المؤلفون: Joelyn Wong, Ben J. Gu, Harry Teoh, Malgorzata Krupa, Mastura Monif, Mark Slee, James S. Wiley

المصدر: Platelets, Vol 33, Iss 4, Pp 621-631 (2022)

مصطلحات موضوعية: apoptotic platelets, extracellular vesicles, p2x1 receptor, p2x7 receptor, platelets, Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Platelets express P2X1 receptors and our data also show the expression of P2X7 receptors. We studied the role of both receptors in platelet apoptosis by incubation of PRP with P2X agonists, then centrifuged to remove viable platelets, and analyzed the supernatant by flow cytometry to identify a sparse platelet-derived population that stained with MitoTracker dyes and CD41. BzATP, a potent agonist of P2X receptors, and ABT737, an activator of intrinsic apoptosis, produced altered platelets that stained moderately for annexin V and corresponded to an early stage apoptotic platelet (ESAP). Over a range of BzATP concentrations, we observed a dose-dependent formation of ESAPs between 5 and 500 uM BzATP, together with a variable formation of ESAPs at nanomolar ATP or BzATP (50–200 nM). Production of ESAPs occurred with αβ-meATP, while responses with either BzATP or αβ-meATP showed desensitization at a higher agonist concentration. Formation of ESAPs by either 100 nM or 0.5 mM BzATP was inhibited by preincubation of platelets with latrunculin A, an inhibitor of the actin cytoskeleton that prevents apoptosis. ESAP production was totally inhibited by preincubation of platelets with methyl-beta-cyclodextrin, which removes cholesterol from lipid rafts. Our data show that both P2X1 and P2X7 receptors are localized in platelet lipid rafts where P2X-agonists act to produce early stage apoptotic platelets.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/0953-7104Test; https://doaj.org/toc/1369-1635Test

الوصول الحر: https://doaj.org/article/b6de5b1298f249f9ade198faf80948d7Test

المؤلفون: Ching Yi Wu, Mengliang Wu, Xin Huang, Ben J. Gu, Carole Maldonado-Codina, Philip B. Morgan, Laura E. Downie, Holly R. Chinnery

المصدر: International Journal of Molecular Sciences, Vol 23, Iss 17, p 9589 (2022)

مصطلحات موضوعية: meibomian gland, resident immune cell, dendritic cell, benzalkonium chloride, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Meibomian gland orifices (MGOs) are located along the eyelid margin and secrete meibum into the tear film. The profile of resident innate immune cells (ICs) at this site is not well understood. The distribution and phenotype of resident ICs around MGOs in mice was investigated and herein defined as MGO-associated immune cells (MOICs). The effect of topical 0.1% benzalkonium chloride (BAK) on MOICs was also assessed. Eyelids from healthy CD11ceYFP and Cx3cr1gfp/gfp mice aged three or seven months were compared. ICs were identified as CD11c+, Cx3cr1+, and MHC-II+ using four-colour immunostaining and confocal microscopy. MOIC density was variable but clustered around MGOs. There were more CD11c+ MOICs in three-month-old compared with seven-month-old mice (three-month-old: 893 ± 449 cells/mm2 vs. seven-month-old: 593 ± 493 cells/mm2, p = 0.004). Along the eyelid margin, there was a decreasing gradient of CD11c+ MOIC density in three-month-old mice (nasal: 1003 ± 369 cells/mm2, vs. central: 946 ± 574 cells/mm2, vs. temporal: 731 ± 353 cells/mm2, p = 0.044). Cx3cr1-deficient mice had two-fold fewer MHC-II+ MOICs, suggesting a role for Cx3cr1 receptor signaling in meibomian gland surveillance. CD11c+ MOIC density was lower in BAK-exposed eyes compared to saline-treated controls, suggesting a change in homeostasis. This study provides novel insight into resident ICs located at MGOs, and their contribution to MG homeostasis.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/23/17/9589Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/35727b343d434283bd6d0849ebce7d51Test

المؤلفون: Yihan Li, Xin Huang, Christopher Fowler, Yen Y. Lim, Simon M. Laws, Noel Faux, James D. Doecke, Brett Trounson, Kelly Pertile, Rebecca Rumble, Vincent Doré, Victor L. Villemagne, Christopher C. Rowe, James S. Wiley, Paul Maruff, Colin L. Masters, Ben J. Gu

المصدر: International Journal of Molecular Sciences, Vol 23, Iss 14, p 7867 (2022)

مصطلحات موضوعية: myeloid cells, purinergic receptors, episodic memory, the Preclinical Alzheimer’s Cognitive Composite (PACC), CSF T-tau, CSF Aβ1-42, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Alzheimer’s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ −ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/23/14/7867Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/8af6721597d74e71aa5875b5ecaf241cTest

المؤلفون: Ben J. Gu, Xin Huang, Pavan K. Avula, Emily Caruso, Candace Drysdale, Kirstan A. Vessey, Amber Ou, Christopher Fowler, Tian-Hua Liu, Yong Lin, Adam Horton, Colin L. Masters, James S. Wiley, Robyn H. Guymer, Erica L. Fletcher

المصدر: Frontiers in Medicine, Vol 8 (2021)

مصطلحات موضوعية: monocytes, phagocytosis, drusen, reticular pseudodrusen, glatiramer acetate, Medicine (General), R5-920

الوصف: Age-related macular degeneration (AMD) is characterized by the accumulation of debris in the posterior eye. In this study we evaluated peripheral blood monocyte phagocytic function at various stages of AMD and in aged matched control participants. Real-time tri-color flow cytometry was used to quantify phagocytic function of peripheral blood monocyte subsets (non-classic, intermediate and classic) isolated from subjects with intermediate or late AMD and compared with age matched healthy controls. Assessment of phagocytic function of monocytes isolated from those with and without reticular pseudodrusen was also made, and the effect of glatiramer acetate on phagocytic function assessed. Phagocytic function was reduced in all subjects with AMD, irrespective of stage of disease. However, there was no correlation between phagocytic function and drusen load, nor any difference between the level of phagocytosis in those with or without reticular pseudodrusen. Treatment with glatiramer acetate increased phagocytosis of classical and non-classical monocytes, normalizing the reduction in phagocytosis observed in those with AMD. These findings suggest that defective systemic phagocytosis is associated with both intermediate and late stages of AMD, highlighting a potential role in the accumulation of debris that occurs early in the disease process. Assessing peripheral monocyte phagocytic function provides further insights into the etiology of this disease and offer a novel therapeutic target.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fmed.2021.634177/fullTest; https://doaj.org/toc/2296-858XTest

الوصول الحر: https://doaj.org/article/46bdd72e10094b2f8229071672c38f6dTest

المؤلفون: Joelyn Wong (11967052), Ben J. Gu (11967055), Harry Teoh (11967058), Malgorzata Krupa (11967061), Mastura Monif (7342067), Mark Slee (301671), James S. Wiley (11967064)

مصطلحات موضوعية: Biochemistry, Cell Biology, Pharmacology, Immunology, Developmental Biology, Marine Biology, Cancer, Inorganic Chemistry, Hematology, Chemical Sciences not elsewhere classified, Apoptotic platelets, extracellular vesicles, P2X1 receptor, P2X7 receptor, Platelets

الوصف: Platelets express P2X1 receptors and our data also show the expression of P2X7 receptors. We studied the role of both receptors in platelet apoptosis by incubation of PRP with P2X agonists, then centrifuged to remove viable platelets, and analyzed the supernatant by flow cytometry to identify a sparse platelet-derived population that stained with MitoTracker dyes and CD41. BzATP, a potent agonist of P2X receptors, and ABT737, an activator of intrinsic apoptosis, produced altered platelets that stained moderately for annexin V and corresponded to an early stage apoptotic platelet (ESAP). Over a range of BzATP concentrations, we observed a dose-dependent formation of ESAPs between 5 and 500 uM BzATP, together with a variable formation of ESAPs at nanomolar ATP or BzATP (50–200 nM). Production of ESAPs occurred with αβ-meATP, while responses with either BzATP or αβ-meATP showed desensitization at a higher agonist concentration. Formation of ESAPs by either 100 nM or 0.5 mM BzATP was inhibited by preincubation of platelets with latrunculin A, an inhibitor of the actin cytoskeleton that prevents apoptosis. ESAP production was totally inhibited by preincubation of platelets with methyl-beta-cyclodextrin, which removes cholesterol from lipid rafts. Our data show that both P2X1 and P2X7 receptors are localized in platelet lipid rafts where P2X-agonists act to produce early stage apoptotic platelets.

العلاقة: https://figshare.com/articles/journal_contribution/Flow_Cytometry_Identifies_an_Early_Stage_of_Platelet_Apoptosis_Produced_by_Agonists_of_the_P2X1_and_P2X7_Receptors/18666460Test

الإتاحة: https://doi.org/10.6084/m9.figshare.18666460.v1Test

المؤلفون: Hannah C Leeson, Tailoi Chan-Ling, Michael D Lovelace, Jeremy C Brownlie, Ben J Gu, Michael W Weible

المصدر: Neural Regeneration Research, Vol 14, Iss 10, Pp 1684-1694 (2019)

مصطلحات موضوعية: P2X7, P2X7R, adult neurogenesis, neural stem cells, neural progenitor cells, hippocampus, SGZ, calcium signaling, purinergic signaling, Neurology. Diseases of the nervous system, RC346-429

الوصف: Neurogenesis is a persistent and essential feature of the adult mammalian hippocampus. Granular neurons generated from resident pools of stem or progenitor cells provide a mechanism for the formation and consolidation of new memories. Regulation of hippocampal neurogenesis is complex and multifaceted, and numerous signaling pathways converge to modulate cell proliferation, apoptosis, and clearance of cellular debris, as well as synaptic integration of newborn immature neurons. The expression of functional P2X7 receptors in the central nervous system has attracted much interest and the regulatory role of this purinergic receptor during adult neurogenesis has only recently begun to be explored. P2X7 receptors are exceptionally versatile: in their canonical role they act as adenosine triphosphate-gated calcium channels and facilitate calcium-signaling cascades exerting control over the cell via calcium-encoded sensory proteins and transcription factor activation. P2X7 also mediates transmembrane pore formation to regulate cytokine release and facilitate extracellular communication, and when persistently stimulated by high extracellular adenosine triphosphate levels large P2X7 pores form, which induce apoptotic cell death through cytosolic ion dysregulation. Lastly, as a scavenger receptor P2X7 directly facilitates phagocytosis of the cellular debris that arises during neurogenesis, as well as during some disease states. Understanding how P2X7 receptors regulate the physiology of stem and progenitor cells in the adult hippocampus is an important step towards developing useful therapeutic models for regenerative medicine. This review considers the relevant aspects of adult hippocampal neurogenesis and explores how P2X7 receptor activity may influence the molecular physiology of the hippocampus, and neural stem and progenitor cells.

وصف الملف: electronic resource

العلاقة: http://www.nrronline.org/article.asp?issn=1673-5374;year=2019;volume=14;issue=10;spage=1684;epage=1694;aulast=LeesonTest; https://doaj.org/toc/1673-5374Test

الوصول الحر: https://doaj.org/article/69abd65d339a4b419b119a09615f1f70Test

المؤلفون: Xin Huang, Yihan Li, Christopher Fowler, James D. Doecke, Yen Ying Lim, Candace Drysdale, Vicky Zhang, Keunha Park, Brett Trounson, Kelly Pertile, Rebecca Rumble, John W. Pickering, Robert A. Rissman, Floyd Sarsoza, Sara Abdel‐Latif, Yong Lin, Vincent Doré, Victor Villemagne, Christopher C. Rowe, Jurgen Fripp, Ralph Martins, James S. Wiley, Paul Maruff, Jacobo E. Mintzer, Colin L. Masters, Ben J. Gu

المصدر: Alzheimer's & Dementia. 19:2084-2094

مصطلحات موضوعية: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology

الوصف: Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions.In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses.We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aβ status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts.Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::34bf0b2975507ade597946d9ddd753bfTest
https://doi.org/10.1002/alz.12813Test

المؤلفون: Yihan Li, Xin Huang, Christopher Fowler, James D Doecke, Brett Trounson, Kelly Pertile, Rebecca Rumble, Yen Ying Lim, Paul Maruff, Jacobo E. Mintzer, Vincent Dore, Christopher Rowe, Jurgen Fripp, James S Wiley, Colin L. Masters, Ben J Gu

المصدر: Alzheimer's & Dementia. 18

مصطلحات موضوعية: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::ffddeb917f67fd2eea669eb6b4ee15eaTest
https://doi.org/10.1002/alz.065030Test

المؤلفون: Yihan Li, Colin L. Masters, Xin Huang, Luke A. Miles, Simon M. Laws, James S. Wiley, Ben J. Gu

المصدر: Cellular and Molecular Life Sciences. 78:7397-7426

مصطلحات موضوعية: Pharmacology, Innate immune system, TREM2, Cell Biology, Biology, Acquired immune system, PICALM, Cellular and Molecular Neuroscience, Immune system, Immunology, Molecular Medicine, Aducanumab, Cognitive decline, Molecular Biology, Exome sequencing

الوصف: Alzheimer's disease (AD) is a chronic neurodegenerative disease characterised by cognitive impairment, behavioural alteration, and functional decline. Over 130 AD-associated susceptibility loci have been identified by genome-wide association studies (GWAS), while whole genome sequencing (WGS) and whole exome sequencing (WES) studies have identified AD-associated rare variants. These variants are enriched in APOE, TREM2, CR1, CD33, CLU, BIN1, CD2AP, PILRA, SCIMP, PICALM, SORL1, SPI1, RIN3, and more genes. Given that aging is the single largest risk factor for late-onset AD (LOAD), the accumulation of somatic mutations in the brain and blood of AD patients have also been explored. Collectively, these genetic findings implicate the role of innate and adaptive immunity in LOAD pathogenesis and suggest that a systemic failure of cell-mediated amyloid-β (Aβ) clearance contributes to AD onset and progression. AD-associated variants are particularly enriched in myeloid-specific regulatory regions, implying that AD risk variants are likely to perturbate the expression of myeloid-specific AD-associated genes to interfere Aβ clearance. Defective phagocytosis, endocytosis, and autophagy may drive Aβ accumulation, which may be related to naturally-occurring antibodies to Aβ (Nabs-Aβ) produced by adaptive responses. Passive immunisation is providing efficiency in clearing Aβ and slowing cognitive decline, such as aducanumab, donanemab, and lecanemab (ban2401). Causation of AD by impairment of the innate immunity and treatment using the tools of adaptive immunity is emerging as a new paradigm for AD, but immunotherapy that boosts the innate immune functions of myeloid cells is highly expected to modulate disease progression at asymptomatic stage.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::c1ee861a64f1cd1982ca197a5014c1cdTest
https://doi.org/10.1007/s00018-021-03986-5Test

المؤلفون: Yihan Li, Ben J. Gu

المصدر: Journal of Exploratory Research in Pharmacology. :000-000

مصطلحات موضوعية: General Medicine

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::9595b60cb345473ed4c04435120755e3Test
https://doi.org/10.14218/jerp.2023.00006Test