Hongbin Xu
University of Ottawa
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Publication
Featured researches published by Hongbin Xu.
Neuroscience & Biobehavioral Reviews | 2013
Graham Mazereeuw; Nathan Herrmann; Steffany A. L. Bennett; Walter Swardfager; Hongbin Xu; Nico Valenzuela; Stephen Fai; Krista L. Lanctôt
The persistence of a depressive episode in coronary artery disease (CAD) patients not only heightens the risk of acute ischemic events, but it is also associated with accelerated cognitive decline. Antidepressant interventions for depression in CAD have only modest effects and novel approaches are limited by a poor understanding of etiological mechanisms. This review proposes that the platelet activating factor (PAF) family of lipids might be associated with the persistence of a depressive episode and related neurodegenerative pathology in CAD due to their association with leading etiological mechanisms for depression in CAD such as inflammation, oxidative and nitrosative stress, vascular endothelial dysfunction, and platelet reactivity. The evidence implicating PAFs in CAD, vascular pathology, and neurodegenerative processes is also presented. We also propose future directions for the investigation of PAFs as mediators of persistent depression. In summary, PAFs are implicated in leading mechanisms associated with depression in CAD. PAFs may therefore be associated with the persistence of depression in CAD and related to neurodegenerative and cognitive sequelae.
Frontiers in Physiology | 2013
Steffany A. L. Bennett; Nicolas Valenzuela; Hongbin Xu; Bettina Franko; Stephen Fai; Daniel Figeys
Not all of the mysteries of life lie in our genetic code. Some can be found buried in our membranes. These shells of fat, sculpted in the central nervous system into the cellular (and subcellular) boundaries of neurons and glia, are themselves complex systems of information. The diversity of neural phospholipids, coupled with their chameleon-like capacity to transmute into bioactive molecules, provides a vast repertoire of immediate response second messengers. The effects of compositional changes on synaptic function have only begun to be appreciated. Here, we mined 29 neurolipidomic datasets for changes in neuronal membrane phospholipid metabolism in Alzheimers Disease (AD). Three overarching metabolic disturbances were detected. We found that an increase in the hydrolysis of platelet activating factor precursors and ethanolamine-containing plasmalogens, coupled with a failure to regenerate relatively rare alkyl-acyl and alkenyl-acyl structural phospholipids, correlated with disease severity. Accumulation of specific bioactive metabolites [i.e., PC(O-16:0/2:0) and PE(P-16:0/0:0)] was associated with aggravating tau pathology, enhancing vesicular release, and signaling neuronal loss. Finally, depletion of PI(16:0/20:4), PI(16:0/22:6), and PI(18:0/22:6) was implicated in accelerating Aβ42 biogenesis. Our analysis further suggested that converging disruptions in platelet activating factor, plasmalogen, phosphoinositol, phosphoethanolamine (PE), and docosahexaenoic acid metabolism may contribute mechanistically to catastrophic vesicular depletion, impaired receptor trafficking, and morphological dendritic deformation. Together, this analysis supports an emerging hypothesis that aberrant phospholipid metabolism may be one of multiple critical determinants required for Alzheimer disease conversion.
FEBS Journal | 2013
Hongbin Xu; Nicolas Valenzuela; Stephen Fai; Daniel Figeys; Steffany A. L. Bennett
Glycerophosphocholines are the major building blocks of biological membranes. They are also precursors of low‐molecular‐weight second messengers with mass to charge ratios of 450–600. These messengers include lysophosphatidylcholines (LPCs) and lyso‐platelet activating factors (PAFs) that may be further processed into PAFs. Often considered as a single species, LPCs, PAFs and lyso‐PAFs are, in fact, families of glycerophosphocholine‐derived lipids distinguished by the linkage of their sn‐1 carbon chains to the phosphoglyceride backbone (ester or ether), their sn‐1 carbon chain length and degree of unsaturation, and the identity of their sn‐2 constituents (a hydroxyl or acetyl group). Each LPC and PAF species exhibits a different affinity for its cognate G‐protein‐coupled receptors, and each species elicits receptor‐independent actions that play critical signalling roles. Targeted mass spectrometry‐based lipidomic approaches are enabling the molecular identification and quantification of these low‐abundance second messengers. Variations between datasets map the temporal landscape of second messengers available for signalling, and provide snapshots of the state of structural membrane compositional remodelling at the time of extraction. Here, we review a number of advances in lipidomic methodologies used to identify LPCs, lyso‐PAFs and PAFs, and highlight how these targeted approaches are providing valuable insight into the roles played by the cellular lipidome in cell function and disease susceptibility.
Journal of Neurochemistry | 2013
Renée E. Haskew-Layton; Jimmy B. Payappilly; Hongbin Xu; Steffany A. L. Bennett; Rajiv R. Ratan
Astrocytes are critical for the antioxidant support of neurons. Recently, we demonstrated that low level hydrogen peroxide (H2O2) facilitates astrocyte‐dependent neuroprotection independent of the antioxidant transcription factor Nrf2, leaving the identity of the endogenous astrocytic Nrf2 activator to question. In this study, we show that an endogenous electrophile, 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2), non‐cell autonomously protects neurons from death induced by depletion of the major antioxidant glutathione. Nrf2 knockdown in astrocytes abrogated 15d‐PGJ2s neuroprotective effect as well as 15d‐PGJ2 facilitated Nrf2‐target gene induction. In contrast, knockdown of the transcription factor peroxisome proliferator activated‐receptor gamma (PPARγ), a well‐characterized 15d‐PGJ2 target, did not alter 15d‐PGJ2 non‐cell autonomous neuroprotection. In addition, several PPARγ agonists of the thiazolidinedione (TZD) family failed to induce neuroprotection. Unexpectedly, however, the TZD troglitazone (which contains a chromanol moiety found on vitamin E) induced astrocyte‐mediated neuroprotection, an effect which was mimicked by the vitamin E analogs alpha‐tocopherol or alpha‐tocotrienol. Our findings lead to two important conclusions: (i) 15d‐PGJ2 induces astrocyte‐mediated neuroprotection via an Nrf2 but not PPARγ mediated pathway, suggesting that 15d‐PGJ2 is a candidate endogenous modulator of Nrf2 protective pathways in astrocytes; (ii) selective astrocyte treatment with analogs or compounds containing the chromanol moiety of vitamin E facilitates non‐cell autonomous neuroprotection.
Bioinformatics | 2013
Alexandre P. Blanchard; Graeme S. V. McDowell; Nico Valenzuela; Hongbin Xu; Sarah Gelbard; Martin Bertrand; Gary W. Slater; Daniel Figeys; Stephen Fai; Steffany A. L. Bennett
Motivation: Establishing phospholipid identities in large lipidomic datasets is a labour-intensive process. Where genomics and proteomics capitalize on sequence-based signatures, glycerophospholipids lack easily definable molecular fingerprints. Carbon chain length, degree of unsaturation, linkage, and polar head group identity must be calculated from mass to charge (m/z) ratios under defined mass spectrometry (MS) conditions. Given increasing MS sensitivity, many m/z values are not represented in existing prediction engines. To address this need, Visualization and Phospholipid Identification is a web-based application that returns all theoretically possible phospholipids for any m/z value and MS condition. Visualization algorithms produce multiple chemical structure files for each species. Curated lipids detected by the Canadian Institutes of Health Research Training Program in Neurodegenerative Lipidomics are provided as high-resolution structures. Availability: VaLID is available through the Canadian Institutes of Health Research Training Program in Neurodegenerative Lipidomics resources web site at https://www.med.uottawa.ca/lipidomics/resources.html. Contacts: [email protected] Supplementary Information: Supplementary data are available at Bioinformatics online.
Proteomics | 2013
Fangjun Wang; Alexandre P. Blanchard; Fred Elisma; Matthew W. Granger; Hongbin Xu; Steffany A. L. Bennett; Daniel Figeys; Hanfa Zou
Sustained exposure to soluble amyloid β (Aβ42) oligomers is predicted to impair synaptic function in the hippocampal‐entorhinal circuit, signaling synaptic loss and precipitating cognitive impairment in Alzheimers disease. Regional changes in overall patterns of protein phosphorylation are likely crucial to promote transition from a presymptomatic to a symptomatic state in response to accumulating Aβ42. Here, we used unbiased proteomic approaches to compare the phosphoproteome of presymptomatic and symptomatic TgCRND8 mice and identify network disruptions in signaling pathways implicated in the manifestation of behavioral indices of learning and memory impairment. Phosphopeptide enrichment with triple isotopic dimethylation labeling combined with online multidimensional separation and MS was used to profile phosphoproteome changes in 2‐ and 6‐month‐old TgCRND8 mice and congenic littermate controls. We identified 1026 phosphopeptides representing 1168 phosphorylation sites from 476 unique proteins. Of these, 595 phosphopeptides from 293 unique proteins were reliably quantified and 139 phosphopeptides were found to change significantly in the hippocampus of TgCRND8 mice following conversion from a presymptomatic to a symptomatic state.
Neuropsychiatric Disease and Treatment | 2015
Graham Mazereeuw; Nathan Herrmann; Hongbin Xu; Alexandre P. Blanchard; Daniel Figeys; Paul Oh; Steffany A. L. Bennett; Krista L. Lanctôt
Introduction Depression is a frequent complication of coronary artery disease (CAD) with an unknown etiology. Platelet activating factor (PAF) lipids, which are associated with CAD, have recently been linked with novel proposed etiopathological mechanisms for depression such as inflammation, oxidative/nitrosative stress, and vascular endothelial dysfunction. Methods and results This hypothesis-generating study investigated the relationships between various PAF species and depressive symptoms in 26 CAD patients (age: 60.6±9.2 years, 69% male, mean Hamilton Depression Rating Scale [HAM-D] score: 11.8±5.2, HAM-D range: 3–20). Plasma PAF analyses were performed using high performance liquid chromatography electrospray ionization mass spectrometry in precursor ion scan. Significant associations between depressive symptom severity (HAM-D score) and a greater plasma abundance of the PAFs phosphocholine (PC) PC(O-12:0/2:0) (r=0.49, P=0.01), PC(O-14:1/2:0) (r=0.43, P=0.03), PC(O-17:3/2:0) (r=0.44, P=0.04), and PC(O-18:3/2:0) (r=0.50, P=0.01) were observed. Associations between those PAFs and HAM-D score persisted after adjusting for age and sex. Conclusion These preliminary findings support the exploration of the PAF lipidome for depressive symptom biomarkers in CAD patients. Patients were recruited as part of the following clinical trial: NCT00981383.
Circulation | 2016
Catriona Syme; Simon Czajkowski; Jean Shin; Michal Abrahamowicz; Gabriel Leonard; Michel Perron; Louis Richer; Suzanne Veillette; Daniel Gaudet; Lisa J. Strug; Yun Wang; Hongbin Xu; Graeme Taylor; Tomáš Paus; Steffany A. L. Bennett; Zdenka Pausova
Background: Glycerophosphocholine (GPC) metabolites modulate atherosclerosis and thus risk for cardiovascular disease (CVD). Preclinical CVD may start during adolescence. Here, we used targeted serum lipidomics to identify a new panel of GPCs, and tested whether any of these GPCs are associated, in adolescence, with classical risk factors of CVD, namely excess visceral fat (VF), elevated blood pressure, insulin resistance, and atherogenic dyslipidemia. Methods: We studied a population-based sample of 990 adolescents (12–18 years, 48% male), as part of the Saguenay Youth Study. Using liquid chromatography-electrospray ionization-mass spectrometry, we identified 69 serum GPCs within the 450 to 680 m/z range. We measured VF with MRI. Results: We identified several novel GPCs that were associated with multiple CVD risk factors. Most significantly, PC16:0/2:0 was negatively associated with VF (P=1.4×10–19), blood pressure (P=7.7×10–5), and fasting triacylglycerols (P=9.0×10–5), and PC14:1/0:0 was positively associated with VF (P=3.0×10–7), fasting insulin (P=5.4×10–32), and triacylglycerols (P=1.4×10–29). The Sobel test of mediation revealed that both GPCs mediated their respective relations between VF (as a potential primary exposure) and CVD risk factors (as outcomes, P values<1.3×10–3). Furthermore, a GPC shown recently to predict incident coronary heart disease in older adults, PC18:2/0:0, was associated with several CVD risk factors in adolescents; these associations were less strong than those with the newly identified GPCs. Conclusions: We identified novel GPCs strongly associated with multiple CVD risk factors in adolescents. These GPCs may be sensitive indicators of obesity-related risk for CVD outcomes in adults, and may improve biological understanding of CVD risk.
Journal of Neuroinflammation | 2014
Graham Mazereeuw; Nathan Herrmann; Hongbin Xu; Daniel Figeys; Paul Oh; Steffany A. L. Bennett; Krista L. Lanctôt
BackgroundPatients with coronary artery disease (CAD) are at risk of accelerated cognitive decline, particularly those with major depression. Mechanisms for cognitive deficits associated with CAD, and the effects of depression, remain poorly understood. However, CAD is associated with inflammatory processes that have been linked to neurodegeneration, may contribute to cognitive decline, and are elevated in depression. Platelet-activating factors (PAFs) are emerging as key lipid mediators that may be central to those processes and highly relevant to cognitive decline in CAD.MethodsThis cross-sectional study investigated relationships between various PAFs and cognitive performance in 24 patients with CAD (age, 60.3 ± 9.4; 70.8% male). Analyses were repeated in a subgroup of 15 patients with CAD with major depression (DSM-IV). Cognitive performance was assessed using a standardized battery and summary z scores were calculated based on age, sex, and education norms. Global cognitive performance was the average of domain-specific z scores. Plasma PAF analyses were performed using electrospray ionization mass spectrometry (precursor ion scan).ResultsA greater abundance of PAF PC(O-18:0/2:0) was associated with poorer global cognitive performance in patients with CAD (r = -0.45, P = 0.03). In the major depressed subgroup, PAF PC(O-18:0/2:0) (r = -0.59, P = 0.02) as well as PC(O-16:0/2:0) (r = -0.52, P = 0.04), and lyso-PAF PC(O-16:0/0:0) (r = -0.53, P = 0.04) were associated with poorer global cognitive performance. A greater abundance of PAF PC(O-19:5/2:0) was associated with better global cognitive performance (r = 0.55, P = 0.03), suggesting a possible compensatory species.ConclusionsThis study suggests that certain PAFs might be associated with global cognitive performance in patients with CAD, with stronger relationships observed in those with major depression. Confirmation of these preliminary findings is warranted.
Human Mutation | 2017
Kristin D. Kernohan; Laure Frésard; Zachary Zappala; Taila Hartley; Kevin S. Smith; Justin D. Wagner; Hongbin Xu; Arran McBride; Pierre R. Bourque; Steffany A. L. Bennett; David A. Dyment; Kym M. Boycott; Stephen B. Montgomery; Jodi Warman Chardon
At least 15% of the disease‐causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in noncoding regions. Whole‐transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease‐relevant tissue for RNA. Here, we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation (c.458A>G;p.Tyr153Cys). Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(p<10−16). Subsequent Sanger‐sequencing identified the splice mutation responsible for the isoform (c.504A>C;p.Lys168Asn) and provided a molecular diagnosis of autosomal‐recessive spinal muscular atrophy with progressive myoclonic epilepsy. Our findings demonstrate the utility of RNA sequencing from blood to identify splice‐impacting disease mutations for nonhematological conditions, providing a diagnosis for these otherwise unsolved patients.