The Experts below are selected from a list of 1635 Experts worldwide ranked by ideXlab platform
Stephane Savary - One of the best experts on this subject based on the ideXlab platform.
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Dehydroepiandrosterone Induction of the ABCD2 and Abcd3 Genes encoding peroxisomal ABC Transporters
Advances in Experimental Medicine and Biology, 2020Co-Authors: Fabien Gueugnon, Catherine Gondcaille, Jerome Bellenger, Stephane Savary, Stephane Fourcade, Francoise Cadepond, Fabrice Lambert, Maurice BugautAbstract:Dehydroepiandrosterone (DHEA) is a peroxisome proliferator known to increase the expression of the genes encoding the peroxisomal s-oxidation enzymes in rodents. Using RT-PCR, we analysed the expression of the ABCD2 and Abcd3 genes encoding the peroxisomal ABC transporters ALDRP (ALD related protein) and PMP70 (70 kDa peroxisomal membrane protein) in primary cultures of rats hepatocytes treated with sulfated DHEA. We observed a time (12-72h) and dose (125-500μM) dependent increase in the expression of both genes.
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crispr cas9 mediated knockout of abcd1 and ABCD2 genes in bv 2 cells novel microglial models for x linked adrenoleukodystrophy
Biochimica et Biophysica Acta, 2019Co-Authors: Quentin Raas, Catherine Gondcaille, Doriane Trompier, Gerard Lizard, Franck Ménétrier, Yannick Hamon, Valerio Leoni, Claudio Caccia, Stephane SavaryAbstract:X-linked adrenoleukodystrophy (X-ALD), the most frequent peroxisomal disorder, is associated with mutation in the ABCD1 gene which encodes a peroxisomal ATP-binding cassette transporter for very long-chain fatty acids (VLCFA). The biochemical hallmark of the disease is the accumulation of VLCFA. Peroxisomal defect in microglia being now considered a priming event in the pathology, we have therefore generated murine microglial cells mutated in the Abcd1 gene and its closest homolog, the ABCD2 gene. Using CRISPR/Cas9 gene editing strategy, we obtained 3 cell clones with a single or double deficiency. As expected, only the combined absence of ABCD1 and ABCD2 proteins resulted in the accumulation of VLCFA. Ultrastructural analysis by electron microscopy revealed in the double mutant cells the presence of lipid inclusions similar to those observed in brain macrophages of patients. These observations are likely related to the increased level of cholesterol and the accumulation of neutral lipids that we noticed in mutant cells. A preliminary characterization of the impact of peroxisomal defects on the expression of key microglial genes such as Trem2 suggests profound changes in microglial functions related to inflammation and phagocytosis. The expression levels of presumed modifier genes have also been found modified in mutant cells, making these novel cell lines relevant for use as in vitro models to better understand the physiopathogenesis of X-ALD and to discover new therapeutic targets.
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regulation of the adrenoleukodystrophy related gene ABCD2 focus on oxysterols and lxr antagonists
Biochemical and Biophysical Research Communications, 2014Co-Authors: Doriane Trompier, Catherine Gondcaille, Gerard Lizard, Stephane SavaryAbstract:Abstract The regulation of the ABCD2 gene is recognized as a possible therapeutic target for X-linked adrenoleukodystrophy, a rare neurodegenerative disease caused by mutations in the ABCD1 gene. Up-regulation of ABCD2 expression has indeed been demonstrated to compensate for ABCD1 deficiency, restoring peroxisomal β-oxidation of very-long-chain fatty acids. Besides the known inducers of the ABCD2 gene (phenylbutyrate and histone deacetylase inhibitors, fibrates, dehydroepiandrosterone, thyroid hormone and thyromimetics), this review will focus on LXR antagonists and 22S-hydroxycholesterol, recently described as inducers of ABCD2 expression. Several LXR antagonists have been identified and their possible indication for neurodegenerative disorders will be discussed.
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substrate specificity overlap and interaction between adrenoleukodystrophy protein aldp abcd1 and adrenoleukodystrophy related protein aldrp ABCD2
Journal of Biological Chemistry, 2011Co-Authors: Emmanuelle C Genin, Catherine Gondcaille, Doriane Trompier, Flore Geillon, Anne Athias, Philippe Gambert, Stephane SavaryAbstract:X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene, which encodes a peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D called ALDP. ALDP is supposed to function as a homodimer allowing the entry of CoA-esters of very-long chain fatty acids (VLCFA) into the peroxisome, the unique site of their β-oxidation. ALDP deficiency can be corrected by overexpression of ALDRP, its closest homolog. However, the exact nature of the substrates transported by ALDRP and its relationships with ALDP still remain unclear. To gain insight into the function of ALDRP, we used cell models allowing the induction in a dose-dependent manner of a wild type or a mutated non-functional ALDRP-EGFP fusion protein. We explored the consequences of the changes of ALDRP expression levels on the fatty acid content (saturated, monounsaturated, and polyunsaturated fatty acids) in phospholipids as well as on the levels of β-oxidation of 3 suspected substrates: C26:0, C24:0, and C22:6n-3 (DHA). We found an inverse correlation between the fatty acid content of saturated (C26:0, C24:0) and monounsaturated (C26:1, C24:1) VLCFA and the expression level of ALDRP. Interestingly, we obtained a transdominant-negative effect of the inactive ALDRP-EGFP on ALDP function. This effect is due to a physical interaction between ALDRP and ALDP that we evidenced by proximity ligation assays and coimmunoprecipitation. Finally, the β-oxidation assays demonstrate a role of ALDRP in the metabolism of saturated VLCFA (redundant with that of ALDP) but also a specific involvement of ALDRP in the metabolism of DHA.
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Peroxisomal and mitochondrial status of two murine oligodendrocytic cell lines (158N, 158JP): potential models for the study of peroxisomal disorders associated with dysmyelination processes.
Journal of Neurochemistry, 2009Co-Authors: Mauhamad Baarine, Doriane Trompier, Pierre Andreoletti, Kevin Ragot, Emmanuelle Genin, Hammam El Hajj, M Said Ghandour, Franck Ménétrier, Mustapha Cherkaoui-malki, Stephane SavaryAbstract:In some neurodegenerative disorders (leukodystrophies) characterized by myelin alterations, the defect of peroxisomal functions on myelin-producing cells (oligodendrocytes) are poorly understood. The development of in vitro models is fundamental to understanding the physiopathogenesis of these diseases. We characterized two immortalized murine oligodendrocyte cell lines: a normal (158N) and a jimpy (158JP) cell line mutated for the proteolipid protein PLP/DM20. Fluorescence microscopy, flow cytometry, and western blotting analysis allow to identify major myelin proteins (PLP colocalizing with mitochondria; myelin basic protein), oligodendrocyte (CNPase and myelin oligodendrocyte glycoprotein), and peroxisomal markers [adrenoleukodystrophy protein, PMP70, acyl-CoA oxidase 1 (ACOX1), l-peroxisomal bifunctional enzyme, and catalase]. Using electron microscopy, peroxisomes were identified in the two cell lines. Gene expression (ATP-binding cassette, Abcd1, ABCD2, Abcd3, and Acox1) involved in peroxisomal transport or beta-oxidation of fatty acids was evaluated using quantitative PCR. 4-phenylbutyrate treatment increases expression of ACOX1, l-peroxisomal bifunctional enzyme, PLP, myelin oligodendrocyte glycoprotein, and CNPase, mainly in 158N cells. In both cell lines, 4-phenylbutyrate-induced ACOX1 and catalase activities while only ABCD2 gene was up-regulated in 158JP. Moreover, the higher mitochondrial activity and content observed in 158JP were associated with higher glutathione content and increased basal production of reactive oxygen species revealing different redox statuses. Altogether, 158N and 158JP cells will permit studying the relationships between peroxisomal defects, mitochondrial activity, and oligodendrocyte functions.
Per Wester - One of the best experts on this subject based on the ideXlab platform.
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Prediction of recurrent stroke with ABCD2 and ABCD3 scores in patients with symptomatic 50-99% carotid stenosis
BMC Neurology, 2014Co-Authors: Elias Johansson, Jakob Bjellerup, Per WesterAbstract:Although it is preferable that all patients with a recent Transient Ischemic Attack (TIA) undergo acute carotid imaging, there are centers with limited access to such acute examinations. It is controversial whether ABCD2 or ABCD3 scores can be used to triage patients to acute or delayed carotid imaging. It would be acceptable that some patients with a symptomatic carotid stenosis are detected with a slight delay as long as those who will suffer an early recurrent stroke are detected within 24 hours. The aim of this study is to analyze the ability of ABCD2 and ABCD3 scores to predict ipsilateral ischemic stroke among patients with symptomatic 50-99% carotid stenosis. In this secondary analysis of the ANSYSCAP-study, we included 230 consecutive patients with symptomatic 50-99% carotid stenosis. We analyzed the risk of recurrent ipsilateral ischemic stroke before carotid endarterectomy based on each parameter of the ABCD2 and ABCD3 scores separately, and for total ABCD2 and ABCD3 scores. We used Kaplan-Meier analysis. None of the parameters in the ABCD2 or ABCD3 scores could alone predict all 12 of the ipsilateral ischemic strokes that occurred within 2 days of the presenting event, but clinical presentation tended to be a statistically significant risk factor for recurrent ipsilateral ischemic stroke (p = 0.06, log rank test). An ABCD2 score ≥2 and an ABCD3 score ≥4 could predict all 12 of these strokes as well as all 25 ipsilateral ischemic strokes that occurred within 14 days. To use ABCD3 score seems preferable over the ABCD2 score because a higher proportion of low risk patients were identified (17% of the patients had an ABCD3 score
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prediction of recurrent stroke with ABCD2 and abcd3 scores in patients with symptomatic 50 99 carotid stenosis
BMC Neurology, 2014Co-Authors: Elias Johansson, Jakob Bjellerup, Per WesterAbstract:Although it is preferable that all patients with a recent Transient Ischemic Attack (TIA) undergo acute carotid imaging, there are centers with limited access to such acute examinations. It is controversial whether ABCD2 or ABCD3 scores can be used to triage patients to acute or delayed carotid imaging. It would be acceptable that some patients with a symptomatic carotid stenosis are detected with a slight delay as long as those who will suffer an early recurrent stroke are detected within 24 hours. The aim of this study is to analyze the ability of ABCD2 and ABCD3 scores to predict ipsilateral ischemic stroke among patients with symptomatic 50-99% carotid stenosis. In this secondary analysis of the ANSYSCAP-study, we included 230 consecutive patients with symptomatic 50-99% carotid stenosis. We analyzed the risk of recurrent ipsilateral ischemic stroke before carotid endarterectomy based on each parameter of the ABCD2 and ABCD3 scores separately, and for total ABCD2 and ABCD3 scores. We used Kaplan-Meier analysis. None of the parameters in the ABCD2 or ABCD3 scores could alone predict all 12 of the ipsilateral ischemic strokes that occurred within 2 days of the presenting event, but clinical presentation tended to be a statistically significant risk factor for recurrent ipsilateral ischemic stroke (p = 0.06, log rank test). An ABCD2 score ≥2 and an ABCD3 score ≥4 could predict all 12 of these strokes as well as all 25 ipsilateral ischemic strokes that occurred within 14 days. To use ABCD3 score seems preferable over the ABCD2 score because a higher proportion of low risk patients were identified (17% of the patients had an ABCD3 score <4 while only 6% had an ABCD2 < 2). Although it is preferable that carotid imaging be performed within 24 hours, our data support that an ABCD3 score ≥4 might be used for triaging patients to acute carotid imaging in clinical settings with limited access to carotid imaging. However, our findings should be validated in a larger cohort study.
Borislav D Dimitrov - One of the best experts on this subject based on the ideXlab platform.
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long term risk of stroke after transient ischaemic attack a hospital based validation of the ABCD2 rule
BMC Research Notes, 2014Co-Authors: Rose Galvin, Penka A Atanassova, Nicola Motterlini, Tom Fahey, Borislav D DimitrovAbstract:Background The ABCD2 clinical prediction rule is a seven point summation of clinical factors independently predictive of stroke risk. The purpose of this cohort study is to validate the ABCD2 rule in a Bulgarian hospital up to three years after TIA.
Ahmad Chitsaz - One of the best experts on this subject based on the ideXlab platform.
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Predicting Long‑Term Cardiovascular Events after Transient Ischemic Attacks: Carotid Artery Intima‑Media Thickness or ABCD2 Score or Both?
International Journal of Preventive Medicine, 2018Co-Authors: Fariborz Khorvash, Helia Hemasian, Shahab Shahabi, Arvin Shahzamani, Erfan Sheikhbahaei, Ahmad ChitsazAbstract:Background: Patients who experienced transient ischemic attack (TIA) are at high-risk for cardiovascular events. This study aims to evaluate diagnostic value of carotid artery intima-media thickness (CIMT) and ABCD2 score for predicting cardiovascular events in long-term follow-up after TIA. We prospectively included sixty patients with TIA who admitted to hospital from March 2016 to August 2016. Methods: Duplex ultrasonography of internal carotid arteries was performed. ABCD2 scores were evaluated for each patient. At a median follow-up of 20 months, patients were asked about new cardiovascular events. We used IBM SPSS software version 22.0 with Chi-squared, t-test, ANOVA, receiver operating characteristic, and area under the curve (AUC) analysis for our work. Results: Sensitivity and negative predictive value of the combined score (ABCD2+CIMT) was the highest (96.3% and 90.9%, respectively), and the specificity and positive predictive value of the CIMT were the highest (57.5% and 63.1%, respectively) to predict cardiovascular events in long-term. Conclusion: Compared to ABCD2 score, CIMT proved to be more accurate to predict cardiovascular events in long-term follow-ups (AUC = 0.736 vs. AUC = 0.640). However, adding CIMT value to ABCD2 score was even better (AUC = 0.750). Therefore, CIMT measurement in the ABCD2 score after TIA enables prediction of long-term cardiovascular events.
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predicting long term cardiovascular events after transient ischemic attacks carotid artery intima media thickness or ABCD2 score or both
International Journal of Preventive Medicine, 2018Co-Authors: Fariborz Khorvash, Helia Hemasian, Shahab Shahabi, Arvin Shahzamani, Erfan Sheikhbahaei, Ahmad ChitsazAbstract:Background: Patients who experienced transient ischemic attack (TIA) are at high-risk for cardiovascular events. This study aims to evaluate diagnostic value of carotid artery intima-media thickness (CIMT) and ABCD2 score for predicting cardiovascular events in long-term follow-up after TIA. We prospectively included sixty patients with TIA who admitted to hospital from March 2016 to August 2016. Methods: Duplex ultrasonography of internal carotid arteries was performed. ABCD2 scores were evaluated for each patient. At a median follow-up of 20 months, patients were asked about new cardiovascular events. We used IBM SPSS software version 22.0 with Chi-squared, t-test, ANOVA, receiver operating characteristic, and area under the curve (AUC) analysis for our work. Results: Sensitivity and negative predictive value of the combined score (ABCD2+CIMT) was the highest (96.3% and 90.9%, respectively), and the specificity and positive predictive value of the CIMT were the highest (57.5% and 63.1%, respectively) to predict cardiovascular events in long-term. Conclusion: Compared to ABCD2 score, CIMT proved to be more accurate to predict cardiovascular events in long-term follow-ups (AUC = 0.736 vs. AUC = 0.640). However, adding CIMT value to ABCD2 score was even better (AUC = 0.750). Therefore, CIMT measurement in the ABCD2 score after TIA enables prediction of long-term cardiovascular events.
Joan T Moroney - One of the best experts on this subject based on the ideXlab platform.
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population based study of ABCD2 score carotid stenosis and atrial fibrillation for early stroke prediction after transient ischemic attack the north dublin tia study
Stroke, 2010Co-Authors: Orla Sheehan, Aine Merwick, Lisa A Kelly, Niamh Hannon, Michael Marnane, Lorraine Kyne, Patricia M E Mccormack, Joseph Duggan, Alan Moore, Joan T MoroneyAbstract:Background and Purpose— Transient ischemic attack (TIA) etiologic data and the ABCD2 score may improve early stroke risk prediction, but studies are required in population-based cohorts. We investigated the external validity of the ABCD2 score, carotid stenosis, and atrial fibrillation for prediction of early recurrent stroke after TIA. Methods— Patients with TIA in the North Dublin city population (N=294 529) were ascertained by using overlapping hospital and community sources. The relations between individual ABCD2 items, carotid stenosis, atrial fibrillation, and early stroke were examined. Results— In confirmed TIA cases (n=443), carotid stenosis predicted 90-day stroke (hazard ratio=2.56; 95% CI, 1.27 to 5.15, P=0.003). Stroke risk rose with increasing grade of carotid stenosis, ranging from 5.4% (95% CI, 3.3% to 8.7%) with <50% stenosis to 17.2% (95% CI, 9.7% to 29.7%) with severe stenosis/occlusion (hazard ratio=3.3; 95% CI, 1.5 to 7.4, P=0.002). In confirmed TIA cases (n=443), the ABCD2 score perf...
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diagnostic usefulness of the ABCD2 score to distinguish transient ischemic attack and minor ischemic stroke from noncerebrovascular events the north dublin tia study
Stroke, 2009Co-Authors: Orla Sheehan, Aine Merwick, Lisa A Kelly, Niamh Hannon, Michael Marnane, Lorraine Kyne, Patricia M E Mccormack, Joseph Duggan, Alan Moore, Joan T MoroneyAbstract:Background and Purpose— Transient ischemic attack (TIA) diagnosis is frequently difficult in clinical practice. Noncerebrovascular symptoms are often misclassified as TIA by nonspecialist physicians. Clinical prediction rules such as ABCD2 improve the identification of patients with TIA at high risk of early stroke. We hypothesized that the ABCD2 score may partly improve risk stratification due to improved discrimination of true TIA and minor ischemic stroke (MIS) from noncerebrovascular events. Methods— Consecutive patients with TIA were identified within a prospective population-based cohort study of stroke and TIA. The cohort was expanded by inclusion of patients with MIS and noncerebrovascular events referred to a daily TIA clinic serving the population. Diagnosis was assigned by a trained stroke physician independent of ABCD2 score. Results— Five hundred ninety-four patients were included (292 [49.2%] TIA, 45 [7.6%] MIS, and 257 [43.3%] noncerebrovascular). The mean ABCD2 score showed a graded increa...
