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An Outbreak of Oxidative Stress in Pathogenesis of Alzheimer's Disease
Published in Suvardhan Kanchi, Rajasekhar Chokkareddy, Mashallah Rezakazemi, Smart Nanodevices for Point-of-Care Applications, 2022
Sourbh Suren Garg, Poojith Nuthalapati, Sruchi Devi, Atulika Sharma, Debasis Sahu, Jeena Gupta
Cholesterol is a sterol having a molecular formula of C17H62O23 and, present in the cell membranes [32]. The abundance of cholesterols in microdomains of cell membranes is called lipid raft [33]. The binding of APP with these rafts commands the β-secretase to insert APP in a monolayer of phospholipids which accumulate the Aβ1–42 peptides through a mechanism called the amyloidogenic pathway [34]. The mechanism of propagation of Aβ is favored by esterified cholesterols. The elimination of excess cholesterols in the brain can be achieved by an oxidation reaction. Oxysterols are liberated as an end product of oxidation. The oxidation of cholesterols is helpful to prevent their accumulation in the brain. Cholesterol is the major component of the brain. The biochemical event of cholesterol 24-hydroxylase lays the formation of 24-hydroxycholesterol, which has the potential to cross the blood-brain barrier [35]. The brain is the major site for their formation. In astrocytes, the liver-X-receptor controlled pathway is responsible for mediating the efflux of apoE cholesterols. Together, oxysterol and efflux of apoE upregulate the cholesterol homeostasis in the brain which directly links with the progression of AD [36].
Dynein in Endosome and Phagosome Maturation
Published in Keiko Hirose, Handbook of Dynein, 2019
Ashim Rai, Divya Pathak, Roop Mallik
Lipid microdomains were suggested to form on phagosomes because of the localization of a microdomain marker protein Flotillin-1 on phagosomes [16]. Furthermore, proteomic characterization found Rab7 enriched in these phagosomal domains. Similar to the endocytic pathway, Rab7 recruits dynein onto late phagosomes through its interaction with RILP [37]. Interestingly, dynein recruitment is intimately linked to cholesterol levels on the membrane of endo-phagosomes. A Rab7 effector protein ORP1L (oxysterol binding protein related protein 1L) binds to cholesterol on the membrane [77]. Under low cholesterol conditions, ORP1L binds to RILP and an ER-associated protein VAP (vesicle-associated membrane protein (VAMP)-associated protein) at the same time, thereby forming ER-late endosome contact sites. VAP in turns interacts with the Rab7-RILP complex causing the release of the p150 subunit of dynactin from the Rab7-RILP complex. This causes inhibition of dynein-dependent late endosome transport under low cholesterol conditions. However, when cholesterol levels on late endosomes are high, ORP1L interacts with the membrane cholesterol and frees the Rab7-RILP complex to interact with dynein-dynactin complex. This stimulates dynein-driven late endosome transport. Cholesterol has been implicated in late endosome positioning through several observations. In Niemann Pick C disease, cholesterol accumulates in excessive amounts on late endosomes [15]. A distinct phenotype of this disease is the accumulation of cholesterol-laden “paralyzed” late endosomes at microtubule minus ends. This is likely caused by overstimulation of dynein dependent transport of these organelles. Increasing cholesterol on late endosomes by the drug U18666A also shows the same behavior. Conversely, depleting cholesterol on late endosomes leads to the localization of late endosomes around the cell periphery. All these observations suggest a link between dynein driven transport and cholesterol levels on late endosomes/phagosomes.
Hyperlipidemia and male infertility
Published in Egyptian Journal of Basic and Applied Sciences, 2021
Zainab Bubakr Hamad Zubi, Hamad Abdulsalam Hamad Alfarisi
Liver X receptors (LXRs) are nuclear receptors with transcription factor characteristics [73]. They are stimulated by oxysterols, metabolic derivatives or oxidized forms of cholesterol. They have important roles in controlling of lipid, cholesterol and metabolic homeostasis and regulation of proliferation, differentiation, inflammation and reproduction [74]. There are two isoforms of LXRs; LXRα (NR1H3) which are expressed mainly in the tissues that have important activities in lipid metabolism such as liver and brown adipose tissue. The second isoform is LXRβ (NR1H2) which is ubiquitously represented [75]. Several studies have emphasized on the importance of LXRs in male fertility. Liver X receptors Knockout (LXRα; β−/−) male mice demonstrated a dramatic reduction in the fertility capacity with aging, where there is abrupt fertility reduction around the age of 6 months followed by a complete loss of mature germ cells at the age of 10 months [Frenoux et al., 8; 76]. Liver X receptors alpha (LXRα) are abundantly expressed in Leydig and germ cells; whereas, LXRβ are mainly expressed in Sertoli cells and to a less extent in the germ cells [77]. Loss of LXRβ disrupts cholesterol homeostasis resulting in an accumulation of cholesterol esters in the Sertoli cells, which leads ultimately to testicular destruction that is more severe in the absence of the two isoforms of LXRs [76].
Reactions of singlet oxygen with cholesterol: a computational study
Published in Molecular Physics, 2023
Anna M. Tsouri, David Robinson
Photooxidation of natural unsaturated molecules, especially those found in foodstuffs, is a major issue for global food security. In the type II mechanism, a photosensitiser absorbs UV or visible light, and the excited singlet state undergoes intersystem crossing to a triplet electronic state, after which energy transfer occurs from the photosensitiser to O2, leading to singlet oxygen (1Δg) generation. Singlet oxygen then reacts with unsaturated C = C bonds, often forming hydroperoxyl moieties. Various vitamins act as photosensitisers, leading to generation of singlet oxygen, including vitamin A, riboflavin (vitamin B2) and vitamin E, among many others [1–5]. Many vitamins which are commonly cited as anti-oxidants, such as B3, D2, D3 and E, were found to generate singlet oxygen when pre-irradiated with UVB, followed by UVA [2]. Riboflavin-sensitised reactions have been investigated in different foodstuffs, including model fatty acids, bulk oil and milk [3–5]. Where singlet oxygen is generated in vivo, damage to the cell leading to long-term health effects can occur. A recent study by Yeo and Shahidi [6] investigated the possible mechanism of development of cardiovascular diseases from photooxidation of low-density lipoprotein particles, with riboflavin acting as the sensitiser [6]. Oxidation of cholesterol has been also been linked to cardiovascular disease. The central nervous system is particularly rich in cholesterol [7], and oxysterol derivatives have been linked to neurodegenerative diseases, including Alzheimer’s disease [8], amyotrophic lateral sclerosis (also known as motor neurone disease) [9,10] and Lewy body dementia [11] via modification of important proteins. The presence of 5,6-epoxide derivatives of cholesterol has been detected at ppm levels in human blood and appears to be related liver function [12]. Singlet oxygen also reacts with surrounding solvent, to produce hydrogen peroxide [13].