المؤلفون: James Hennegan, Aled H. Bryant, Lauren Griffiths, Matthieu Trigano, Oliver J.M. Bartley, Joanna J. Bartlett, Carys Minahan, Willy Antoni Abreu de Oliveira, Eylan Yutuc, Sotirios Ntikas, Christos S. Bartsocas, Margarita Markouri, Eleni Antoniadou, Ioanna Laina, Owain W. Howell, Meng Li, Yuqin Wang, William J. Griffiths, Emma L. Lane, Mariah J. Lelos, Spyridon Theofilopoulos

المصدر: iScience, Vol 27, Iss 1, Pp 108670- (2024)

مصطلحات موضوعية: Biological sciences, neuroscience, Molecular neuroscience, Science

الوصف: Summary: Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25R)26-dihydroxycholesterol (7α,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson’s disease (PD). In this study we investigated the role of 7α,26-diHC in midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, increases the number of mDA neurons and prevents the loss of mDA neurons induced by 7α,26-diHC. These effects are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1+ oculomotor neurons. Furthermore, our results suggest that elevated 24(S),25-epoxycholesterol, which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. These findings suggest that voriconazole, and/or other azole CYP7B1 inhibitors may have implications in PD therapy development.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2589004223027475; https://doaj.org/toc/2589-0042

URL الوصول: https://doaj.org/article/cc11eaec18cb42d988985f04f6f16725

المؤلفون: Alison Dickson, Eylan Yutuc, Catherine A. Thornton, James E. Dunford, Udo Oppermann, Yuqin Wang, William J. Griffiths

المصدر: Open Biology, Vol 13, Iss 5 (2023)

مصطلحات موضوعية: HSD3B1, oxysterol, placenta, mass spectrometry, bile acid, pregnancy, Biology (General), QH301-705.5

الوصف: Most biologically active oxysterols have a 3β-hydroxy-5-ene function in the ring system with an additional site of oxidation at C-7 or on the side-chain. In blood plasma oxysterols with a 7α-hydroxy group are also observed with the alternative 3-oxo-4-ene function in the ring system formed by ubiquitously expressed 3β-hydroxy-Δ5-C27-steroid oxidoreductase Δ5-isomerase, HSD3B7. However, oxysterols without a 7α-hydroxy group are not substrates for HSD3B7 and are not usually observed with the 3-oxo-4-ene function. Here we report the unexpected identification of oxysterols in plasma derived from umbilical cord blood and blood from pregnant women taken before delivery at 37+ weeks of gestation, of side-chain oxysterols with a 3-oxo-4-ene function but no 7α-hydroxy group. These 3-oxo-4-ene oxysterols were also identified in placenta, leading to the hypothesis that they may be formed by a previously unrecognized 3β-hydroxy-Δ5-C27-steroid oxidoreductase Δ5-isomerase activity of HSD3B1, an enzyme which is highly expressed in placenta. Proof-of-principle experiments confirmed that HSD3B1 has this activity. We speculate that HSD3B1 in placenta is the source of the unexpected 3-oxo-4-ene oxysterols in cord and pregnant women's plasma and may have a role in controlling the abundance of biologically active oxysterols delivered to the fetus.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2046-2441

URL الوصول: https://doaj.org/article/17d9e78ab32f4d83adb33f794fb2752d

المؤلفون: Alison L. Dickson, Eylan Yutuc, Catherine A. Thornton, Yuqin Wang, William J. Griffiths

المصدر: Frontiers in Endocrinology, Vol 13 (2022)

مصطلحات موضوعية: sterol, oxysterol, bile acids, CYP11A1, LC-MS, CYP27A1, Diseases of the endocrine glands. Clinical endocrinology, RC648-665

الوصف: The aim of this study was to identify oxysterols and any down-stream metabolites in placenta, umbilical cord blood plasma, maternal plasma and amniotic fluid to enhance our knowledge of the involvement of these molecules in pregnancy. We confirm the identification of 20S-hydroxycholesterol in human placenta, previously reported in a single publication, and propose a pathway from 22R-hydroxycholesterol to a C27 bile acid of probable structure 3β,20R,22R-trihydroxycholest-5-en-(25R)26-oic acid. The pathway is evident not only in placenta, but pathway intermediates are also found in umbilical cord plasma, maternal plasma and amniotic fluid but not non-pregnant women.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fendo.2022.1031013/full; https://doaj.org/toc/1664-2392

URL الوصول: https://doaj.org/article/8398923c7ed5473f819bac8cda43fde6

المؤلفون: Harald C. Köfeler, Thomas O. Eichmann, Robert Ahrends, John A. Bowden, Niklas Danne-Rasche, Edward A. Dennis, Maria Fedorova, William J. Griffiths, Xianlin Han, Jürgen Hartler, Michal Holčapek, Robert Jirásko, Jeremy P. Koelmel, Christer S. Ejsing, Gerhard Liebisch, Zhixu Ni, Valerie B. O’Donnell, Oswald Quehenberger, Dominik Schwudke, Andrej Shevchenko, Michael J. O. Wakelam, Markus R. Wenk, Denise Wolrab, Kim Ekroos

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-4 (2021)

مصطلحات موضوعية: Science

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2041-1723

URL الوصول: https://doaj.org/article/83316378728a498088000222c0fb33af

المؤلفون: Zack Saud, Victoria J. Tyrrell, Andreas Zaragkoulias, Majd B. Protty, Evelina Statkute, Anzelika Rubina, Kirsten Bentley, Daniel A. White, Patricia Dos Santos Rodrigues, Robert C. Murphy, Harald Köfeler, William J. Griffiths, Jorge Alvarez-Jarreta, Richard William Brown, Robert G. Newcombe, James Heyman, Manon Pritchard, Robert WJ. Mcleod, Arvind Arya, Ceri-Ann Lynch, David Owens, P Vince Jenkins, Niklaas J. Buurma, Valerie B. O’Donnell, David W. Thomas, Richard J. Stanton

المصدر: Journal of Lipid Research, Vol 63, Iss 6, Pp 100208- (2022)

مصطلحات موضوعية: phospholipids, lipidomics, inflammation, virology, clinical trials, aminophospholipids, Biochemistry, QD415-436

الوصف: The lipid envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an essential component of the virus; however, its molecular composition is undetermined. Addressing this knowledge gap could support the design of antiviral agents as well as further our understanding of viral-host protein interactions, infectivity, pathogenicity, and innate immune system clearance. Lipidomics revealed that the virus envelope comprised mainly phospholipids (PLs), with some cholesterol and sphingolipids, and with cholesterol/phospholipid ratio similar to lysosomes. Unlike cellular membranes, procoagulant amino-PLs were present on the external side of the viral envelope at levels exceeding those on activated platelets. Accordingly, virions directly promoted blood coagulation. To investigate whether these differences could enable selective targeting of the viral envelope in vivo, we tested whether oral rinses containing lipid-disrupting chemicals could reduce infectivity. Products containing PL-disrupting surfactants (such as cetylpyridinium chloride) met European virucidal standards in vitro; however, components that altered the critical micelle concentration reduced efficacy, and products containing essential oils, povidone-iodine, or chlorhexidine were ineffective. This result was recapitulated in vivo, where a 30-s oral rinse with cetylpyridinium chloride mouthwash eliminated live virus in the oral cavity of patients with coronavirus disease 19 for at least 1 h, whereas povidone-iodine and saline mouthwashes were ineffective. We conclude that the SARS-CoV-2 lipid envelope i) is distinct from the host plasma membrane, which may enable design of selective antiviral approaches; ii) contains exposed phosphatidylethanolamine and phosphatidylserine, which may influence thrombosis, pathogenicity, and inflammation; and iii) can be selectively targeted in vivo by specific oral rinses.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S0022227522000414; https://doaj.org/toc/0022-2275

URL الوصول: https://doaj.org/article/6b2447ff65c14140a877f16e61623047

المؤلفون: William J. Griffiths, Yuqin Wang

المصدر: Journal of Lipid Research, Vol 63, Iss 2, Pp 100165- (2022)

مصطلحات موضوعية: oxysterol, hydroxycholesterol, accessible cholesterol, macrophage, B cell, T cell, Biochemistry, QD415-436

الوصف: Oxysterols, the oxidized forms of cholesterol or of its precursors, are formed in the first steps of cholesterol metabolism. Oxysterols have interested chemists, biologists, and physicians for many decades, but their exact biological relevance in vivo, other than as intermediates in bile acid biosynthesis, has long been debated. However, in the first quarter of this century, a role for side-chain oxysterols and their C-7 oxidized metabolites has been convincingly established in the immune system. 25-Hydroxycholesterol has been shown to be synthesized by macrophages in response to the activation of Toll-like receptors and to offer protection against microbial pathogens, whereas 7α,25-dihydroxycholesterol has been shown to act as a chemoattractant to lymphocytes expressing the G protein-coupled receptor Epstein-Barr virus-induced gene 2 and to be important in coordinating the action of B cells, T cells, and dendritic cells in secondary lymphoid tissue. There is a growing body of evidence that not only these two oxysterols but also many of their isomers are of importance to the proper function of the immune system. Here, we review recent findings related to the roles of oxysterols in immunology.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S0022227521001486; https://doaj.org/toc/0022-2275

URL الوصول: https://doaj.org/article/52ba49eb884242a2b4e72fee5f7da67b

المؤلفون: Gerhard Liebisch, Eoin Fahy, Junken Aoki, Edward A. Dennis, Thierry Durand, Christer S. Ejsing, Maria Fedorova, Ivo Feussner, William J. Griffiths, Harald Köfeler, Alfred H. Merrill, Jr., Robert C. Murphy, Valerie B. O'Donnell, Olga Oskolkova, Shankar Subramaniam, Michael J.O. Wakelam, Friedrich Spener

المصدر: Journal of Lipid Research, Vol 61, Iss 12, Pp 1539-1555 (2020)

مصطلحات موضوعية: mass spectrometry, lipidomics, fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, Biochemistry, QD415-436

الوصف: A comprehensive and standardized system to report lipid structures analyzed by MS is essential for the communication and storage of lipidomics data. Herein, an update on both the LIPID MAPS classification system and shorthand notation of lipid structures is presented for lipid categories Fatty Acyls (FA), Glycerolipids (GL), Glycerophospholipids (GP), Sphingolipids (SP), and Sterols (ST). With its major changes, i.e., annotation of ring double bond equivalents and number of oxygens, the updated shorthand notation facilitates reporting of newly delineated oxygenated lipid species as well. For standardized reporting in lipidomics, the hierarchical architecture of shorthand notation reflects the diverse structural resolution powers provided by mass spectrometric assays. Moreover, shorthand notation is expanded beyond mammalian phyla to lipids from plant and yeast phyla. Finally, annotation of atoms is included for the use of stable isotope-labeled compounds in metabolic labeling experiments or as internal standards. This update on lipid classification, nomenclature, and shorthand annotation for lipid mass spectra is considered a standard for lipid data presentation.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S0022227520600177; https://doaj.org/toc/0022-2275

URL الوصول: https://doaj.org/article/2bd36b12c88941a5aed54ffa6bbb5b4e

المؤلفون: Nicholas J. Hudson, Antonio Reverter, William J. Griffiths, Eylan Yutuc, Yuqin Wang, Angela Jeanes, Sean McWilliam, David W. Pethick, Paul L. Greenwood

المصدر: BMC Genomics, Vol 21, Iss 1, Pp 1-23 (2020)

مصطلحات موضوعية: Bovine fat depots, Kidney, Omental, Intermuscular, Biotechnology, TP248.13-248.65, Genetics, QH426-470

الوصف: Abstract Background This study used a genome-wide screen of gene expression to better understand the metabolic and functional differences between commercially valuable intramuscular fat (IMF) and commercially wasteful subcutaneous (SC) fat depots in Bos taurus beef cattle. Results We confirmed many findings previously made at the biochemical level and made new discoveries. The fundamental lipogenic machinery, such as ACACA and FASN encoding the rate limiting Acetyl CoA carboxylase and Fatty Acid synthase were expressed at 1.6–1.8 fold lower levels in IMF, consistent with previous findings. The FA elongation pathway including the rate limiting ELOVL6 was also coordinately downregulated in IMF compared to SC as expected. A 2-fold lower expression in IMF of ACSS2 encoding Acetyl Coenzyme A synthetase is consistent with utilisation of less acetate for lipogenesis in IMF compared to SC as previously determined using radioisotope incorporation. Reduced saturation of fat in the SC depot is reflected by 2.4 fold higher expression of the SCD gene encoding the Δ9 desaturase enzyme. Surprisingly, CH25H encoding the cholesterol 25 hydroxylase enzyme was ~ 36 fold upregulated in IMF compared to SC. Moreover, its expression in whole muscle tissue appears representative of the proportional representation of bovine marbling adipocytes. This suite of observations prompted quantification of a set of oxysterols (oxidised forms of cholesterol) in the plasma of 8 cattle exhibiting varying IMF. Using Liquid Chromatography-Mass Spectrometry (LC-MS) we found the levels of several oxysterols were significantly associated with multiple marbling measurements across the musculature, but (with just one exception) no other carcass phenotypes. Conclusions These data build on our molecular understanding of ruminant fat depot biology and suggest oxysterols represent a promising circulating biomarker for cattle marbling.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1471-2164

URL الوصول: https://doaj.org/article/5da402a1a6004aa7b0a3321a239f0d5e

المؤلفون: William J. Griffiths, Yuqin Wang

المصدر: Frontiers in Physiology, Vol 12 (2021)

مصطلحات موضوعية: 25-hydroxycholesterol, SREBP pathway, INSIG, HMG-CoA reductase, SARS-CoV-2, hedgehog signalling pathway, Physiology, QP1-981

الوصف: In this article we discuss the concept of accessible plasma membrane cholesterol and its involvement as a signalling molecule. Changes in plasma membrane accessible cholesterol, although only being minor in the context of total cholesterol plasma membrane cholesterol and total cell cholesterol, are a key regulator of overall cellular cholesterol homeostasis by the SREBP pathway. Accessible cholesterol also provides the second messenger between patched 1 and smoothened in the hedgehog signalling pathway important during development, and its depletion may provide a mechanism of resistance to microbial pathogens including SARS-CoV-2. We revise the hypothesis that oxysterols are a signalling form of cholesterol, in this instance as a rapidly acting and paracrine version of accessible cholesterol.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fphys.2021.723224/full; https://doaj.org/toc/1664-042X

URL الوصول: https://doaj.org/article/f54d4d6f6ac147e78323d1aceabdcea9

المؤلفون: William J. Griffiths, Jonas Abdel-Khalik, Sarah F. Moore, Ruwani S. Wijeyekoon, Peter J. Crick, Eylan Yutuc, Krista Farrell, David P. Breen, Caroline H. Williams-Gray, Spyridon Theofilopoulos, Ernest Arenas, Miles Trupp, Roger A. Barker, Yuqin Wang

المصدر: Frontiers in Aging Neuroscience, Vol 13 (2021)

مصطلحات موضوعية: sterol, oxysterol, dihydroxycholesterol, bile acid biosynthesis, mass spectrometry, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Disordered cholesterol metabolism is linked to neurodegeneration. In this study we investigated the profile of cholesterol metabolites found in the cerebrospinal fluid (CSF) of Parkinson’s disease (PD) patients. When adjustments were made for confounding variables of age and sex, 7α,(25R)26-dihydroxycholesterol and a second oxysterol 7α,x,y-trihydroxycholest-4-en-3-one (7α,x,y-triHCO), whose exact structure is unknown, were found to be significantly elevated in PD CSF. The likely location of the additional hydroxy groups on the second oxysterol are on the sterol side-chain. We found that CSF 7α-hydroxycholesterol levels correlated positively with depression in PD patients, while two presumptively identified cholestenoic acids correlated negatively with depression.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fnagi.2021.685594/full; https://doaj.org/toc/1663-4365

URL الوصول: https://doaj.org/article/abaae19036454c66a3664ff79c96a45e