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
【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
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
Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids ha...Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.展开更多
Cholesterol and cholesterol oxides impact on the functional properties of cells, in respect of the intracellular and extracellular distribution of compounds across cell membranes, carcinogenesis and drug resistance. A...Cholesterol and cholesterol oxides impact on the functional properties of cells, in respect of the intracellular and extracellular distribution of compounds across cell membranes, carcinogenesis and drug resistance. Abnormal levels of cholesterol oxides and steroids in cancerous tissues promote interest in steroid receptor cross-talk during cell-signalling and the steroid metabolome of cancer patients. The research literature links the cytotoxic properties of oxysterols to interference with the NO/cGMP pathway. cGMP participates in cell-signalling and has a molecular structure that relates to cancer-inducing and cancer-preventing agents. This study uses a molecular modelling approach to compare the structures of cholesterol oxides to cGMP. Cholesterol and cholesterol oxide structures fit to a cGMP structural template in several ways, some of which are replicated by corticosteroids and gonadal steroid hormones. The results of this study support the concept that cholesterol oxides modulate cell apoptosis and autophagy via the NO/cGMP pathway and in conjunction with steroid hormones participate in modulating regulation of cell function by cGMP.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.
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。
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。
基金supported by MH101874, MH114866, MH122379 from the National Institute of Mental Health (to CFZ)the Taylor Family Institute for Innovative Psychiatric Research and the Bantly Foundation (to CFZ)。
文摘Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.
文摘Cholesterol and cholesterol oxides impact on the functional properties of cells, in respect of the intracellular and extracellular distribution of compounds across cell membranes, carcinogenesis and drug resistance. Abnormal levels of cholesterol oxides and steroids in cancerous tissues promote interest in steroid receptor cross-talk during cell-signalling and the steroid metabolome of cancer patients. The research literature links the cytotoxic properties of oxysterols to interference with the NO/cGMP pathway. cGMP participates in cell-signalling and has a molecular structure that relates to cancer-inducing and cancer-preventing agents. This study uses a molecular modelling approach to compare the structures of cholesterol oxides to cGMP. Cholesterol and cholesterol oxide structures fit to a cGMP structural template in several ways, some of which are replicated by corticosteroids and gonadal steroid hormones. The results of this study support the concept that cholesterol oxides modulate cell apoptosis and autophagy via the NO/cGMP pathway and in conjunction with steroid hormones participate in modulating regulation of cell function by cGMP.
