Even the potential of T cell-mimicking nanotrap for long term viral control due to its overcoming of human immunodeficiency virus(HIV)genetic diversity and viral resistance,the robust HIV inhibition was not expected b...Even the potential of T cell-mimicking nanotrap for long term viral control due to its overcoming of human immunodeficiency virus(HIV)genetic diversity and viral resistance,the robust HIV inhibition was not expected because these nanotraps displayed no obvious advantages compared with the infinite host cells.Herein,a glycoprotein 120(gp120)-targeting polypeptide UM15 reinforced lymphocyte-mimicking nanotrap was constructed,and its improved HIV-1 inhibiting efficacy was validated.According to the results,the constructed nanotraps exhibited evident escaping ability from uptake of the mononuclear phagocyte system and highly improved binding ability with gp120 proteins.The constructed nanotraps neutralized all tested HIV-1 pseudo typed viruses with IC80 of 21.0μg/mL,and inhibited both X4-tropic and R5-tropic HIV-1 with IC80 of 34.4 and 20.6μg/mL,respectively.Approximately 40%of gp120 was observed to be shed from pseudo virus,and above 40%bystander T cells were prevented from gp120-induced death by the constructed nanotraps.The safety of the constructed nanotraps was confirmed both in vitro and in mice.Therefore,the constructed nanotraps could specifically neutralize free HIV-1,selectively bind with gp120 expressing HIV-1 infected cells,cause gp120 shedding,inhibit gp120-induced bystander T cell killing on the premise of safety,and were considered as promising therapeutic agents for precise inhibition of HIV.展开更多
Circulating peptide is a potential source of biomarkers for cancer detection.However,the existence of large molecular weight proteins in plasma have a disastrous effect on circulating peptides isolating and detecting....Circulating peptide is a potential source of biomarkers for cancer detection.However,the existence of large molecular weight proteins in plasma have a disastrous effect on circulating peptides isolating and detecting.Herein,nanotrap fractionation following by mass spectrometry have been applied to quantify the levels of bradykinin (BK) and hydroxylated bradykinin (Hyp-BK) as a relative measure of KRAS-regulated prolyl-4-hydroxylase alpha-1 (P4HA1) which may serve as early diagnosis marker for pancreatic ductal adenocarcinoma (PDAC).We found that P4HA1 can be upregulated by KRASG12v,which is a PDAC driver mutation,using HPNE/KRAS and HPNE cells.And we revealed that P4HA1 is overexpressed in PDAC tumors,compared to normal and inflamed pancreatic tissues.RNA interference revealed that P4HA1 activity was primarily responsible for Hyp-BK production.Mass spectrometry analysis revealed that plasma Hyp-BK/BK ratio was higher in PDAC than pancreatitis patients and healthy controls,while the area under the receiver operating characteristic (ROC) curve (AUC) is 0.8209 (95%Cl,0.7269-0.9149).The Hyp-BK/BK association with PDAC was reproduced in another cohort,where this ratio was found to increase with advancing tumor stage.These novel findings paved the way for wider applications of Nanotrap coupled mass spectrometry as a powerful tool for revealing biosignatures from plasma.展开更多
基金The current work was supported by the National Natural Science Foundation of China(No.81502675).
文摘Even the potential of T cell-mimicking nanotrap for long term viral control due to its overcoming of human immunodeficiency virus(HIV)genetic diversity and viral resistance,the robust HIV inhibition was not expected because these nanotraps displayed no obvious advantages compared with the infinite host cells.Herein,a glycoprotein 120(gp120)-targeting polypeptide UM15 reinforced lymphocyte-mimicking nanotrap was constructed,and its improved HIV-1 inhibiting efficacy was validated.According to the results,the constructed nanotraps exhibited evident escaping ability from uptake of the mononuclear phagocyte system and highly improved binding ability with gp120 proteins.The constructed nanotraps neutralized all tested HIV-1 pseudo typed viruses with IC80 of 21.0μg/mL,and inhibited both X4-tropic and R5-tropic HIV-1 with IC80 of 34.4 and 20.6μg/mL,respectively.Approximately 40%of gp120 was observed to be shed from pseudo virus,and above 40%bystander T cells were prevented from gp120-induced death by the constructed nanotraps.The safety of the constructed nanotraps was confirmed both in vitro and in mice.Therefore,the constructed nanotraps could specifically neutralize free HIV-1,selectively bind with gp120 expressing HIV-1 infected cells,cause gp120 shedding,inhibit gp120-induced bystander T cell killing on the premise of safety,and were considered as promising therapeutic agents for precise inhibition of HIV.
文摘Circulating peptide is a potential source of biomarkers for cancer detection.However,the existence of large molecular weight proteins in plasma have a disastrous effect on circulating peptides isolating and detecting.Herein,nanotrap fractionation following by mass spectrometry have been applied to quantify the levels of bradykinin (BK) and hydroxylated bradykinin (Hyp-BK) as a relative measure of KRAS-regulated prolyl-4-hydroxylase alpha-1 (P4HA1) which may serve as early diagnosis marker for pancreatic ductal adenocarcinoma (PDAC).We found that P4HA1 can be upregulated by KRASG12v,which is a PDAC driver mutation,using HPNE/KRAS and HPNE cells.And we revealed that P4HA1 is overexpressed in PDAC tumors,compared to normal and inflamed pancreatic tissues.RNA interference revealed that P4HA1 activity was primarily responsible for Hyp-BK production.Mass spectrometry analysis revealed that plasma Hyp-BK/BK ratio was higher in PDAC than pancreatitis patients and healthy controls,while the area under the receiver operating characteristic (ROC) curve (AUC) is 0.8209 (95%Cl,0.7269-0.9149).The Hyp-BK/BK association with PDAC was reproduced in another cohort,where this ratio was found to increase with advancing tumor stage.These novel findings paved the way for wider applications of Nanotrap coupled mass spectrometry as a powerful tool for revealing biosignatures from plasma.
