The oxysterol-binding protein-related protein(ORP)family is a group of proteins that mediate oxysterol metabolism and bioactivity in cells.ORPs constitute a large family of lipid transfer proteins.Much of the current ...The oxysterol-binding protein-related protein(ORP)family is a group of proteins that mediate oxysterol metabolism and bioactivity in cells.ORPs constitute a large family of lipid transfer proteins.Much of the current evidence indicates that certain members of the family of oxysterol-binding proteins(OSBPs)can lead to cancer.Many studies have revealed the putative roles of OSBPs in various cancer types.However,the exact effects and mechanisms of action of members of the OSBP/ORP family in cancer initiation and progression are currently unclear.This review focuses on ORP family members that can accelerate human tumour cell proliferation,migration,and invasion.The mechanisms and functions of various ORPs are introduced in detail.We also attempt to identify the roles of these proteins in malignant tumours with the ultimate aim of determining the exact role of the OSBP/ORP family in human tumour cells.展开更多
BACKGROUND Bone tissue engineering is an area of continued interest within orthopaedic surgery,as it promises to create implantable bone substitute materials that obviate the need for autologous bone graft.Recently,ox...BACKGROUND Bone tissue engineering is an area of continued interest within orthopaedic surgery,as it promises to create implantable bone substitute materials that obviate the need for autologous bone graft.Recently,oxysterols–oxygenated derivatives of cholesterol-have been proposed as a novel class of osteoinductive small molecules for bone tissue engineering.Here,we present the first systematic review of the in vivo evidence describing the potential therapeutic utility of oxysterols for bone tissue engineering.AIM To systematically review the available literature examining the effect of oxysterols on in vivo bone formation.METHODS We conducted a systematic review of the literature following PRISMA guidelines.Using the PubMed/MEDLINE,Embase,and Web of Science databases,we queried all publications in the English-language literature investigating the effect of oxysterols on in vivo bone formation.Articles were screened for eligibility using PICOS criteria and assessed for potential bias using an expanded version of the SYRCLE Risk of Bias assessment tool.All full-text articles examining the effect of oxysterols on in vivo bone formation were included.Extracted data included:Animal species,surgical/defect model,description of therapeutic and control treatments,and method for assessing bone growth.Primary outcome was fusion rate for spinal fusion models and percent bone regeneration for critical-sized defect models.Data were tabulated and described by both surgical/defect model and oxysterol employed.Additionally,data from all included studies were aggregated to posit the mechanism by which oxysterols may mediate in vivo bone formation.RESULTS Our search identified 267 unique articles,of which 27 underwent full-text review.Thirteen studies(all preclinical)met our inclusion/exclusion criteria.Of the 13 included studies,5 employed spinal fusion models,2 employed critical-sized alveolar defect models,and 6 employed critical-sized calvarial defect models.Based upon SYRCLE criteria,the included studies were found to possess an overall“unclear risk of bias”;54%of studies reported treatment randomization and 38%reported blinding at any level.Overall,seven unique oxysterols were evaluated:20(S)-hydroxycholesterol,22(R)-hydroxycholesterol,22(S)-hydroxycholesterol,Oxy4/Oxy34,Oxy18,Oxy21/Oxy133,and Oxy49.All had statistically significant in vivo osteoinductive properties,with Oxy4/Oxy34,Oxy21/Oxy133,and Oxy49 showing a dose-dependent effect in some cases.In the eight studies that directly compared oxysterols to rhBMP-2-treated animals,similar rates of bone growth occurred in the two groups.Biochemical investigation of these effects suggests that they may be primarily mediated by direct activation of Smoothened in the Hedgehog signaling pathway.CONCLUSION Present preclinical evidence suggests oxysterols significantly augment in vivo bone formation.However,clinical trials are necessary to determine which have the greatest therapeutic potential for orthopaedic surgery patients.展开更多
Amyloid peptide, the main component of senile plaques, is a major biological characteristic of Alzheimer’s disease (AD). The aim of the present study conducted on human neuronal SK-N-BE cells was to evaluate whether ...Amyloid peptide, the main component of senile plaques, is a major biological characteristic of Alzheimer’s disease (AD). The aim of the present study conducted on human neuronal SK-N-BE cells was to evaluate whether oligomerized Aβ1-40-induced cell damages was associated with lipid modifications. Under treatment with Aβ1-40 (10 - 100 μM;24 - 48 h), cell viability was recorded with the MTT test and by measuring LDH activity. Mitochondrial transmembrane potential and ATP production were assessed using flow cytometry and a luciferase-based ATP bioluminescence assay, respectively. Annexin V-CF647 staining assay for cell apoptosis detection was performed using flow cytometry. Potentially intracellular cytotoxic lipids (oxysterols: 7α-hydroxycholesterol (7α-OHC), 7β-hydroxycholesterol (7β-OHC), and 7-ketocholesterol (7KC), 24(S)-hydroxycholesterol;arachidonic acid (C20:4 n-6);VLCFAs (C22:0, C24:0, C24:6 and C26:0)) were measured using gas chromatography coupled with mass spectrometry. The cellular level of docosahexaenoic acid (C22:6 n-3), often altered in AD, was also quantified. In the presence of Aβ1-40, the percentage of MTT-positive cells decreased and was associated with an increase in LDH activity. In addition, treatment with oligomerized Aβ1-40 induced a decrease of mitochondrial transmembrane potential as well as an apoptotic cell death. Sterol analysis revealed a higher cholesterol level and a significant increase of cytotoxic oxysterols per cell (7KC + 7β-OHC), and of the [(7β-OHC + 7KC)/cholesterol] ratio, considered as a lipid peroxidation index, in Aβ1-40-treated cells. An enhancement of C20:4 n-6, C22:6 n-3 and saturated VLCFAs was also observed. Therefore, Aβ1-40-induced side effects are associated with intracellular accumulation of lipids, especially cholesterol, oxysterols (7β-OHC, 7KC), C20:4 n-6, and saturated VLCFAs, which could in turn contribute to neurotoxicity.展开更多
Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross t...Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross the blood brain barrier.The present study aimed to elucidate the distribution of cholesterol 24-hydroxylase in the monkey brain.Methods The distribution of cholesterol 24-hydroxylase in the monkey brain was examined using Western blot and immunohistochemistry methods,and was observed under light microscopy and electron microscopy.Results High levels of cholesterol 24-hydroxylase were observed in projection neurons and neuropil in structures derived from telencephalon,including the cerebral neocortex,hippocampus,amygdala,nucleus basalis of Meynert,and striatum.Electron microscopy revealed that the enzyme was localized in the axon terminals.One the other hand,cholesterol 24-hydroxylase was expressed at a lower level in the thalamus,globus pallidus and brainstem.Conclusion The high level of cholesterol 24-hydroxylase in the telencephalon possibly reflects a high rate of cholesterol turnover in this part of brain.展开更多
【目的】了解稻瘟病菌中氧固醇结合蛋白(oxysterol-binding proteins related proteins,缩写为ORPs)家族成员组成情况,构建MgORP1基因缺失突变株和互补株,对MgORP1基因功能进行初步研究。【方法】以ORPs家族的典型结构域"ORD"...【目的】了解稻瘟病菌中氧固醇结合蛋白(oxysterol-binding proteins related proteins,缩写为ORPs)家族成员组成情况,构建MgORP1基因缺失突变株和互补株,对MgORP1基因功能进行初步研究。【方法】以ORPs家族的典型结构域"ORD"为靶标,对稻瘟病菌基因组数据库进行BlastP搜索。通过同源重组的策略,构建MgORP1基因缺失突变体,再通过重新导入该基因全长片段获得互补株。然后对野生型、突变体和互补株进行菌落、分生孢子和附着胞形态或形成情况、以及致病力进行比较分析。【结果】稻瘟病菌基因组中含有6个可能的ORPs族蛋白,其中MgORP1基因的破坏降低了稻瘟菌在完全培养基上的菌落生长速率和产孢量。但对菌丝、分生孢子和附着胞的形态,以及在水稻上的致病力没有明显影响。【结论】MgORP1基因可能与稻瘟病菌的菌落生长和产孢量相关。展开更多
It has been estimated that Alzheimer＇s disease （AD）, the most common form of dementia, will affect approximately 81 million individuals by 2040. To date, the actual cause and cascade of events in the progression of...It has been estimated that Alzheimer＇s disease （AD）, the most common form of dementia, will affect approximately 81 million individuals by 2040. To date, the actual cause and cascade of events in the progression of this disease have not been fully determined. Furthermore, there is currently no definitive blood test or simple diagnostic method for AD. Considerable efforts have been put into proteomic approaches to develop a diagnostic blood test, but to date these efforts have not been successful. More recently, there has been a stronger focus on lipidomic studies in the hope of increasing our understanding of the underlying mechanisms leading to AD and developing an AD blood test. It is well known that the strongest genetic risk factor for AD is the e4 variant of apolipoprotein E （APOE）. Evidence suggests that the ApoE protein, a major lipid transporter, plays a key role in the pathogenesis of AD, and its role in both normal and aberrant lipid metabolism warrants further extensive investigation. Here, we review ApoE-lipid interactions, as well as the roles that lipids may play in the pathogenesis of AD.展开更多
Cholesterol is an essential component of the mammalian plasma membrane because it promotes membrane stability without comprising membrane fluidity. Given this important cellular role, cholesterol levels are tightly co...Cholesterol is an essential component of the mammalian plasma membrane because it promotes membrane stability without comprising membrane fluidity. Given this important cellular role, cholesterol levels are tightly controlled at multiple levels. It has been clearly shown that cholesterol redistribution and depletion from the sperm membrane is a key part of the spermatozoon＇s preparation for fertilization. Some factors that regulate these events are described （e.g., bicarbonate, calcium） but the mechanisms underlying cholesterol export are poorly understood. How does a hydrophobic cholesterol molecule inserted in the sperm plasma membrane enter the energetically unfavorable aqueous surroundings？ This review will provide an overview of knowledge in this area and highlight our gaps in understanding. The overall aim is to better understand cholesterol redistribution in the sperm plasma membrane, its relation to the possible activation of a cholesterol transporter and the role of cholesterol acceptors. Armed with such knowledlze, sl）erm handlin~ techniques can be adapted to better prepare spermatozoa for in vitro and in vivo fertilization.展开更多
氧化固醇结合蛋白(oxysterol-binding proteins related proteins,缩写为ORPs)是真核生物中广泛存在的一类保守的蛋白,主要参与细胞内脂类的合成、转运以及信号转导等。以酵母OSH蛋白、哺乳动物ORPs家族蛋白等为例,对氧化固醇结合蛋白...氧化固醇结合蛋白(oxysterol-binding proteins related proteins,缩写为ORPs)是真核生物中广泛存在的一类保守的蛋白,主要参与细胞内脂类的合成、转运以及信号转导等。以酵母OSH蛋白、哺乳动物ORPs家族蛋白等为例,对氧化固醇结合蛋白基因结构特征、生物学功能的研究进展做一介绍。展开更多
文摘The oxysterol-binding protein-related protein(ORP)family is a group of proteins that mediate oxysterol metabolism and bioactivity in cells.ORPs constitute a large family of lipid transfer proteins.Much of the current evidence indicates that certain members of the family of oxysterol-binding proteins(OSBPs)can lead to cancer.Many studies have revealed the putative roles of OSBPs in various cancer types.However,the exact effects and mechanisms of action of members of the OSBP/ORP family in cancer initiation and progression are currently unclear.This review focuses on ORP family members that can accelerate human tumour cell proliferation,migration,and invasion.The mechanisms and functions of various ORPs are introduced in detail.We also attempt to identify the roles of these proteins in malignant tumours with the ultimate aim of determining the exact role of the OSBP/ORP family in human tumour cells.
文摘BACKGROUND Bone tissue engineering is an area of continued interest within orthopaedic surgery,as it promises to create implantable bone substitute materials that obviate the need for autologous bone graft.Recently,oxysterols–oxygenated derivatives of cholesterol-have been proposed as a novel class of osteoinductive small molecules for bone tissue engineering.Here,we present the first systematic review of the in vivo evidence describing the potential therapeutic utility of oxysterols for bone tissue engineering.AIM To systematically review the available literature examining the effect of oxysterols on in vivo bone formation.METHODS We conducted a systematic review of the literature following PRISMA guidelines.Using the PubMed/MEDLINE,Embase,and Web of Science databases,we queried all publications in the English-language literature investigating the effect of oxysterols on in vivo bone formation.Articles were screened for eligibility using PICOS criteria and assessed for potential bias using an expanded version of the SYRCLE Risk of Bias assessment tool.All full-text articles examining the effect of oxysterols on in vivo bone formation were included.Extracted data included:Animal species,surgical/defect model,description of therapeutic and control treatments,and method for assessing bone growth.Primary outcome was fusion rate for spinal fusion models and percent bone regeneration for critical-sized defect models.Data were tabulated and described by both surgical/defect model and oxysterol employed.Additionally,data from all included studies were aggregated to posit the mechanism by which oxysterols may mediate in vivo bone formation.RESULTS Our search identified 267 unique articles,of which 27 underwent full-text review.Thirteen studies(all preclinical)met our inclusion/exclusion criteria.Of the 13 included studies,5 employed spinal fusion models,2 employed critical-sized alveolar defect models,and 6 employed critical-sized calvarial defect models.Based upon SYRCLE criteria,the included studies were found to possess an overall“unclear risk of bias”;54%of studies reported treatment randomization and 38%reported blinding at any level.Overall,seven unique oxysterols were evaluated:20(S)-hydroxycholesterol,22(R)-hydroxycholesterol,22(S)-hydroxycholesterol,Oxy4/Oxy34,Oxy18,Oxy21/Oxy133,and Oxy49.All had statistically significant in vivo osteoinductive properties,with Oxy4/Oxy34,Oxy21/Oxy133,and Oxy49 showing a dose-dependent effect in some cases.In the eight studies that directly compared oxysterols to rhBMP-2-treated animals,similar rates of bone growth occurred in the two groups.Biochemical investigation of these effects suggests that they may be primarily mediated by direct activation of Smoothened in the Hedgehog signaling pathway.CONCLUSION Present preclinical evidence suggests oxysterols significantly augment in vivo bone formation.However,clinical trials are necessary to determine which have the greatest therapeutic potential for orthopaedic surgery patients.
文摘Amyloid peptide, the main component of senile plaques, is a major biological characteristic of Alzheimer’s disease (AD). The aim of the present study conducted on human neuronal SK-N-BE cells was to evaluate whether oligomerized Aβ1-40-induced cell damages was associated with lipid modifications. Under treatment with Aβ1-40 (10 - 100 μM;24 - 48 h), cell viability was recorded with the MTT test and by measuring LDH activity. Mitochondrial transmembrane potential and ATP production were assessed using flow cytometry and a luciferase-based ATP bioluminescence assay, respectively. Annexin V-CF647 staining assay for cell apoptosis detection was performed using flow cytometry. Potentially intracellular cytotoxic lipids (oxysterols: 7α-hydroxycholesterol (7α-OHC), 7β-hydroxycholesterol (7β-OHC), and 7-ketocholesterol (7KC), 24(S)-hydroxycholesterol;arachidonic acid (C20:4 n-6);VLCFAs (C22:0, C24:0, C24:6 and C26:0)) were measured using gas chromatography coupled with mass spectrometry. The cellular level of docosahexaenoic acid (C22:6 n-3), often altered in AD, was also quantified. In the presence of Aβ1-40, the percentage of MTT-positive cells decreased and was associated with an increase in LDH activity. In addition, treatment with oligomerized Aβ1-40 induced a decrease of mitochondrial transmembrane potential as well as an apoptotic cell death. Sterol analysis revealed a higher cholesterol level and a significant increase of cytotoxic oxysterols per cell (7KC + 7β-OHC), and of the [(7β-OHC + 7KC)/cholesterol] ratio, considered as a lipid peroxidation index, in Aβ1-40-treated cells. An enhancement of C20:4 n-6, C22:6 n-3 and saturated VLCFAs was also observed. Therefore, Aβ1-40-induced side effects are associated with intracellular accumulation of lipids, especially cholesterol, oxysterols (7β-OHC, 7KC), C20:4 n-6, and saturated VLCFAs, which could in turn contribute to neurotoxicity.
基金supported by the National Natural Science Foundation of China(No.30901940)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,Education Ministry of China
文摘Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross the blood brain barrier.The present study aimed to elucidate the distribution of cholesterol 24-hydroxylase in the monkey brain.Methods The distribution of cholesterol 24-hydroxylase in the monkey brain was examined using Western blot and immunohistochemistry methods,and was observed under light microscopy and electron microscopy.Results High levels of cholesterol 24-hydroxylase were observed in projection neurons and neuropil in structures derived from telencephalon,including the cerebral neocortex,hippocampus,amygdala,nucleus basalis of Meynert,and striatum.Electron microscopy revealed that the enzyme was localized in the axon terminals.One the other hand,cholesterol 24-hydroxylase was expressed at a lower level in the thalamus,globus pallidus and brainstem.Conclusion The high level of cholesterol 24-hydroxylase in the telencephalon possibly reflects a high rate of cholesterol turnover in this part of brain.
文摘【目的】了解稻瘟病菌中氧固醇结合蛋白(oxysterol-binding proteins related proteins,缩写为ORPs)家族成员组成情况,构建MgORP1基因缺失突变株和互补株,对MgORP1基因功能进行初步研究。【方法】以ORPs家族的典型结构域"ORD"为靶标,对稻瘟病菌基因组数据库进行BlastP搜索。通过同源重组的策略,构建MgORP1基因缺失突变体,再通过重新导入该基因全长片段获得互补株。然后对野生型、突变体和互补株进行菌落、分生孢子和附着胞形态或形成情况、以及致病力进行比较分析。【结果】稻瘟病菌基因组中含有6个可能的ORPs族蛋白,其中MgORP1基因的破坏降低了稻瘟菌在完全培养基上的菌落生长速率和产孢量。但对菌丝、分生孢子和附着胞的形态,以及在水稻上的致病力没有明显影响。【结论】MgORP1基因可能与稻瘟病菌的菌落生长和产孢量相关。
基金Wei Ling Florence Lim and Ian J. Martins are supported by National Health and Medical Research Council (NHMRC) grant of AustraliaRalph N. Martins is supported by grants from McCusker Alzheimer’s Disease Research Foundation and NHMRC
文摘It has been estimated that Alzheimer＇s disease （AD）, the most common form of dementia, will affect approximately 81 million individuals by 2040. To date, the actual cause and cascade of events in the progression of this disease have not been fully determined. Furthermore, there is currently no definitive blood test or simple diagnostic method for AD. Considerable efforts have been put into proteomic approaches to develop a diagnostic blood test, but to date these efforts have not been successful. More recently, there has been a stronger focus on lipidomic studies in the hope of increasing our understanding of the underlying mechanisms leading to AD and developing an AD blood test. It is well known that the strongest genetic risk factor for AD is the e4 variant of apolipoprotein E （APOE）. Evidence suggests that the ApoE protein, a major lipid transporter, plays a key role in the pathogenesis of AD, and its role in both normal and aberrant lipid metabolism warrants further extensive investigation. Here, we review ApoE-lipid interactions, as well as the roles that lipids may play in the pathogenesis of AD.
文摘Cholesterol is an essential component of the mammalian plasma membrane because it promotes membrane stability without comprising membrane fluidity. Given this important cellular role, cholesterol levels are tightly controlled at multiple levels. It has been clearly shown that cholesterol redistribution and depletion from the sperm membrane is a key part of the spermatozoon＇s preparation for fertilization. Some factors that regulate these events are described （e.g., bicarbonate, calcium） but the mechanisms underlying cholesterol export are poorly understood. How does a hydrophobic cholesterol molecule inserted in the sperm plasma membrane enter the energetically unfavorable aqueous surroundings？ This review will provide an overview of knowledge in this area and highlight our gaps in understanding. The overall aim is to better understand cholesterol redistribution in the sperm plasma membrane, its relation to the possible activation of a cholesterol transporter and the role of cholesterol acceptors. Armed with such knowledlze, sl）erm handlin~ techniques can be adapted to better prepare spermatozoa for in vitro and in vivo fertilization.
文摘氧化固醇结合蛋白(oxysterol-binding proteins related proteins,缩写为ORPs)是真核生物中广泛存在的一类保守的蛋白,主要参与细胞内脂类的合成、转运以及信号转导等。以酵母OSH蛋白、哺乳动物ORPs家族蛋白等为例,对氧化固醇结合蛋白基因结构特征、生物学功能的研究进展做一介绍。
