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Article: Oxysterols as Biomarkers of Aging and Disease.

Dias, Irundika H K / Shokr, Hala

Advances in experimental medicine and biology

2023 Volume 1440, Page(s) 307–336

Abstract: Oxysterols derive from either enzymatic or non-enzymatic oxidation of cholesterol. Even though they are produced as intermediates of bile acid synthesis pathway, they are recognised as bioactive compounds in cellular processes. Therefore, their absence ... ...

Abstract	Oxysterols derive from either enzymatic or non-enzymatic oxidation of cholesterol. Even though they are produced as intermediates of bile acid synthesis pathway, they are recognised as bioactive compounds in cellular processes. Therefore, their absence or accumulation have been shown to be associated with disease phenotypes. This chapter discusses the contribution of oxysterol to ageing, age-related diseases such as neurodegeneration and various disorders such as cancer, cardiovascular disease, diabetes, metabolic and ocular disorders. It is clear that oxysterols play a significant role in development and progression of these diseases. As a result, oxysterols are being investigated as suitable markers for disease diagnosis purposes and some drug targets are in development targeting oxysterol pathways. However, further research will be needed to confirm the suitability of these potentials.
MeSH term(s)	Humans ; Oxysterols/metabolism ; Cholesterol/metabolism ; Neoplasms ; Aging ; Biomarkers
Chemical Substances	Oxysterols ; Cholesterol (97C5T2UQ7J) ; Biomarkers
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	410187-X
ISSN	0065-2598
ISSN	0065-2598
DOI	10.1007/978-3-031-43883-7_16
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Article ; Online: Effects of carotenoids on mitochondrial dysfunction.

Ademowo, Opeyemi Stella / Oyebode, Olubukola / Edward, Roshita / Conway, Myra E / Griffiths, Helen R / Dias, Irundika H K

Biochemical Society transactions

2024 Volume 52, Issue 1, Page(s) 65–74

Abstract: Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species (ROS) or inadequate antioxidant protection. ROS are produced through several ... ...

Abstract	Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species (ROS) or inadequate antioxidant protection. ROS are produced through several mechanisms in cells including during mitochondrial oxidative phosphorylation. Increased mitochondrial-derived ROS are associated with mitochondrial dysfunction, an early event in age-related diseases such as Alzheimer's diseases (ADs) and in metabolic disorders including diabetes. AD post-mortem investigations of affected brain regions have shown the accumulation of oxidative damage to macromolecules, and oxidative stress has been considered an important contributor to disease pathology. An increase in oxidative stress, which leads to increased levels of superoxide, hydrogen peroxide and other ROS in a potentially vicious cycle is both causative and a consequence of mitochondrial dysfunction. Mitochondrial dysfunction may be ameliorated by molecules with antioxidant capacities that accumulate in mitochondria such as carotenoids. However, the role of carotenoids in mitigating mitochondrial dysfunction is not fully understood. A better understanding of the role of antioxidants in mitochondrial function is a promising lead towards the development of novel and effective treatment strategies for age-related diseases. This review evaluates and summarises some of the latest developments and insights into the effects of carotenoids on mitochondrial dysfunction with a focus on the antioxidant properties of carotenoids. The mitochondria-protective role of carotenoids may be key in therapeutic strategies and targeting the mitochondria ROS is emerging in drug development for age-related diseases.
MeSH term(s)	Humans ; Antioxidants/metabolism ; Reactive Oxygen Species/metabolism ; Carotenoids/metabolism ; Carotenoids/pharmacology ; Oxidative Stress ; Mitochondrial Diseases/metabolism
Chemical Substances	Antioxidants ; Reactive Oxygen Species ; Carotenoids (36-88-4)
Language	English
Publishing date	2024-02-19
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20230193
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Article ; Online: Cholesterol homeostasis in hair follicle keratinocytes is disrupted by impaired ABCA5 activity.

Palmer, Megan A / Dias, Irundika H K / Smart, Eleanor / Benatzy, Yvonne / Haslam, Iain S

Biochimica et biophysica acta. Molecular and cell biology of lipids

2023 Volume 1868, Issue 9, Page(s) 159361

Abstract: The importance of cholesterol in hair follicle biology is underscored by its links to the pathogenesis of alopecias and hair growth disorders. Reports have associated defects in ABCA5, a membrane transporter, with altered keratinocyte cholesterol ... ...

Abstract	The importance of cholesterol in hair follicle biology is underscored by its links to the pathogenesis of alopecias and hair growth disorders. Reports have associated defects in ABCA5, a membrane transporter, with altered keratinocyte cholesterol distribution in individuals with a form of congenital hypertrichosis, yet the biological basis for this defect in hair growth remains unknown. This study aimed to determine the impact of altered ABCA5 activity on hair follicle keratinocyte behaviour. Primary keratinocytes isolated from the outer root sheath of plucked human hair follicles were utilised as a relevant cell model. Following exogenous cholesterol loading, an increase in ABCA5 co-localisation to intracellular organelles was seen. Knockdown of ABCA5 revealed a dysregulation in cholesterol homeostasis, with LXR agonism leading to partial restoration of the homeostatic response. Filipin staining and live BODIPY cholesterol immunofluorescence microscopy revealed a reduction in endo-lysosomal cholesterol following ABCA5 knockdown. Analysis of oxysterols showed a significant increase in the fold change of 25-hydroxycholesterol and 7-β-hydroxycholesterol following cholesterol loading in ORS keratinocytes, after ABCA5 knockdown. These data suggest a role for ABCA5 in the intracellular compartmentalisation of free cholesterol in primary hair follicle keratinocytes. The loss of normal homeostatic response, following the delivery of excess cholesterol after ABCA5 knockdown, suggests an impact on LXR-mediated transcriptional activity. The loss of ABCA5 in the hair follicle could lead to impaired endo-lysosomal cholesterol transport, impacting pathways known to influence hair growth. This avenue warrants further investigation.
MeSH term(s)	Humans ; Hair Follicle/metabolism ; Keratinocytes/metabolism ; Hypertrichosis/metabolism ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Homeostasis ; Cholesterol/metabolism
Chemical Substances	ATP-Binding Cassette Transporters ; Cholesterol (97C5T2UQ7J) ; ABCA5 protein, human
Language	English
Publishing date	2023-06-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbalip.2023.159361
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Article ; Online: Oxysterols and Oxysterol Sulfates in Alzheimer's Disease Brain and Cerebrospinal Fluid.

Dias, Irundika H K / Shokr, Hala / Shephard, Freya / Chakrabarti, Lisa

Journal of Alzheimer's disease : JAD

2022 Volume 87, Issue 4, Page(s) 1527–1536

Abstract: Background: Brain cholesterol levels are tightly regulated but increasing evidence indicates that cholesterol metabolism may drive Alzheimer's disease (AD)-associated pathological changes. Recent advances in understanding of mitochondrial dysfunction in ...

Abstract	Background: Brain cholesterol levels are tightly regulated but increasing evidence indicates that cholesterol metabolism may drive Alzheimer's disease (AD)-associated pathological changes. Recent advances in understanding of mitochondrial dysfunction in AD brain have presented a vital role played by mitochondria in oxysterol biosynthesis and their involvement in pathophysiology. Oxysterol accumulation in brain is controlled by various enzymatic pathways including sulfation. While research into oxysterol is under the areas of active investigation, there is less evidence for oxysterol sulfate levels in human brain. Objective: This study investigates the hypothesis that AD brain oxysterol detoxification via sulfation is impaired in later stages of disease resulting in oxysterol accumulation. Methods: Lipids were extracted from postmortem frozen brain tissue and cerebrospinal (CSF) from late- (Braak stage III-IV) and early- (Braak stage I-II) stage AD patients. Samples were spiked with internal standards prior to lipid extraction. Oxysterols were enriched with a two-step solid phase extraction using a polymeric SPE column and further separation was achieved by LC-MS/MS. Results: Oxysterols, 26-hydroxycholesterol (26-OHC), 25-hydroxycholesterol (25-OHC), and 7-oxycholesterol levels were higher in brain tissue and mitochondria extracted from late-stage AD brain tissue except for 24S-hydroxycholesterol, which was decreased in late AD. However, oxysterol sulfates are significantly lower in the AD frontal cortex. Oxysterols, 25-OHC, and 7-oxocholesterol was higher is CSF but 26-OHC and oxysterol sulfate levels were not changed. Conclusion: Our results show oxysterol metabolism is altered in AD brain mitochondria, favoring synthesis of 26-OHC, 25-OHC, and 7-oxocholesterol, and this may influence brain mitochondrial function and acceleration of the disease.
MeSH term(s)	Alzheimer Disease/pathology ; Brain/pathology ; Chromatography, Liquid ; Humans ; Hydroxycholesterols/metabolism ; Oxysterols/metabolism ; Sulfates/metabolism ; Tandem Mass Spectrometry
Chemical Substances	Hydroxycholesterols ; Oxysterols ; Sulfates
Language	English
Publishing date	2022-05-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-220083
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Article ; Online: Current and Future Directions for Targeting Lipoxin A4 in Alzheimer's Disease.

Dias, Irundika H K / Griffiths, Helen R

Journal of Alzheimer's disease : JAD

2021 Volume 81, Issue 1, Page(s) 87–90

Abstract: Neuroinflammation has been implicated in Alzheimer's disease onset and progression. Chronic neuroinflammation is initiated by amyloid-β-activated microglial cells that secrete immuno-modulatory molecules within the brain and into the vasculature. ... ...

Abstract	Neuroinflammation has been implicated in Alzheimer's disease onset and progression. Chronic neuroinflammation is initiated by amyloid-β-activated microglial cells that secrete immuno-modulatory molecules within the brain and into the vasculature. Inflammation is normally self-limiting and actively resolves by "switching off" the generation of pro-inflammatory mediators and by non-phlogistic clearance of spent cells and their debris to restore tissue homeostasis. Deficits in these anti-inflammatory/pro-resolution pathways may predispose to the development of chronic inflammation. The synthesis of endogenous lipid mediators from arachidonic acid, lipoxins via cyclooxygenase 2 and lipoxygenases, and conversion of exogenous polyunsaturated fatty acids, namely docosahexaenoic acid and eicosapentaenoic acid, to resolvins contributes to effective, timely resolution of acute inflammation. Work by Xiuzhe et al., 2020 in the Journal of Alzheimer's Disease reported that plasma level of LXA4 is related to cognitive status in ischemic stroke patients suggesting that decreased LXA4 may be a potential risk factor for post post-stroke cognitive impairment. As evident by recent clinical trials and development of drug analogues, there is recent drive to search for lipoxin analogues as therapeutics for inflammatory diseases. Understanding how bioactive lipid signaling is involved in resolution will increase our understanding of controlling inflammation and may facilitate the discovery of new classes of therapeutic pro-resolution agents for evaluation in AD prevention studies.
MeSH term(s)	Alzheimer Disease/metabolism ; Animals ; Brain/metabolism ; Humans ; Inflammation/metabolism ; Inflammation Mediators/metabolism ; Lipoxins/metabolism
Chemical Substances	Inflammation Mediators ; Lipoxins ; lipoxin A4
Language	English
Publishing date	2021-03-15
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-210121
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Article ; Online: Microvascular function and oxidative stress in adult individuals with early onset of cardiovascular disease.

Shokr, Hala / Dias, Irundika H K / Gherghel, Doina

Scientific reports

2020 Volume 10, Issue 1, Page(s) 4881

Abstract: The current study aims to investigate retinal vascular function and its relationship with systemic anti-oxidative defence capacity in normal individuals versus those with early hypertensive changes according to the current ESC/ESH guidelines. Retinal ... ...

Abstract	The current study aims to investigate retinal vascular function and its relationship with systemic anti-oxidative defence capacity in normal individuals versus those with early hypertensive changes according to the current ESC/ESH guidelines. Retinal microvascular function was assessed in 201 participants by means of dynamic retinal vessel analysis. Blood pressure, lipid panel, oxidized (GSH) & reduced glutathione (GSSG) were also evaluated for each participant. Individuals classed as grade 1 hypertension demonstrated higher retinal arterial baseline diameter fluctuation (p = 0.0012), maximum dilation percentage (p = 0.0007), time to maximum constriction (p = 0.0003) and lower arterial constriction slope (p = 0.0131). Individuals classed as high normal and grade 1 hypertension also demonstrated higher time to maximum dilation than individuals classed as optimal or normal. GSH levels correlated negatively with SBP, DBP and MBP values in all participants (p = 0.0010; p = 0.0350 and p = 0.0050) as well as with MBP values in high normal and grade 1 hypertension (p = 0.0290). The levels of GSSG correlated positively with SBP, DBP and MBP values in all participants (p = 0.0410; p = 0.0330 and, p = 0.0220). Our results point to the fact that microvascular alterations can be identifiable at BP values still considered within normal values and go in parallel with the changes observed in the level of oxidative stress.
MeSH term(s)	Adult ; Biomarkers/metabolism ; Blood Pressure/genetics ; Blood Pressure/physiology ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/physiopathology ; Female ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Humans ; Male ; Middle Aged ; Oxidative Stress/genetics ; Oxidative Stress/physiology ; Retina/metabolism
Chemical Substances	Biomarkers ; Glutathione (GAN16C9B8O) ; Glutathione Disulfide (ULW86O013H)
Language	English
Publishing date	2020-03-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-60766-0
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Article: TNF-α-Mediated Endothelial Cell Apoptosis Is Rescued by Hydrogen Sulfide.

Diaz Sanchez, Lorena / Sanchez-Aranguren, Lissette / Wang, Keqing / Spickett, Corinne M / Griffiths, Helen R / Dias, Irundika H K

Antioxidants (Basel, Switzerland)

2023 Volume 12, Issue 3

Abstract: Endothelial dysfunction is implicated in the development and aggravation of cardiovascular complications. Among the endothelium-released vasoactive factors, hydrogen sulfide ( ... ...

Abstract	Endothelial dysfunction is implicated in the development and aggravation of cardiovascular complications. Among the endothelium-released vasoactive factors, hydrogen sulfide (H
Language	English
Publishing date	2023-03-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12030734
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Article ; Online: TNF-α-Mediated Endothelial Cell Apoptosis Is Rescued by Hydrogen Sulfide

Diaz Sanchez, Lorena / Sanchez-Aranguren, Lissette / Wang, Keqing / Spickett, Corinne M. / Griffiths, H. R. / Dias, Irundika H. K.

Antioxidants. 2023 Mar. 16, v. 12, no. 3

2023

Abstract: Endothelial dysfunction is implicated in the development and aggravation of cardiovascular complications. Among the endothelium-released vasoactive factors, hydrogen sulfide (H₂S) has been investigated for its beneficial effects on the vasculature ... ...

Abstract	Endothelial dysfunction is implicated in the development and aggravation of cardiovascular complications. Among the endothelium-released vasoactive factors, hydrogen sulfide (H₂S) has been investigated for its beneficial effects on the vasculature through anti-inflammatory and redox-modulating regulatory mechanisms. Reduced H₂S bioavailability is reported in chronic diseases such as cardiovascular disease, diabetes, atherosclerosis and preeclampsia, suggesting the value of investigating mechanisms, by which H₂S acts as a vasoprotective gasotransmitter. We explored whether the protective effects of H₂S were linked to the mitochondrial health of endothelial cells and the mechanisms by which H₂S rescues apoptosis. Here, we demonstrate that endothelial dysfunction induced by TNF-α increased endothelial oxidative stress and induced apoptosis via mitochondrial cytochrome c release and caspase activation over 24 h. TNF-α also affected mitochondrial morphology and altered the mitochondrial network. Post-treatment with the slow-releasing H₂S donor, GYY4137, alleviated oxidising redox state, decreased pro-caspase 3 activity, and prevented endothelial apoptosis caused by TNF-α alone. In addition, exogenous GYY4137 enhanced S-sulfhydration of pro-caspase 3 and improved mitochondrial health in TNF-α exposed cells. These data provide new insights into molecular mechanisms for cytoprotective effects of H₂S via the mitochondrial-driven pathway.
Keywords	apoptosis ; atherosclerosis ; bioavailability ; caspases ; diabetes ; endothelial cells ; hydrogen sulfide ; mitochondria ; oxidative stress ; pre-eclampsia
Language	English
Dates of publication	2023-0316
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12030734
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Article ; Online: Antioxidant Micronutrients and Oxidative Stress Biomarkers.

Dias, Irundika H K / Griffiths, Helen R / Milward, Mike R / Ling, Martin R / Chapple, Iain L C / Grant, Melissa M

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2588, Page(s) 41–58

Abstract: Chronic inflammatory diseases are the major causes of mortality in humans and recent research has improved our understanding of the major impact of lifestyle factors upon inflammatory diseases and conditions. One of the most influential of these is ... ...

Abstract	Chronic inflammatory diseases are the major causes of mortality in humans and recent research has improved our understanding of the major impact of lifestyle factors upon inflammatory diseases and conditions. One of the most influential of these is nutrition, which may drive both pro-inflammatory as well as anti-inflammatory cascades at molecular and cellular levels. There are a variety of model systems that may be employed to investigate the impact of micronutrients and macronutrients upon inflammatory pathways, many of which operate through oxidative stress, either at the level of controlling the redox state of the cell and downstream redox-regulated gene transcription factors, and other acting as free radical generating or scavenging agents. This chapter focuses upon biological sample preparation prior to assay and details methods for analyzing certain antioxidant micronutrients and biomarkers of oxidative stress.
MeSH term(s)	Humans ; Antioxidants/pharmacology ; Antioxidants/metabolism ; Micronutrients ; Oxidative Stress ; Biomarkers/metabolism ; Oxidation-Reduction
Chemical Substances	Antioxidants ; Micronutrients ; Biomarkers
Language	English
Publishing date	2022-11-23
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2780-8_4
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Article ; Online: Chromatography of oxysterols.

Dias, Irundika H K / Wilson, Steven R / Roberg-Larsen, Hanne

Biochimie

2018 Volume 153, Page(s) 3–12

Abstract: Oxysterols play important roles in development and diseases, but can be highly challenging to analyze. To ensure satisfactory measurements, oxysterols must typically be separated with chromatography prior to detection. Here, we will devote attention to ... ...

Abstract	Oxysterols play important roles in development and diseases, but can be highly challenging to analyze. To ensure satisfactory measurements, oxysterols must typically be separated with chromatography prior to detection. Here, we will devote attention to the chromatography of oxysterols, focusing on gas chromatography and liquid chromatography. We will present the role of stationary phases, mobile phases, and dimensions and geometries of particles/columns. We discuss how these parameters may affect the chromatography, regarding factors such as speed and resolution. Finally, we present some less explored avenues for separation of oxysterols.
MeSH term(s)	Chromatography, Gas/methods ; Chromatography, Liquid/methods ; Oxysterols/isolation & purification
Chemical Substances	Oxysterols
Language	English
Publishing date	2018-05-09
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	120345-9
ISSN	1638-6183 ; 0300-9084
ISSN (online)	1638-6183
ISSN	0300-9084
DOI	10.1016/j.biochi.2018.05.004
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