The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunct...The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Neph-rin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an ex-tracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2 , a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient re-ceptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of protein-uria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside ne-phropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier func-tion. These molecules could be targets to establish a novel therapy for nephrotic syndrome.展开更多
Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refract...Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refractory seizures;other limitations in most traditional ASMs include poor tolerability and drug-drug interactions.Therefore,there is an urgent need to develop alternative ASMs.Levetiracetam(LEV)is a first-line ASM that is well tolerated,has promising efficacy,and has little drug-drug interaction.Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein(SV)2A,the molecular basis of its action remains unknown.Even so,the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success.This review highlights the research and development(R&D)process of LEV and its analogs,brivaracetam and padsevonil,to provide ideas and experience for the R&D of novel ASMs.展开更多
大多数细胞内都包含靶向不同细胞器的各种运输囊泡,其运输机制在进化上是高度保守的。Sec1/Munc-18(SM)蛋白在膜泡运输中起着重要的调控作用,它能够与SNARE(Soluble N-ethylmaleimide-sensitive factorattachment protein receptor)蛋...大多数细胞内都包含靶向不同细胞器的各种运输囊泡,其运输机制在进化上是高度保守的。Sec1/Munc-18(SM)蛋白在膜泡运输中起着重要的调控作用,它能够与SNARE(Soluble N-ethylmaleimide-sensitive factorattachment protein receptor)蛋白结合,共同在细胞内各个膜融合发生部位发挥重要作用。SM蛋白和SNARE复合体中的Syntaxin蛋白结合,调节SNARE复合体的装配,并与SNARE协同作用促进整个膜融合过程。文章对SM蛋白在结构和功能分析方面的最新研究进展进行了概述。展开更多
The Polian vesicle is the main accessory structure in the water vascular system of sea cucumbers.It can function to hold water vascular fluid under slight pressure and act as a hematopoiesis,excretory,and inflammatory...The Polian vesicle is the main accessory structure in the water vascular system of sea cucumbers.It can function to hold water vascular fluid under slight pressure and act as a hematopoiesis,excretory,and inflammatory response organ.Being the only organ to remain after evisceration,the Polian vesicle may function in the survival and regeneration of sea cucumber.We performed Tandem Mass Tag(TMT)-based proteomics to identify how proteins in the Polian vesicle of Apostichopus japonicus respond to evisceration.Among the 8453 proteins identified from vesicle samples before evisceration(PVOh)and at 6-h post-evisceration(PV6h)and 3-d post-evisceration(PV3d),we detected 222 differentially abundant proteins(DAPs).Most of the annotated DAPs were associated with cell growth and proliferation,immune response and wound healing,substance transport and metabolism,cytoskeleton/cilia/flagella,extracellular matrix,energy production and conversion,protein synthesis and modification,and signal recognition and transduction.Compared with PVOh,fewer DAPs were identified at PV6h,and more DAPs were found at PV3d,and these DAPs were widely distributed among multiple biological processes.Our results indicate that a wide range of biological processes was induced in Polian vesicles in response to evisceration.In particular,Polian vesicles may play important roles in the re storation of coelomocyte s,immune defense,and wound healing in sea cucumber.We propose that the Polian vesicle may be involved in visceral regeneration through nutrition and energy supply and by promoting dedifferentiation and migration.Together,these results provided new insights into the function of the Polian vesicle in A.japonicus post-evisceration.展开更多
Organization of proteins into complexes is crucial for many cellular functions. Recently, the SUT1 protein was shown to form homodimeric complexes, to be associated with lipid raft-like microdomains in yeast as well a...Organization of proteins into complexes is crucial for many cellular functions. Recently, the SUT1 protein was shown to form homodimeric complexes, to be associated with lipid raft-like microdomains in yeast as well as in plants and to undergo endocytosis in response to brefeldin A. We therefore aimed to identify SUTl-interacting proteins that might be involved in dimerization, endocytosis, or targeting of SUT1 to raft-like microdomains. Therefore, we identified potato membrane proteins, which are associated with the detergent-resistant membrane （DRM） fraction. Among the proteins identified, we clearly confirmed StSUT1 as part of DRM in potato source leaves. We used the yeast two-hybrid split ubiq- uitin system （SUS） to systematically screen for interaction between the sucrose transporter StSUT1 and other membrane- associated or soluble proteins in vivo. The SUS screen was followed by immunoprecipitation using affinity-purified StSUTl-specific peptide antibodies and mass spectrometric analysis of co-precipitated proteins. A large overlap was ob- served between the StSUTl-interacting proteins identified in the co-immunoprecipitation and the detergent-resistant membrane fraction. One of the SUTl-interacting proteins, a protein disulfide isomerase （PDI）, interacts also with other sucrose transporter proteins. A potential role of the PDI as escort protein is discussed.展开更多
文摘The slit diaphragm bridging the neighboring foot pro-cesses functions as a fnal barrier of glomerular capil-lary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Neph-rin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an ex-tracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2 , a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient re-ceptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of protein-uria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside ne-phropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier func-tion. These molecules could be targets to establish a novel therapy for nephrotic syndrome.
基金supported by funding from the High-level New R&D Institute(2019B090904008)the High-level Innovative Research Institute(2021B0909050003)of the Department of Science and Technology of Guangdong Province+4 种基金National Science and Technology Innovation 2030 Major Program(2021ZD0200900)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)Zhongshan Municipal Bureau of Science and Technology(CXTD2022013)the National Science Fund for Distinguished Young Scholars(81825021)the funding from Zhongshan Municipal Bureau of Science and Technology(210724194041939).
文摘Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refractory seizures;other limitations in most traditional ASMs include poor tolerability and drug-drug interactions.Therefore,there is an urgent need to develop alternative ASMs.Levetiracetam(LEV)is a first-line ASM that is well tolerated,has promising efficacy,and has little drug-drug interaction.Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein(SV)2A,the molecular basis of its action remains unknown.Even so,the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success.This review highlights the research and development(R&D)process of LEV and its analogs,brivaracetam and padsevonil,to provide ideas and experience for the R&D of novel ASMs.
文摘大多数细胞内都包含靶向不同细胞器的各种运输囊泡,其运输机制在进化上是高度保守的。Sec1/Munc-18(SM)蛋白在膜泡运输中起着重要的调控作用,它能够与SNARE(Soluble N-ethylmaleimide-sensitive factorattachment protein receptor)蛋白结合,共同在细胞内各个膜融合发生部位发挥重要作用。SM蛋白和SNARE复合体中的Syntaxin蛋白结合,调节SNARE复合体的装配,并与SNARE协同作用促进整个膜融合过程。文章对SM蛋白在结构和功能分析方面的最新研究进展进行了概述。
基金Supported by the National Natural Science Foundation of China(Nos.31872544,42076112)the Scientific Research Foundation of Yancheng Institute of Technology(Nos.XJ201725,XJ201726)。
文摘The Polian vesicle is the main accessory structure in the water vascular system of sea cucumbers.It can function to hold water vascular fluid under slight pressure and act as a hematopoiesis,excretory,and inflammatory response organ.Being the only organ to remain after evisceration,the Polian vesicle may function in the survival and regeneration of sea cucumber.We performed Tandem Mass Tag(TMT)-based proteomics to identify how proteins in the Polian vesicle of Apostichopus japonicus respond to evisceration.Among the 8453 proteins identified from vesicle samples before evisceration(PVOh)and at 6-h post-evisceration(PV6h)and 3-d post-evisceration(PV3d),we detected 222 differentially abundant proteins(DAPs).Most of the annotated DAPs were associated with cell growth and proliferation,immune response and wound healing,substance transport and metabolism,cytoskeleton/cilia/flagella,extracellular matrix,energy production and conversion,protein synthesis and modification,and signal recognition and transduction.Compared with PVOh,fewer DAPs were identified at PV6h,and more DAPs were found at PV3d,and these DAPs were widely distributed among multiple biological processes.Our results indicate that a wide range of biological processes was induced in Polian vesicles in response to evisceration.In particular,Polian vesicles may play important roles in the re storation of coelomocyte s,immune defense,and wound healing in sea cucumber.We propose that the Polian vesicle may be involved in visceral regeneration through nutrition and energy supply and by promoting dedifferentiation and migration.Together,these results provided new insights into the function of the Polian vesicle in A.japonicus post-evisceration.
文摘Organization of proteins into complexes is crucial for many cellular functions. Recently, the SUT1 protein was shown to form homodimeric complexes, to be associated with lipid raft-like microdomains in yeast as well as in plants and to undergo endocytosis in response to brefeldin A. We therefore aimed to identify SUTl-interacting proteins that might be involved in dimerization, endocytosis, or targeting of SUT1 to raft-like microdomains. Therefore, we identified potato membrane proteins, which are associated with the detergent-resistant membrane （DRM） fraction. Among the proteins identified, we clearly confirmed StSUT1 as part of DRM in potato source leaves. We used the yeast two-hybrid split ubiq- uitin system （SUS） to systematically screen for interaction between the sucrose transporter StSUT1 and other membrane- associated or soluble proteins in vivo. The SUS screen was followed by immunoprecipitation using affinity-purified StSUTl-specific peptide antibodies and mass spectrometric analysis of co-precipitated proteins. A large overlap was ob- served between the StSUTl-interacting proteins identified in the co-immunoprecipitation and the detergent-resistant membrane fraction. One of the SUTl-interacting proteins, a protein disulfide isomerase （PDI）, interacts also with other sucrose transporter proteins. A potential role of the PDI as escort protein is discussed.
