. g/obosa, S. schenckii, and S. inflata; these strains might be considered tolerant. The species showed differences in susceptibility to antifungal drugs and should therefore be properly identified during diagnosis prior to designing therapeutic strategies.
基金This research was funded by grants from National Key Research and Development Program of China(2018YFC0311002)High-Level Talent Special Support Plan of Zhejiang Province(2019R52009).
文摘Metabolites of microorganisms have long been considered as potential sources for drug discovery.In this study,fve new depsidone derivatives,talaronins A-E(1-5)and three new xanthone derivatives,talaronins F-H(6-8),together with 16 known compounds(9-24),were isolated from the ethyl acetate extract of the mangrove-derived fungus Talaromyces species WHUF0362.The structures were elucidated by analysis of spectroscopic data and chemical methods including alkaline hydrolysis and Mosher’s method.Compounds 1 and 2 each attached a dimethyl acetal group at the aromatic ring.A putative biogenetic relationship of the isolated metabolites was presented and suggested that the depsidones and the xanthones probably had the same biosynthetic precursors such as chrysophanol or rheochrysidin.The antimicrobial activity assay indicated that compounds 5,9,10,and 14 showed potent activity against Helicobacter pylori with minimum inhibitory concentration(MIC)values in the range of 2.42-36.04μmol/L.While secalonic acid D(19)demonstrated signifcant antimicrobial activity against four strains of H.pylori with MIC values in the range of 0.20 to 1.57μmol/L.Furthermore,secalonic acid D(19)exhibited cytotoxicity against cancer cell lines Bel-7402 and HCT-116 with IC_(50) values of 0.15 and 0.19μmol/L,respectively.The structure–activity relationship of depsidone derivatives revealed that the presence of the lactone ring and the hydroxyl at C-10 was crucial to the antimicrobial activity against H.pylori.The depsidone derivatives are promising leads to inhibit H.pylori and provide an avenue for further development of novel antibiotics.
文摘Managing Editor:Peng Lyu.Chemotherapy-induced thrombocytopenia(CIT)is a common complication that increases bleeding risks and necessitates chemotherapy dose reduction or discontinuation,which decreases therapeutic benefits and worsens the chances of survival.1 Current therapeutic options,such as platelet transfusion,administration of recombinant interleukin(IL)-11,and treatment with thrombopoietin receptor agonists,have potential drawbacks,including transfusion-related allergic reactions,fluid retention-induced heart disease,and the emergence of anti-thrombopoietin antibodies.
基金supported by the Grant of National Natural Science Foundation of China (Grant number 81271824, 81772190, 81601755)the Grant of National Science and Technology Major Project (Grant number 2012ZX10001009-002003)
文摘The development of a vaccine based on human immunodeficiency virus type 1(HIV-1) envelope glycoprotein(Env) that elicits potent protective antibodies against infection has been challenging. Recently, we compared the antibody production patterns of HIV-1 Env gp120 and hepatitis B virus surface antigen(HBsAg) to provide insights into how we may improve the protective efficacy of Env-based immunogens. Our previous study showed that HIV Env and HBsAg display different mechanisms of antibody elicitation and that T cells facilitate the responses to repeated immunizations. Here, to elucidate the detailed roles of primary immunization in immune memory response formation and antibody production, we immunized C57BL/6 mice with each antigen and evaluated the development of T follicular helper(Tfh) cells, germinal centers,and the memory responses involved in prime and boost immunizations. We found that after prime immunization, compared with HBsAg, gp120 induced higher frequencies of Tfh cells and programmed death(PD)-1^+T cells, greater major histocompatibility complex II expression on B cells, comparable activated B cells, but weaker germinal center(GC)reactions and memory B cell responses in the draining lymph nodes, accompanied by slower antibody recall responses and poor immune memory responses. The above results suggested that more PD-1^+T cells arising in primary immunization may serve as major contributors to the slow antibody recall response elicited by HIV-1 Env.
基金We thank Dr Jinsheng Guo at Shanghai Zhongshan Hospital for providing the murine hepatic stellate cell line JS1The work was funded by the National Science Foundation of China(No.81471983 and No.81171606)+1 种基金the National Basic Research Program of China(No.2010CB530001)the Science Foundation of Anhui Province(No.KJ2014A106 and No.1308085MH124).
文摘Recent studies indicated that type II Toxoplasma gondii(Tg)GRA15II favored the generation of classically activated macrophages(M1),whereas type I/III TgROP16I/III promoted the polarization of alternatively activated macrophages(M2).A number of studies have demonstrated that M2 cells are involved in the pathogenesis of the liver fibrogenesis caused by Schistosoma japonicum.The purpose of the present study was to explore the inhibitory effect of Toxoplasma-derived TgGRA15II on mouse hepatic fibrosis with schistosomiasis.The gra15II and rop16I/III genes were amplified from strains T.gondii PRU and Chinese 1 Wh3,respectively.Lentiviral vectors containing the gra15II or rop16I/III plasmid were constructed and used to infect the RAW264.7 cell line.The polarization of the transfected cells was evaluated,followed by co-culture of the biased macrophages with mouse hepatic stellate JS1 cells.Then,mice were injected with GRA15II-driven macrophages via the tail vein and infected with S.japonicum cercariae.TgGRA15II induced a M1-biased response,whereas TgROP16I/III drove the macrophages to a M2-like phenotype.The in vitro experiments indicated that JS1 cell proliferation and collagen synthesis were decreased following co-culture with TgGRA15II-activated macrophages.Furthermore,mice inoculated with TgGRA15II-biased macrophages displayed a notable alleviation of collagen deposition and granuloma formation in their liver tissues.Our results suggest that TgGRA15II-induced M1 cells may dampen the M2 dominant pathogenesis of hepatic fibrosis and granulomatosis.These results provide insights into the use of parasite-derived immunomodulators as potential anti-fibrosis agents and to re-balance the schistosomiasis-induced immune response.
基金supported by the National Basic Research Program of China,Ministry of Science and Technology(2011CB965204,2012CB966802)the National Natural Science Foundation of China(31000402)+3 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA01020401,XDA-01020202)the Ministry of Science and Technology International Technology Cooperation Program(2012DFH30050)the National Science&Technology Major Special Project on Major New Drug Innovation(2011ZX09102-010-01)the Development and Technology Innovation for Equipment Functional Development Project of Chinese Academy of Sciences(yg2011082,yg2011083)
文摘The breakthrough development of induced pluripotent stem cells(iPSCs)raises the prospect of patient-specific treatment for many diseases through the replacement of affected cells.However,whether iPSC-derived functional cell lineages generate a deleterious immune response upon auto-transplantation remains unclear.In this study,we differentiated five human iPSC lines from skin fibroblasts and urine cells into neural progenitor cells(NPCs)and analyzed their immunogenicity.Through co-culture with autogenous peripheral blood mononuclear cells(PBMCs),we showed that both somatic cells and iPSC-derived NPCs do not stimulate significant autogenous PBMC proliferation.However,a significant immune reaction was detected when these cells were co-cultured with allogenous PBMCs.Furthermore,no significant expression of perforin or granzyme B was detected following stimulation of autogenous immune effector cells(CD3+CD8 T cells,CD3+CD8+T cells or CD3 CD56+NK cells)by NPCs in both PBMC and T cell co-culture systems.These results suggest that human iPSC-derived NPCs may not initiate an immune response in autogenous transplants,and thus set a base for further preclinical evaluation of human iPSCs.
基金supported by the National Key R&D Programs of China(No.2018YFC0311003 to H.B.)the National Natural Science Foundation of China(No.U1703118 to J.C.)+5 种基金the Natural Science Foundation of Jiangsu Province(No.BK20181364 to J.C.)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD,to J.C.)the Cooperative Project between Southeast University and Nanjing Medical University(No.2018DN0004 to J.C.)the National Science Foundation of the Jiangsu Higher Education Institutions of China(No.18KJA310002 to H.B.,No.19KJA310003 to J.C)the Jiangsu Specially Appointed Professor and Jiangsu Medical Specialist Programs of China(to H.B.)Jiangsu Province“Innovative and Entrepreneurial Team”Program.
文摘Infectious microbes that spread easily in healthcare facilities remain as the severe threat for the public health,especially among immunocompromised populations.Given the intricate problem of dramatic increase in resistance to common biocides,the development of safe and efficient biocide formulated agents to alleviate drug resistance is highly demanding.In this study,Schiff-base ligands were successfully formed on natural biopolymer of epsilon-poly-L-lysine(ε-PL)decorated aldehyde functionalized mesoporous silica SBA-15(CHO-SBA-15)for the selective coordination of silver ions,which was affirmed by various physicochemical methods.Besides the identified broad-spectrum antibacterial activities,the as-prepared Schiff-base silver nanocomplex(CHO-SBA-15/ε-PL/Ag,CLA-1)exhibited an improved inhibitory effect on infectious pathogen growth typified by Escherichia coli and Staphylococcus aureus in comparison with two control silver complexes without Schiff-base conjugates,SBA-15/ε-PL/Ag and CHO-SBA-15/Ag,respectively.In addition,CLA-1 remarkably inhibited the growth of Mycobacterium tuberculosis due to the excellent antimicrobial activity of silver species.Significantly,CLA-1 kills Candida albicans cells,inhibits biofilm formation,and eliminates preformed biofilms,with no development of resistance during continuous serial passaging.The antifungal activity is connected to disruption of bacterial cell membranes and increased levels of intracellular reactive oxygen species.In mouse models of multidrug-resistant C.albicans infection,CLA-1 exhibited efficient in vivo fungicidal efficacy superior to two antifungal drugs,amphotericin B and fluconazole.Moreover,CLA-1 treatment induces negligible toxicity against normal tissues with safety.Therefore,this study reveals the pivotal role of the molecular design of Schiff-base silver nanocomplex formation on biopolymer surface-functionalized silica mesopores as a green and efficient nanoplatform to tackle infectious microbes.
基金We are grateful to Miguel A.Esteban and his group for supplying the hiPSCs.This work was financially supported by the National Science and Technology Major Project(2013ZX10001-004-002-004)the National Natural Science Foundation of China(No.81200398).
文摘Background:Zinc-finger nucleases(ZFNs)and transcription activator-like effector nucleases(TALENs)have been successfully used to knock out endogenous genes in stem cell research.However,the deficiencies of current gene-based delivery systems may hamper the clinical application of these nucleases.A new delivery method that can improve the utility of these nucleases is needed.Results:In this study,we utilized a cell-penetrating peptide-based system for ZFN and TALEN delivery.Functional TAT-ZFN and TAT-TALEN proteins were generated by fusing the cell-penetrating TAT peptide to ZFN and TALEN,respectively.However,TAT-ZFN was difficult to purify in quantities sufficient for analysis in cell culture.Purified TAT-TALEN was able to penetrate cells and disrupt the gene encoding endogenous human chemokine(C-C motif)receptor 5(CCR5,a co-receptor for HIV-1 entry into cells).Hypothermic treatment greatly enhanced the TAT-TALENmediated gene disruption efficiency.A 5%modification rate was observed in human induced pluripotent stem cells(hiPSCs)treated with TAT-TALEN as measured by the Surveyor assay.Conclusions:TAT-TALEN protein-mediated gene disruption was applicable in hiPSCs and represents a promising technique for gene knockout in stem cells.This new technique may advance the clinical application of TALEN technology.
基金supported by the National Natural Science Foundation of China(Grant Nos.81671983 and 81871628)the Natural Science Funding from Jiangsu province,China(Grant No.BK20161572)+1 种基金the starting package from Nanjing Medical University,Chinathe starting funding for the team of gut microbiota research in Nanjing Medical University,China
文摘The dysbiosis of gut microbiota is associated with the pathogenesis of human diseases.However,observing shifts in the microbe abundance cannot fully reveal underlying perturbations.Examining the relationship alterations(RAs)in the microbiome between health and disease statuses provides additional hints about the pathogenesis of human diseases,but no methods were designed to detect and quantify the RAs between different conditions directly.Here,we present profile monitoring for microbial relationship alteration(PM2 RA),an analysis framework to identify and quantify the microbial RAs.The performance of PM2 RA was evaluated with synthetic data,and it showed higher specificity and sensitivity than the co-occurrence-based methods.Analyses of real microbial datasets showed that PM2 RA was robust for quantifying microbial RAs across different datasets in several diseases.By applying PM2 RA,we identified several novel or previously reported microbes implicated in multiple diseases.PM2 RA is now implemented as a web-based application available at http://www.pm2 ra-xingyinliulab.cn/.
