During malaria infection,elevated levels of pro-inflammatory mediators and nitric;oxide production have been associated with pathogenesis and disease severity.Previous in vitro and in vivo studies have proposed that b...During malaria infection,elevated levels of pro-inflammatory mediators and nitric;oxide production have been associated with pathogenesis and disease severity.Previous in vitro and in vivo studies have proposed that both Plasmodium falciparum hemozoin and glycosylphosphatidylinositols are able to modulate blood mononuclear cells,contributing to stimulation of signal transduction and downstream regulation of the NF-KB signaling pathway,and subsequently leading to the production of pro-inflammatory cytokines,chemokines,and nitric oxide.The present review summarizes the published in vitro and in vivo studies that have investigated the mechanism of intracellular signal transduction and activation of the NF-KB signaling pathway in blood mononuclear cells after being inducted by Plasmodium falciparum malaria components.Particular attention is paid to hemozoin and glycosylphosphatidylinositols which reflect the important mechanism of signaling pathways involved in immune response.展开更多
Approximately 1% of plant proteins are predicted to be post-translationally modified with a glycosylphospha- tidylinositol （GPI） anchor that tethers the polypeptide to the outer leaflet of the plasma membrane. Where...Approximately 1% of plant proteins are predicted to be post-translationally modified with a glycosylphospha- tidylinositol （GPI） anchor that tethers the polypeptide to the outer leaflet of the plasma membrane. Whereas the synthesis and structure of GPI anchors is largely conserved across eukaryotes, the repertoire of functional domains present in the GPl-anchored proteome has diverged substantially. In plants, this includes a large fraction of the GPl-anchored proteome being further modified with plant-specific arabinogalactan （AG） O-glycans. The impor- tance of the GPl-anchored proteome to plant development is underscored by the fact that GPI biosynthetic null mutants exhibit embryo lethality. Mutations in genes encoding specific GPl-anchored proteins （GAPs） further supports their contribution to diverse biological processes, occurring at the interface of the plasma membrane and cell wall, including signaling, cell wall metabolism, cell wall polymer cross-linking, and plasmodesmatal transport. Here, we review the literature concerning plant GPl-anchored proteins, in the context of their potential to act as molecular hubs that mediate interactions between the plasma membrane and the cell wall, and their potential to transduce the signal into the protoplast and, thereby, activate signal transduction pathways.展开更多
The cure or functional cure of the"Berlin patient"and"London patient"indicates that infusion of HIV-resistant cells could be a viable treatment strategy.Very recently,we genetically linked a short-...The cure or functional cure of the"Berlin patient"and"London patient"indicates that infusion of HIV-resistant cells could be a viable treatment strategy.Very recently,we genetically linked a short-peptide fusion inhibitor with a glycosylphosphatidylinositol(GPI)attachment signal,rendering modified cells fully resistant to HIV infection.In this study,GPI-anchored m36.4,a single-domain antibody(nanobody)targeting the coreceptor-binding site of gp120,was constructed with a lentiviral vector.We verified that m36.4 was efficiently expressed on the plasma membrane of transduced TZM-bl cells and targeted lipid raft sites without affecting the expression of HIV receptors(CD4,CCR5,and CXCR4).Significantly,TZM-bl cells expressing GPI-m36.4 were highly resistant to infection with divergent HIV-1 subtypes and potently blocked HIV-1 envelope-mediated cell-cell fusion and cell-cell viral transmission.Furthermore,we showed that GPI-m36.4-modified human CEMss-CCR5 cells were nonpermissive to both CCR5-and CXCR4-tropic HIV-1 isolates and displayed a strong survival advantage over unmodified cells.It was found that GPI-m36.4 could also Impair HIV-1 Env processing and viral infectivity in transduced cells,underlying a multifaceted mechanism of antiviral action.In conclusion,our studies characterize m36.4 as a powerful nanobody that can generate HIV-resistant cells,offering a novel gene therapy approach that can be used alone or in combination.展开更多
The transfer of proteins and nucleic acids from donor to acceptor cells via small membrane vesicles has been implicated with (patho)physiological consequences. Previously the upregulation of esterification and downreg...The transfer of proteins and nucleic acids from donor to acceptor cells via small membrane vesicles has been implicated with (patho)physiological consequences. Previously the upregulation of esterification and downregulation of lipolysis in small rat adipocytes upon incubation with exosomes and microvesicles (EMVs) released from large adipocytes and harbouring the glycosylphosphatidylinositol (GPI)-anchored proteins, Gce1 and CD73, transcripts specific for FSP27 and GPAT3, and microRNAs, miR-16 and miR-222 was demonstrated. Here the release of EMVs from large (but not small) primary and differentiated and human rat adipocytes in response to palmitate, H2O2 and the anti-diabetic sulfonylurea, glimepiride, is shown to be significantly reduced upon inhibition of histone H3 lysine9 methyltransferase G9a by trans-2-phenylcyclopropylamine (tPCPA) and histone H3 lysine4 demethylase LSD1 by BIX01294. Inhibition of EMV release by tPCPA and BIX01294 was not caused by apoptosis but accompanied by upregulation of the H2O2-induced stimulation of lipid synthesis and downregulation of lipolysis in large (but not small) primary and differentiated rat and human adipocytes. In contrast, the simultaneous presence of tPCPA and BIX-01294 had almost no effect on the induced release of EMVs and lipid metabolism. These findings argue for regulation of the release of EMVs harbouring specific GPI-anchored proteins, transcripts and microRNAs from rat and human adipocytes by histone H3 methylation at lysines 4 and 9 in interdependent fashion. Thus the EMV-mediated transfer of lipogenic and anti-lipolytic information between large and small adipocytes in response to certain physiological and pharmacological stimuli seems to be controlled by epigenetic mechanisms.展开更多
抗真菌药物研究的两大策略,一是改造氮唑类或棘白菌素类抗真菌药物分子产生“Me Better”的新药分子,二是发现作用于新靶点的全新结构的“First in Class”的原创新药。后者已进入临床研究阶段的重要原创候选药物有靶向Sec14的Turbinmi...抗真菌药物研究的两大策略,一是改造氮唑类或棘白菌素类抗真菌药物分子产生“Me Better”的新药分子,二是发现作用于新靶点的全新结构的“First in Class”的原创新药。后者已进入临床研究阶段的重要原创候选药物有靶向Sec14的Turbinmicin、靶向糖基化磷脂酰肌醇(glycosylphosphatidylinositol,GPI)锚定蛋白合成转运的氨基吡啶类化合物,靶向二氢乳清酸脱氢酶(dihydroorotate dehydrogenase,DHODH)的F901318等。其中GPI锚定蛋白合成转运途径药物的发现已有10多年历史,研究比较充分,且具有广谱高效抗真菌和增强宿主抗真菌免疫反应的双重作用,本文主要综述靶向GPI生物合成的抗真菌药物的研究进展。展开更多
基金Supported by the Institute of Research and Development,Walailak University,Nakhon Si Thammarat,Thailand
文摘During malaria infection,elevated levels of pro-inflammatory mediators and nitric;oxide production have been associated with pathogenesis and disease severity.Previous in vitro and in vivo studies have proposed that both Plasmodium falciparum hemozoin and glycosylphosphatidylinositols are able to modulate blood mononuclear cells,contributing to stimulation of signal transduction and downstream regulation of the NF-KB signaling pathway,and subsequently leading to the production of pro-inflammatory cytokines,chemokines,and nitric oxide.The present review summarizes the published in vitro and in vivo studies that have investigated the mechanism of intracellular signal transduction and activation of the NF-KB signaling pathway in blood mononuclear cells after being inducted by Plasmodium falciparum malaria components.Particular attention is paid to hemozoin and glycosylphosphatidylinositols which reflect the important mechanism of signaling pathways involved in immune response.
基金supported by the ARC Centre of Excellence in Plant Cell Walls grant (CE1101007)supported by a postdoctoral fellowship from the Philomathia Foundation
文摘Approximately 1% of plant proteins are predicted to be post-translationally modified with a glycosylphospha- tidylinositol （GPI） anchor that tethers the polypeptide to the outer leaflet of the plasma membrane. Whereas the synthesis and structure of GPI anchors is largely conserved across eukaryotes, the repertoire of functional domains present in the GPl-anchored proteome has diverged substantially. In plants, this includes a large fraction of the GPl-anchored proteome being further modified with plant-specific arabinogalactan （AG） O-glycans. The impor- tance of the GPl-anchored proteome to plant development is underscored by the fact that GPI biosynthetic null mutants exhibit embryo lethality. Mutations in genes encoding specific GPl-anchored proteins （GAPs） further supports their contribution to diverse biological processes, occurring at the interface of the plasma membrane and cell wall, including signaling, cell wall metabolism, cell wall polymer cross-linking, and plasmodesmatal transport. Here, we review the literature concerning plant GPl-anchored proteins, in the context of their potential to act as molecular hubs that mediate interactions between the plasma membrane and the cell wall, and their potential to transduce the signal into the protoplast and, thereby, activate signal transduction pathways.
基金supported by grants from the CAMS Innovation Fund for Medical Sciences(2017-I2M-1-014)National Science and Technology Major Project of China(2018ZX10301103 and 2017ZX10202102-001-003)National Natural Science Foundation of China(81630061).
文摘The cure or functional cure of the"Berlin patient"and"London patient"indicates that infusion of HIV-resistant cells could be a viable treatment strategy.Very recently,we genetically linked a short-peptide fusion inhibitor with a glycosylphosphatidylinositol(GPI)attachment signal,rendering modified cells fully resistant to HIV infection.In this study,GPI-anchored m36.4,a single-domain antibody(nanobody)targeting the coreceptor-binding site of gp120,was constructed with a lentiviral vector.We verified that m36.4 was efficiently expressed on the plasma membrane of transduced TZM-bl cells and targeted lipid raft sites without affecting the expression of HIV receptors(CD4,CCR5,and CXCR4).Significantly,TZM-bl cells expressing GPI-m36.4 were highly resistant to infection with divergent HIV-1 subtypes and potently blocked HIV-1 envelope-mediated cell-cell fusion and cell-cell viral transmission.Furthermore,we showed that GPI-m36.4-modified human CEMss-CCR5 cells were nonpermissive to both CCR5-and CXCR4-tropic HIV-1 isolates and displayed a strong survival advantage over unmodified cells.It was found that GPI-m36.4 could also Impair HIV-1 Env processing and viral infectivity in transduced cells,underlying a multifaceted mechanism of antiviral action.In conclusion,our studies characterize m36.4 as a powerful nanobody that can generate HIV-resistant cells,offering a novel gene therapy approach that can be used alone or in combination.
文摘The transfer of proteins and nucleic acids from donor to acceptor cells via small membrane vesicles has been implicated with (patho)physiological consequences. Previously the upregulation of esterification and downregulation of lipolysis in small rat adipocytes upon incubation with exosomes and microvesicles (EMVs) released from large adipocytes and harbouring the glycosylphosphatidylinositol (GPI)-anchored proteins, Gce1 and CD73, transcripts specific for FSP27 and GPAT3, and microRNAs, miR-16 and miR-222 was demonstrated. Here the release of EMVs from large (but not small) primary and differentiated and human rat adipocytes in response to palmitate, H2O2 and the anti-diabetic sulfonylurea, glimepiride, is shown to be significantly reduced upon inhibition of histone H3 lysine9 methyltransferase G9a by trans-2-phenylcyclopropylamine (tPCPA) and histone H3 lysine4 demethylase LSD1 by BIX01294. Inhibition of EMV release by tPCPA and BIX01294 was not caused by apoptosis but accompanied by upregulation of the H2O2-induced stimulation of lipid synthesis and downregulation of lipolysis in large (but not small) primary and differentiated rat and human adipocytes. In contrast, the simultaneous presence of tPCPA and BIX-01294 had almost no effect on the induced release of EMVs and lipid metabolism. These findings argue for regulation of the release of EMVs harbouring specific GPI-anchored proteins, transcripts and microRNAs from rat and human adipocytes by histone H3 methylation at lysines 4 and 9 in interdependent fashion. Thus the EMV-mediated transfer of lipogenic and anti-lipolytic information between large and small adipocytes in response to certain physiological and pharmacological stimuli seems to be controlled by epigenetic mechanisms.
文摘抗真菌药物研究的两大策略,一是改造氮唑类或棘白菌素类抗真菌药物分子产生“Me Better”的新药分子,二是发现作用于新靶点的全新结构的“First in Class”的原创新药。后者已进入临床研究阶段的重要原创候选药物有靶向Sec14的Turbinmicin、靶向糖基化磷脂酰肌醇(glycosylphosphatidylinositol,GPI)锚定蛋白合成转运的氨基吡啶类化合物,靶向二氢乳清酸脱氢酶(dihydroorotate dehydrogenase,DHODH)的F901318等。其中GPI锚定蛋白合成转运途径药物的发现已有10多年历史,研究比较充分,且具有广谱高效抗真菌和增强宿主抗真菌免疫反应的双重作用,本文主要综述靶向GPI生物合成的抗真菌药物的研究进展。
