Increased flux of the plant sterols campesterol and sitosterol across a disrupted blood brain barrier

Saeed, Ahmed; Genové, Guillem; Tian, Li; Hülshorst, Frank; Betsholtz, Christer; Björkhem, Ingemar; Lütjohann, Dieter

doi:10.1016/j.steroids.2015.02.005

Cited by 15 publications

(10 citation statements)

References 115 publications

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“…5). Dietary cholesterol homologues from plants, campesterol and sitosterol, are known to get enriched to some extent in the mammalian brain [44] and were detected in our samples as well. The campesterol was most abundant in the olfactory bulb (Fig.…”

Section: Resultsmentioning

confidence: 68%

Metabolomics of mammalian brain reveals regional differences

et al. 2018

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BackgroundThe mammalian brain is organized into regions with specific biological functions and properties. These regions have distinct transcriptomes, but little is known whether they may also differ in their metabolome. The metabolome, a collection of small molecules or metabolites, is at the intersection of the genetic background of a given cell or tissue and the environmental influences that affect it. Thus, the metabolome directly reflects information about the physiologic state of a biological system under a particular condition. The objective of this study was to investigate whether various brain regions have diverse metabolome profiles, similarly to their genetic diversity. The answer to this question would suggest that not only the genome but also the metabolome may contribute to the functional diversity of brain regions.MethodsWe investigated the metabolome of four regions of the mouse brain that have very distinct functions: frontal cortex, hippocampus, cerebellum, and olfactory bulb. We utilized gas- and liquid- chromatography mass spectrometry platforms and identified 215 metabolites.ResultsPrincipal component analysis, an unsupervised multivariate analysis, clustered each brain region based on its metabolome content, thus providing the unique metabolic profile of each region. A pathway-centric analysis indicated that olfactory bulb and cerebellum had most distinct metabolic profiles, while the cortical parenchyma and hippocampus were more similar in their metabolome content. Among the notable differences were distinct oxidative-anti-oxidative status and region-specific lipid profiles. Finally, a global metabolic connectivity analysis using the weighted correlation network analysis identified five hub metabolites that organized a unique metabolic network architecture within each examined brain region. These data indicate the diversity of global metabolome corresponding to specialized regional brain function and provide a new perspective on the underlying properties of brain regions.ConclusionIn summary, we observed many differences in the metabolome among the various brain regions investigated. All four brain regions in our study had a unique metabolic signature, but the metabolites came from all categories and were not pathway-centric.Electronic supplementary materialThe online version of this article (10.1186/s12918-018-0644-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 68%

Metabolomics of mammalian brain reveals regional differences

et al. 2018

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“…Both β-sitosterol (BSS) and its glycosylated form are found in human plasma and tissues in very low levels, at 800-1,000 less compared to endogenous cholesterol (Pegel, 1997). It has been shown that upon chronic high intake plant sterols accumulate in the brain (Vanmierlo et al, 2012;Saeed et al, 2015). Even though the mammalian blood brain barrier (BBB) is not, or very poorly, permeable to cholesterol, studies have shown that phytosterols like sitosterol and campesterol are able to cross the BBB in mice.…”

Section: Glucosylated Phytosterols and Medicinal Propertiesmentioning

confidence: 99%

Plant Glycosides and Glycosidases: A Treasure-Trove for Therapeutics

et al. 2020

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Plants contain numerous glycoconjugates that are metabolized by specific glucosyltransferases and hydrolyzed by specific glycosidases, some also catalyzing synthetic transglycosylation reactions. The documented value of plant-derived glycoconjugates to beneficially modulate metabolism is first addressed. Next, focus is given to glycosidases, the central theme of the review. The therapeutic value of plant glycosidases is discussed as well as the present production in plant platforms of therapeutic human glycosidases used in enzyme replacement therapies. The increasing knowledge on glycosidases, including structure and catalytic mechanism, is described. The novel insights have allowed the design of functionalized highly specific suicide inhibitors of glycosidases. These so-called activity-based probes allow unprecedented visualization of glycosidases cross-species. Here, special attention is paid on the use of such probes in plant science that promote the discovery of novel enzymes and the identification of potential therapeutic inhibitors and chaperones.

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“…[50] There is no flux of lipoprotein bound cholesterol across the blood brain barrier, but the presence of an alkyl group on the 24-position of cholesterol side chain (campesterol) results in a markedly increased ability to cross the intact blood brain barrier. [51] BNP2069(22 hydroxytingenone or tingenin B), a pentacyclic quinine methide triterpenoid compound has been found to possess antibacterial, antiparasitic and anticancer activities. [52] BNP8864 and ILE2…”

Section: Binding Sites (Swapped Structures)mentioning

confidence: 99%

Binding modes of potential anti-prion phytochemicals to PrPC structures in silico

Neupane¹,

Khadka

Rayamajhi

et al. 2019

Preprint

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Background: Prion diseases involve the conversion of a normal, cell-surface glycoprotein (PrPC ) into a misfolded pathogenic form (PrPSC ). Cellular assays and in vivo experiments have identified various compounds with anti-prion activity which work through various mechanisms. Structures of PrPC have revealed the protein to occur in a swapped or non-swapped, monomeric or dimeric forms. Binding modes of known anti-prions is either not known, or has been determined with only the non-swapped structures of PrPC . In the current study medicinal phytochemicals from various databases have been docked with PrPC in silico to identify potential anti-prions in comparison with known anti-prion compounds to determine their binding modes and speculate possible mechanisms of inhibition of PrPC to PrPSC . Results: Eleven new phytochemicals were identified based on their binding energies and pharmacokinetic properties. The binding sites and interactions of the known and new anti-prion compounds are similar, and differences in binding modes occur in structures with very subtle differences in side chain conformations. Binding of these compounds poses steric hindrance to neighbouring molecules. Residues shown to be associated with inhibition of PrPC to PrPSC conversion form interactions with most of the compounds. Conclusions: The new compounds are mostly highly hydrophobic and are derivatives of terpenes, sterols and quinones. They might act as potent inhibitors of the PrPC to PrPSC conversion through a combination of steric hindrance and stabilization of structure through ionic/hydrophobic interactions. Their high binding energies coupled with identical binding sites as those of the known compounds, and their ability to cross the blood brain barrier makes these phytochemicals a promising group of compounds for further studies on prevention of PrPC to PrPSC .

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Increased flux of the plant sterols campesterol and sitosterol across a disrupted blood brain barrier

Cited by 15 publications

References 115 publications

Metabolomics of mammalian brain reveals regional differences

Metabolomics of mammalian brain reveals regional differences

Plant Glycosides and Glycosidases: A Treasure-Trove for Therapeutics

Binding modes of potential anti-prion phytochemicals to PrPC structures in silico

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