Hepatocellular carcinoma(HCC)arises on the background of chronic liver disease.Despite the development of effective anti-viral therapeutics HCC is continuing to rise,in part driven by the epidemic of non-alcoholic fat...Hepatocellular carcinoma(HCC)arises on the background of chronic liver disease.Despite the development of effective anti-viral therapeutics HCC is continuing to rise,in part driven by the epidemic of non-alcoholic fatty liver disease.Many patients present with advanced disease out with the criteria for transplant,resection or even locoregional therapy.Currently available therapeutics for HCC are effective in a small minority of individuals.However,there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers,great opportunities now exist for treating HCC with newer and more sophisticated agents.Whilst checkpoint inhibitors are at the forefront of this revolution,other therapeutics such as inhibitory cytokine blockade,oncolytic viruses,adoptive cellular therapies and vaccines are emerging.Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response.Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy,either in combination with one another or in combination with treatment modalities such as locoregional therapy.Together these agents are likely to generate new and exciting opportunities for treating HCC,which are summarized in this review.展开更多
AIM: To determine the correlation between invasiveness, migration and prognosis in esophageal squamous cell carcinoma (ESCC) and expression of the B-cell-specific Moloney leukemia virus insert site 1 (Bmi-1) and plasm...AIM: To determine the correlation between invasiveness, migration and prognosis in esophageal squamous cell carcinoma (ESCC) and expression of the B-cell-specific Moloney leukemia virus insert site 1 (Bmi-1) and plasminogen activator inhibitor-1 (PAI-1).展开更多
Neuraminidase (NA) is one of the most important targets to screen the drugs of anti-influenza virus A and B. After virtual screening approaches were applied to a compound database which possesses more than 10000 compo...Neuraminidase (NA) is one of the most important targets to screen the drugs of anti-influenza virus A and B. After virtual screening approaches were applied to a compound database which possesses more than 10000 compound structures, 160 compounds were selected for bioactivity assay, then a High Throughput Screening (HTS) model established for influenza virus NA inhibitors was applied to detect these compounds. Finally, three compounds among them displayed higher inhibitory activities, the range of their IC5o was from 0.1 μmol/L to 3 μmol/L. Their structural scaffolds are novel and different from those of NA inhibitors approved for influenza treatment, and will be useful for the design and research of new NA inhibitors. The result indicated that the combination of virtual screening with HTS was very significant to drug screening and drug discovery.展开更多
Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seaso...Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.展开更多
The phosphatidylinositol 3-kinase(PI3K)-AKT pathway is involved in various cellular functions, including anti-apoptosis, protein synthesis, glucose metabolism and cell cycling. However, the role of the PI3K-AKT pathwa...The phosphatidylinositol 3-kinase(PI3K)-AKT pathway is involved in various cellular functions, including anti-apoptosis, protein synthesis, glucose metabolism and cell cycling. However, the role of the PI3K-AKT pathway in crustaceans remains unclear. In the present study, we cloned and characterized the AKT gene lvakt from Litopenaeus vannamei. The 511-residue LVAKT was highly conserved; contained a PH domain, a catalytic domain and a hydrophobic domain; and was highly expressed in the heart and gills of L. vannamei. We found, using Real-Time Quantitative PCR(Q-PCR) analysis, that lvakt was upregulated during early white spot syndrome virus(WSSV) infection. Moreover, the PI3K-specific inhibitor, LY294002, reduced viral gene transcription, implying that the PI3K-AKT pathway might be hijacked by WSSV. Our results therefore suggest that LVAKT may play an important role in the shrimp immune response against WSSV.展开更多
Bombyx mori cytoplasmic polyhedrosis virus(BmCPV)is a major pathogen of the economic insect silkworm,Bombyx mori.Virus‐encoded microRNAs(miRNAs)have been proven to play important roles in host–pathogen interactions....Bombyx mori cytoplasmic polyhedrosis virus(BmCPV)is a major pathogen of the economic insect silkworm,Bombyx mori.Virus‐encoded microRNAs(miRNAs)have been proven to play important roles in host–pathogen interactions.In this study we identified a BmCPV‐derived miRNA‐like 21 nt small RNA,BmCPV‐miR‐1,from the small RNA deep sequencing of BmCPV‐infected silkworm larvae by stem‐loop quantitative real‐time PCR(qPCR)and investigated its functions with qPCR and lentiviral expression systems.Bombyx mori inhibitor of apoptosis protein(BmIAP)gene was predicted by both target prediction software miRanda and Targetscan to be one of its target genes with a binding site for BmCPV‐miR‐1 at the 5′untranslated region.It was found that the expression of BmCPV‐miR‐1 and its target gene BmIAP were both up‐regulated in BmCPV‐infected larvae.At the same time,it was confirmed that BmCPV‐miR‐1 could up‐regulate the expression of BmIAP gene in HEK293T cells with lentiviral expression systems and in BmN cells by transfecting mimics.Furthermore,BmCPV‐miR‐1 mimics could up‐regulate the expression level of BmIAP gene in midgut and fat body in the silkworm.In the midgut of BmCPV‐infected larvae,BmCPV‐miR‐1 mimics could be further up‐regulated and inhibitors could lower the virus‐mediated expression of BmIAP gene.With the viral genomic RNA segments S1 and S10 as indicators,BmCPV‐miR‐1 mimics could up‐regulate and inhibitors down‐regulate their replication in the infected silkworm.These results implied that BmCPV‐miR‐1 could inhibit cell apoptosis in the infected silkworm through up‐regulating BmIAP expression,providing the virus with a better cell circumstance for its replication.展开更多
文摘Hepatocellular carcinoma(HCC)arises on the background of chronic liver disease.Despite the development of effective anti-viral therapeutics HCC is continuing to rise,in part driven by the epidemic of non-alcoholic fatty liver disease.Many patients present with advanced disease out with the criteria for transplant,resection or even locoregional therapy.Currently available therapeutics for HCC are effective in a small minority of individuals.However,there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers,great opportunities now exist for treating HCC with newer and more sophisticated agents.Whilst checkpoint inhibitors are at the forefront of this revolution,other therapeutics such as inhibitory cytokine blockade,oncolytic viruses,adoptive cellular therapies and vaccines are emerging.Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response.Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy,either in combination with one another or in combination with treatment modalities such as locoregional therapy.Together these agents are likely to generate new and exciting opportunities for treating HCC,which are summarized in this review.
基金Supported by Natural Science Foundation of Xinjiang Uygur Autonomous Region,No.2012211A035Graduate Research and Innovation Project of Xnjiang Uygur Autonomous Region,No.XJGRI2013076Research and Innovation Project of Xinjiang Medical University,No.XJC201314
文摘AIM: To determine the correlation between invasiveness, migration and prognosis in esophageal squamous cell carcinoma (ESCC) and expression of the B-cell-specific Moloney leukemia virus insert site 1 (Bmi-1) and plasminogen activator inhibitor-1 (PAI-1).
文摘Neuraminidase (NA) is one of the most important targets to screen the drugs of anti-influenza virus A and B. After virtual screening approaches were applied to a compound database which possesses more than 10000 compound structures, 160 compounds were selected for bioactivity assay, then a High Throughput Screening (HTS) model established for influenza virus NA inhibitors was applied to detect these compounds. Finally, three compounds among them displayed higher inhibitory activities, the range of their IC5o was from 0.1 μmol/L to 3 μmol/L. Their structural scaffolds are novel and different from those of NA inhibitors approved for influenza treatment, and will be useful for the design and research of new NA inhibitors. The result indicated that the combination of virtual screening with HTS was very significant to drug screening and drug discovery.
基金supported by the National Natural Science Foundation of China (81788101, 81573587 and 81490531)the Ministry of Science and Technology of China (2015CB5534/6)+3 种基金111 project (B08007)the Peking Union Medical College Youth FundFundamental Research Funds for Central Universities (3332013132)the CAMS Innovation Fund for Medical Sciences (2017-I2M-1-009)
文摘Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.
基金Supported by the Scientific Research Foundation of Third Institute of Oceanography,SOA(No.2011018)the Natural Science Foundation of Fujian Province of China(No.2011J05079)+3 种基金the National Natural Science Foundation of China(No.31001125)the Major State Basic Research Development Program of China(973 Program)(No.2012CB114403)the National High Technology Research and Development Program of China(863 Program)(No.2012AA092205)the China Agriculture Research System-47
文摘The phosphatidylinositol 3-kinase(PI3K)-AKT pathway is involved in various cellular functions, including anti-apoptosis, protein synthesis, glucose metabolism and cell cycling. However, the role of the PI3K-AKT pathway in crustaceans remains unclear. In the present study, we cloned and characterized the AKT gene lvakt from Litopenaeus vannamei. The 511-residue LVAKT was highly conserved; contained a PH domain, a catalytic domain and a hydrophobic domain; and was highly expressed in the heart and gills of L. vannamei. We found, using Real-Time Quantitative PCR(Q-PCR) analysis, that lvakt was upregulated during early white spot syndrome virus(WSSV) infection. Moreover, the PI3K-specific inhibitor, LY294002, reduced viral gene transcription, implying that the PI3K-AKT pathway might be hijacked by WSSV. Our results therefore suggest that LVAKT may play an important role in the shrimp immune response against WSSV.
基金This work was financially supported by the National Natural Science Foundation of China(Grant No.31572463).
文摘Bombyx mori cytoplasmic polyhedrosis virus(BmCPV)is a major pathogen of the economic insect silkworm,Bombyx mori.Virus‐encoded microRNAs(miRNAs)have been proven to play important roles in host–pathogen interactions.In this study we identified a BmCPV‐derived miRNA‐like 21 nt small RNA,BmCPV‐miR‐1,from the small RNA deep sequencing of BmCPV‐infected silkworm larvae by stem‐loop quantitative real‐time PCR(qPCR)and investigated its functions with qPCR and lentiviral expression systems.Bombyx mori inhibitor of apoptosis protein(BmIAP)gene was predicted by both target prediction software miRanda and Targetscan to be one of its target genes with a binding site for BmCPV‐miR‐1 at the 5′untranslated region.It was found that the expression of BmCPV‐miR‐1 and its target gene BmIAP were both up‐regulated in BmCPV‐infected larvae.At the same time,it was confirmed that BmCPV‐miR‐1 could up‐regulate the expression of BmIAP gene in HEK293T cells with lentiviral expression systems and in BmN cells by transfecting mimics.Furthermore,BmCPV‐miR‐1 mimics could up‐regulate the expression level of BmIAP gene in midgut and fat body in the silkworm.In the midgut of BmCPV‐infected larvae,BmCPV‐miR‐1 mimics could be further up‐regulated and inhibitors could lower the virus‐mediated expression of BmIAP gene.With the viral genomic RNA segments S1 and S10 as indicators,BmCPV‐miR‐1 mimics could up‐regulate and inhibitors down‐regulate their replication in the infected silkworm.These results implied that BmCPV‐miR‐1 could inhibit cell apoptosis in the infected silkworm through up‐regulating BmIAP expression,providing the virus with a better cell circumstance for its replication.
