Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy and lacks effective treatment.Bulk-sequencing of different gene transcripts by comparing HCC tissues and adjacent normal tissues provides some clues fo...Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy and lacks effective treatment.Bulk-sequencing of different gene transcripts by comparing HCC tissues and adjacent normal tissues provides some clues for investigating the mechanisms or identifying potential targets for tumor progression.However,genes that are exclusively expressed in a subpopulation of HCC may not be enriched or detected through such a screening.In the current study,we performed a single cell-clone-based screening and identified galectin-14 as an essential molecule in the regulation of tumor growth.The aberrant expression of galectin-14 was significantly associated with a poor overall survival of liver cancer patients with database analysis.Knocking down galectin-14 inhibited the proliferation of tumor growth,whereas overexpressing galectin-14 promoted tumor growth in vivo.Non-targeted metabolomics analysis indicated that knocking down galectin-14 decreased glycometabolism;specifically that glycoside synthesis was significantly changed.Further study found that galectin-14 promoted the expression of cell surface heparan sulfate proteoglycans(HSPGs)that functioned as co-receptors,thereby increasing the responsiveness of HCC cells to growth factors,such as epidermal growth factor and transforming growth factor-alpha.In conclusion,the current study identifies a novel HCC-specific molecule galectin-14,which increases the expression of cell surface HSPGs and the uptake of growth factors to promote HCC cell proliferation.展开更多
目的:观察泽泻萜类化合物对ApoE基因敲除小鼠实验性动脉粥样硬化肝脏基底膜硫酸乙酰肝素蛋白多糖的调节作用。方法:将8周龄C57/BL小鼠12只设为正常对照组,8周龄ApoE基因缺陷小鼠36只随机分为3组:模型组、中药组、舒降之阳性对照组。正...目的:观察泽泻萜类化合物对ApoE基因敲除小鼠实验性动脉粥样硬化肝脏基底膜硫酸乙酰肝素蛋白多糖的调节作用。方法:将8周龄C57/BL小鼠12只设为正常对照组,8周龄ApoE基因缺陷小鼠36只随机分为3组:模型组、中药组、舒降之阳性对照组。正常对照组、模型组予0.9%生理盐水灌胃,给药组正常人每kg体重的10倍量灌胃90天后,全自动生化仪测定血清血脂含量,用免疫印记法测定各组肝脏基底膜硫酸乙酰肝素蛋白多糖的表达,用Quantity One 6.0软件进行光密度分析。结果:中药组、阳性对照药组与模型组比较,总胆固醇、低密度脂蛋白水平均明显降低。中药组、阳性对照药组肝脏基底膜HSPG表达与模型组比较明显上调,但与正常对照组比较则明显下调。结论:泽泻萜类化合物对apoE-基因敲除高脂饲料喂养所致动脉粥样硬化小鼠具有降低血清总胆固醇、低密度脂蛋白的作用,对该模型小鼠的肝脏基底膜HSPG表达有调节作用。展开更多
Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain,such as a heparan,dermatan,chondroitin,or keratan sulfate,covalently attached to the protein core.These molecules arecategorized...Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain,such as a heparan,dermatan,chondroitin,or keratan sulfate,covalently attached to the protein core.These molecules arecategorized based on their structure,localization,and function,and can be found in the extracellular matrix,on the cell surface,and in the cytoplasm.Cell-surface heparan sulfate proteoglycans,such as syndecans,are the primary type present in healthy liver tissue.However,deterioration of the liver results in overproduction of other proteoglycan types.The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer.A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans.The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels.This article details and discusses the roles of syndecan-1,glypicans,agrin,perlecan,collagen XVIII/endostatin,endocan,serglycin,decorin,biglycan,asporin,fibromodulin,lumican,and versican in liver function.Specifically,glypicans,agrin,and versican play significant roles in the development of liver cancer.Conversely,the presence of decorin could potentially provide protective effects.展开更多
Proteoglycans in the central nervous system play integral roles as ＂traffic signals＂ for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central n...Proteoglycans in the central nervous system play integral roles as ＂traffic signals＂ for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central nervous system. In this review, the structures of proteoglycans and the evidence suggesting their involvement in the response following spinal cord injury are presented. The review further describes the methods routinely used to determine the effect proteoglycans have on neurite outgrowth. The effects of proteoglycans on neurite outgrowth are not completely understood as there is disagreement on what component of the molecule is interacting with growing neurites and this ambiguity is chronicled in an historical context. Finally, the most recent findings suggesting possible receptors, interactions, and sulfation patterns that may be important in eliciting the effect of proteoglycans on neurite outgrowth are discussed. A greater understanding of the proteoglycan-neurite interaction is necessary for successfully promoting regeneration in the iniured central nervous system.展开更多
Axon growth is a central event in the development and post-injury plasticity of the nervous system. Growing axons encounter a wide variety of environmental instructions. Much like traffic lights in controlling the mig...Axon growth is a central event in the development and post-injury plasticity of the nervous system. Growing axons encounter a wide variety of environmental instructions. Much like traffic lights in controlling the migrating axons, chondroitin sulfate proteoglycans （CSPGs） and heparan sulfate proteoglycans （HSPGs） often lead to ＂stop＂ and ＂go＂ growth responses in the axons, respectively. Recently, the LAR family and NgR family molecules were identified as neuronal receptors for CSPGs and HSPGs. These discoveries provided molecular tools for further study of mechanisms underlying axon growth regulation. More importantly, the identification of these proteoglycan receptors offered potential therapeutic targets for promoting post-injury axon regeneration.展开更多
Diabetic nephropathy(DN),a long term complication of diabetes,is the most common cause of end-stage renal disease,increasing the risk of death.Genetic predispositions play an important role in determining the suscepti...Diabetic nephropathy(DN),a long term complication of diabetes,is the most common cause of end-stage renal disease,increasing the risk of death.Genetic predispositions play an important role in determining the susceptibility of the development of DN.Heparan sulphate proteoglycan(HSPG) and ghrelin(GH) gene polymorphisms are associated with the risk of DN.T allele frequency of the HSPG gene determined by BamHI polymorphism located in intron 6 may be a risk factor for the development of renal dysfunction in DN(Fisher two tailed test,CI = 95%,d.f.= 29,P = 0.016).The ghrelin gene polymorphism is caused by a cytosine-to-adenine transition in exon 2 of the preproghrelin gene forming Leu72Met variant.In Pakistani population,the preproghrelin Leu72Met polymorphism was observed to be not associated with diabetic nephropathy in patients as indicated by statistical analysis(CI = 95%,d.f.= 29,P = 0.691).The allelic frequencies of HSPG genetic polymorphism has the potential to be used as diagnostic markers for diabetic nephropathy disease.展开更多
This paper reports a comparative study of the extraction rate of rat brain proteoglycans (PGs) by three different methods, with chromatography, papain digestion and electrophoretic technique. The results showed: ① T...This paper reports a comparative study of the extraction rate of rat brain proteoglycans (PGs) by three different methods, with chromatography, papain digestion and electrophoretic technique. The results showed: ① The extraction rate of brain PGs by 4mol/L guanidine HCl (GuHCl)was higher than that by phosphate-buffered saline (PBS) In any method, however the protein/PGs ratio in the GuHCl-extract was lower than that in the PBS-extract. ② PBS mainly extracted the soluble chondroitin sulfate proteoglycan (CSPG), whereas the 4mol/L GuHCl could extracted both soluble CSPG and insoluble heparan sulfate proteoglycan (HSPG). ③ After delipidation of brain by organic reagents, the extraction rate of delipidized brain PGs either by the PBS or by the 4mol/L GuHCl decreased obviously. ④ By direct extraction with PBS, GuHCl seguentially, few amount of PGs in the residue from brain was found.展开更多
Heparan sulfate proteoglycans （HSPGs） are critically involved in a variety of biological events. The functions of HSPGs are determined by the nature of the core proteins and modifications of heparan sulfate （HS） g...Heparan sulfate proteoglycans （HSPGs） are critically involved in a variety of biological events. The functions of HSPGs are determined by the nature of the core proteins and modifications of heparan sulfate （HS） glycosaminoglycan （GAG） chains. The distinct O-sulfo- transferases are important for nonrandom modifications at specific positions. Two HS 3-0 sulfotransferase （Hs3st） genes, Hs3st-A and Hs3st-B, were identified in Drosophila. Previous experiments using RNA interference （RNAi） suggested that Hs3st-B was required for Notch signaling. Here, we generated a null mutant of Hs3st-B via ends-out gene targeting and examined its role（s） in development. We found that homozygous Hs3st-B mutants have no neurogenic defects or alterations in the expression of Notch signaling target gene. Thus, our results strongly argue against an essential role for Hs3st-B in Notch signaling. Moreover, we have generated two independent Hs3st-A RNAi lines which worked to deplete Hs3st-A. Importantly, Hs3st-A RNAi combined with Hs3st-B mutant flies did not alter the expression of Notch signaling components, arguing that both Hs3st-A and Hs3st-B were not essential for Notch signaling. The establishment of Hs3st-B mutant and effective Hs3st-A RNAi lines provides essential tools for further studies of the physiological roles of Hs3st-A and Hs3st-B in development and homeostasis.展开更多
目的:探讨DKK-1、DKK-2和人磷脂酰肌醇蛋白聚糖3(glypican3,GPC3)蛋白在肝细胞癌组织中的表达及临床意义。方法:采用组织芯片联合免疫组织化学法检测DKK-1、DKK-2和GPC3蛋白在10例正常肝、12例肝硬化、57例肝细胞癌及癌旁肝组织中的表...目的:探讨DKK-1、DKK-2和人磷脂酰肌醇蛋白聚糖3(glypican3,GPC3)蛋白在肝细胞癌组织中的表达及临床意义。方法:采用组织芯片联合免疫组织化学法检测DKK-1、DKK-2和GPC3蛋白在10例正常肝、12例肝硬化、57例肝细胞癌及癌旁肝组织中的表达差异,并分析其临床意义。结果:免疫组织化学检测结果发现,DKK-1和DKK-2在肝细胞癌组织中阳性染色率分别为59.65%(34/57)和57.89%(33/57);GPC3只在肝细胞癌组织中表达,其阳性染色率为47.37%(27/57),而在正常肝、肝硬化及癌旁肝组织中均呈阴性表达。DKK-1与DKK-2阳性表达之间存在密切相关性(χ2=0.570,P=0.000),DKK-2与GPC3阳性染色之间也存在相关性(χ2=0.272,P=0.041)。统计分析DKK-1、DKK-2及GPC3在肝细胞癌组织中阳性染色与肝癌患者性别、年龄、血清甲胎蛋白(α-fetoprotein,AFP)水平、乙肝表面抗原(hepatitis B surface antigen,HBsAg)、肿瘤大小、病理学分级、静脉浸润以及是否伴随肝硬化等的相关性,结果表明血清AFP水平与GPC3表达呈正相关(P=0.007),HBsAg与DKK-1表达呈正相关(P=0.037),DKK-1阳性染色与肝细胞癌组织分级存在相关性(P=0.014),与其他参数则无相关性。结论:GPC3在肝细胞癌组织的阳性染色率为47.37%,GPC3染色阴性的肝细胞癌组织中DKK-1和DKK-2双阳性染色率为40.00%,而GPC3(+)联合DKK-1(+)/DKK-2(+)/GPC3(-)可将肝细胞癌的免疫组织化学检出率提高至68.42%(39/57),降低肝癌免疫组织化学检测中的假阴性率。展开更多
基金The current study was supported by the National Natural Science Foundation of China(Grant Nos 81972284 and 82273239)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.22KJB310001)Nanjing Medical University Science and Technology Development Foundation(Grant Nos.NMUB-20220050 and NMUB20210006).
文摘Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy and lacks effective treatment.Bulk-sequencing of different gene transcripts by comparing HCC tissues and adjacent normal tissues provides some clues for investigating the mechanisms or identifying potential targets for tumor progression.However,genes that are exclusively expressed in a subpopulation of HCC may not be enriched or detected through such a screening.In the current study,we performed a single cell-clone-based screening and identified galectin-14 as an essential molecule in the regulation of tumor growth.The aberrant expression of galectin-14 was significantly associated with a poor overall survival of liver cancer patients with database analysis.Knocking down galectin-14 inhibited the proliferation of tumor growth,whereas overexpressing galectin-14 promoted tumor growth in vivo.Non-targeted metabolomics analysis indicated that knocking down galectin-14 decreased glycometabolism;specifically that glycoside synthesis was significantly changed.Further study found that galectin-14 promoted the expression of cell surface heparan sulfate proteoglycans(HSPGs)that functioned as co-receptors,thereby increasing the responsiveness of HCC cells to growth factors,such as epidermal growth factor and transforming growth factor-alpha.In conclusion,the current study identifies a novel HCC-specific molecule galectin-14,which increases the expression of cell surface HSPGs and the uptake of growth factors to promote HCC cell proliferation.
文摘目的:观察泽泻萜类化合物对ApoE基因敲除小鼠实验性动脉粥样硬化肝脏基底膜硫酸乙酰肝素蛋白多糖的调节作用。方法:将8周龄C57/BL小鼠12只设为正常对照组,8周龄ApoE基因缺陷小鼠36只随机分为3组:模型组、中药组、舒降之阳性对照组。正常对照组、模型组予0.9%生理盐水灌胃,给药组正常人每kg体重的10倍量灌胃90天后,全自动生化仪测定血清血脂含量,用免疫印记法测定各组肝脏基底膜硫酸乙酰肝素蛋白多糖的表达,用Quantity One 6.0软件进行光密度分析。结果:中药组、阳性对照药组与模型组比较,总胆固醇、低密度脂蛋白水平均明显降低。中药组、阳性对照药组肝脏基底膜HSPG表达与模型组比较明显上调,但与正常对照组比较则明显下调。结论:泽泻萜类化合物对apoE-基因敲除高脂饲料喂养所致动脉粥样硬化小鼠具有降低血清总胆固醇、低密度脂蛋白的作用,对该模型小鼠的肝脏基底膜HSPG表达有调节作用。
基金Supported by Hungarian Research Fund(OTKA)(No.100904 to Kovalszky Iand No.105763 to Baghy K)
文摘Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain,such as a heparan,dermatan,chondroitin,or keratan sulfate,covalently attached to the protein core.These molecules arecategorized based on their structure,localization,and function,and can be found in the extracellular matrix,on the cell surface,and in the cytoplasm.Cell-surface heparan sulfate proteoglycans,such as syndecans,are the primary type present in healthy liver tissue.However,deterioration of the liver results in overproduction of other proteoglycan types.The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer.A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans.The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels.This article details and discusses the roles of syndecan-1,glypicans,agrin,perlecan,collagen XVIII/endostatin,endocan,serglycin,decorin,biglycan,asporin,fibromodulin,lumican,and versican in liver function.Specifically,glypicans,agrin,and versican play significant roles in the development of liver cancer.Conversely,the presence of decorin could potentially provide protective effects.
基金supported by the NIH(NS53470)the Kentucky Spinal Cord and Head Injury Research Trust(#10-11A)the Department of Defense,CDMRP(SC090248/W81XWH-10-1-0778)
文摘Proteoglycans in the central nervous system play integral roles as ＂traffic signals＂ for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central nervous system. In this review, the structures of proteoglycans and the evidence suggesting their involvement in the response following spinal cord injury are presented. The review further describes the methods routinely used to determine the effect proteoglycans have on neurite outgrowth. The effects of proteoglycans on neurite outgrowth are not completely understood as there is disagreement on what component of the molecule is interacting with growing neurites and this ambiguity is chronicled in an historical context. Finally, the most recent findings suggesting possible receptors, interactions, and sulfation patterns that may be important in eliciting the effect of proteoglycans on neurite outgrowth are discussed. A greater understanding of the proteoglycan-neurite interaction is necessary for successfully promoting regeneration in the iniured central nervous system.
文摘Axon growth is a central event in the development and post-injury plasticity of the nervous system. Growing axons encounter a wide variety of environmental instructions. Much like traffic lights in controlling the migrating axons, chondroitin sulfate proteoglycans （CSPGs） and heparan sulfate proteoglycans （HSPGs） often lead to ＂stop＂ and ＂go＂ growth responses in the axons, respectively. Recently, the LAR family and NgR family molecules were identified as neuronal receptors for CSPGs and HSPGs. These discoveries provided molecular tools for further study of mechanisms underlying axon growth regulation. More importantly, the identification of these proteoglycan receptors offered potential therapeutic targets for promoting post-injury axon regeneration.
文摘Diabetic nephropathy(DN),a long term complication of diabetes,is the most common cause of end-stage renal disease,increasing the risk of death.Genetic predispositions play an important role in determining the susceptibility of the development of DN.Heparan sulphate proteoglycan(HSPG) and ghrelin(GH) gene polymorphisms are associated with the risk of DN.T allele frequency of the HSPG gene determined by BamHI polymorphism located in intron 6 may be a risk factor for the development of renal dysfunction in DN(Fisher two tailed test,CI = 95%,d.f.= 29,P = 0.016).The ghrelin gene polymorphism is caused by a cytosine-to-adenine transition in exon 2 of the preproghrelin gene forming Leu72Met variant.In Pakistani population,the preproghrelin Leu72Met polymorphism was observed to be not associated with diabetic nephropathy in patients as indicated by statistical analysis(CI = 95%,d.f.= 29,P = 0.691).The allelic frequencies of HSPG genetic polymorphism has the potential to be used as diagnostic markers for diabetic nephropathy disease.
文摘This paper reports a comparative study of the extraction rate of rat brain proteoglycans (PGs) by three different methods, with chromatography, papain digestion and electrophoretic technique. The results showed: ① The extraction rate of brain PGs by 4mol/L guanidine HCl (GuHCl)was higher than that by phosphate-buffered saline (PBS) In any method, however the protein/PGs ratio in the GuHCl-extract was lower than that in the PBS-extract. ② PBS mainly extracted the soluble chondroitin sulfate proteoglycan (CSPG), whereas the 4mol/L GuHCl could extracted both soluble CSPG and insoluble heparan sulfate proteoglycan (HSPG). ③ After delipidation of brain by organic reagents, the extraction rate of delipidized brain PGs either by the PBS or by the 4mol/L GuHCl decreased obviously. ④ By direct extraction with PBS, GuHCl seguentially, few amount of PGs in the residue from brain was found.
基金supported by the grants from the National Basic Research Program of China(Nos.2011CB943901,2011CB943902 and 2011CB943802)the National Natural Science Foundation of China(Nos.31030049,31271582 and 31071284)Strategic Priority Research Program of the Chinese Academy of Sciences Grant(No.XDA01010101)
文摘Heparan sulfate proteoglycans （HSPGs） are critically involved in a variety of biological events. The functions of HSPGs are determined by the nature of the core proteins and modifications of heparan sulfate （HS） glycosaminoglycan （GAG） chains. The distinct O-sulfo- transferases are important for nonrandom modifications at specific positions. Two HS 3-0 sulfotransferase （Hs3st） genes, Hs3st-A and Hs3st-B, were identified in Drosophila. Previous experiments using RNA interference （RNAi） suggested that Hs3st-B was required for Notch signaling. Here, we generated a null mutant of Hs3st-B via ends-out gene targeting and examined its role（s） in development. We found that homozygous Hs3st-B mutants have no neurogenic defects or alterations in the expression of Notch signaling target gene. Thus, our results strongly argue against an essential role for Hs3st-B in Notch signaling. Moreover, we have generated two independent Hs3st-A RNAi lines which worked to deplete Hs3st-A. Importantly, Hs3st-A RNAi combined with Hs3st-B mutant flies did not alter the expression of Notch signaling components, arguing that both Hs3st-A and Hs3st-B were not essential for Notch signaling. The establishment of Hs3st-B mutant and effective Hs3st-A RNAi lines provides essential tools for further studies of the physiological roles of Hs3st-A and Hs3st-B in development and homeostasis.
文摘目的:探讨DKK-1、DKK-2和人磷脂酰肌醇蛋白聚糖3(glypican3,GPC3)蛋白在肝细胞癌组织中的表达及临床意义。方法:采用组织芯片联合免疫组织化学法检测DKK-1、DKK-2和GPC3蛋白在10例正常肝、12例肝硬化、57例肝细胞癌及癌旁肝组织中的表达差异,并分析其临床意义。结果:免疫组织化学检测结果发现,DKK-1和DKK-2在肝细胞癌组织中阳性染色率分别为59.65%(34/57)和57.89%(33/57);GPC3只在肝细胞癌组织中表达,其阳性染色率为47.37%(27/57),而在正常肝、肝硬化及癌旁肝组织中均呈阴性表达。DKK-1与DKK-2阳性表达之间存在密切相关性(χ2=0.570,P=0.000),DKK-2与GPC3阳性染色之间也存在相关性(χ2=0.272,P=0.041)。统计分析DKK-1、DKK-2及GPC3在肝细胞癌组织中阳性染色与肝癌患者性别、年龄、血清甲胎蛋白(α-fetoprotein,AFP)水平、乙肝表面抗原(hepatitis B surface antigen,HBsAg)、肿瘤大小、病理学分级、静脉浸润以及是否伴随肝硬化等的相关性,结果表明血清AFP水平与GPC3表达呈正相关(P=0.007),HBsAg与DKK-1表达呈正相关(P=0.037),DKK-1阳性染色与肝细胞癌组织分级存在相关性(P=0.014),与其他参数则无相关性。结论:GPC3在肝细胞癌组织的阳性染色率为47.37%,GPC3染色阴性的肝细胞癌组织中DKK-1和DKK-2双阳性染色率为40.00%,而GPC3(+)联合DKK-1(+)/DKK-2(+)/GPC3(-)可将肝细胞癌的免疫组织化学检出率提高至68.42%(39/57),降低肝癌免疫组织化学检测中的假阴性率。
