Mapping the locations of estradiol and potent neuroprotective analogues in phospholipid bilayers by REDOR

Cegelski, Lynette; Rice, Charles V.; O’Connor, Robert; Caruano, Amy L.; Tochtrop, Gregory P.; Cai, Zu Yun; Covey, Douglas F.; Schaefer, Jacob

doi:10.1002/ddr.20048

Cited by 27 publications

(33 citation statements)

References 46 publications

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“…Biomolecules that contain phosphorus atoms that are spatially close to carbons with chemical shifts near 60 to 80 ppm include nucleic acids (phosphorylated ribose), phospholipids, phosphorylated sugars, and proteins that are phosphorylated on serine or threonine residues. The dephasing of the carbonyl peak by phosphorus is consistent with phospholipid and phosphorylated proteins (21,32). If the only phosphorus-containing molecules in the ECM were phospholipids, we would have observed dephasing of the 33-ppm peak corresponding to lipid aliphatics.…”

Section: Fig 5 Phosphorus Contributions To the Ecm (A)supporting

confidence: 54%

Analysis of the Aspergillus fumigatus Biofilm Extracellular Matrix by Solid-State Nuclear Magnetic Resonance Spectroscopy

et al. 2015

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dAspergillus fumigatus is commonly responsible for lethal fungal infections among immunosuppressed individuals. A. fumigatus forms biofilm communities that are of increasing biomedical interest due to the association of biofilms with chronic infections and their increased resistance to antifungal agents and host immune factors. Understanding the composition of microbial biofilms and the extracellular matrix is important to understanding function and, ultimately, to developing strategies to inhibit biofilm formation. We implemented a solid-state nuclear magnetic resonance (NMR) approach to define compositional parameters of the A. fumigatus extracellular matrix (ECM) when biofilms are formed in RPMI 1640 nutrient medium. Whole biofilm and isolated matrix networks were also characterized by electron microscopy, and matrix proteins were identified through protein gel analysis. The 13 C NMR results defined and quantified the carbon contributions in the insoluble ECM, including carbonyls, aromatic carbons, polysaccharide carbons (anomeric and nonanomerics), aliphatics, etc. Additional 15 N and 31 P NMR spectra permitted more specific annotation of the carbon pools according to C-N and C-P couplings. Together these data show that the A. fumigatus ECM produced under these growth conditions contains approximately 40% protein, 43% polysaccharide, 3% aromatic-containing components, and up to 14% lipid. These fundamental chemical parameters are needed to consider the relationships between composition and function in the A. fumigatus ECM and will enable future comparisons with other organisms and with A. fumigatus grown under alternate conditions. A spergillus fumigatus is the most important etiological agent of human aspergillosis and is recognized as a highly allergenic and opportunistic pathogen, causing acute and chronic infections particularly among immunocompromised individuals (1). Hospital-associated outbreaks of A. fumigatus may occur during periods of construction or renovation (2) or when fungi colonize water distribution systems that then lead to spore aerosolization in patient care areas and patient exposure (1). Additionally, A. fumigatus can cause infections as a result of colonizing medical implant devices, including cardiac pacemakers, joint replacements, and breast implants (3). Despite improvements in diagnostics and the antifungal armamentarium, including broad-spectrum azoles and the echinocandin antifungals, mortality due to A. fumigatus invasive infections remains high.Like many microorganisms, A. fumigatus can also assemble into multicellular communities, termed biofilms, composed of cells plus an extracellular matrix (ECM) (4-9). Although more work is needed to fully understand the functional implications of biofilm formation by A. fumigatus, recent evidence suggests that the ECM may provide the infrastructure for enhancing cell density, controlling disaggregation, and altering nutritional needs, as well as providing a protective physical and chemical barrier that can decrease sensitivity to competi...

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Section: Fig 5 Phosphorus Contributions To the Ecm (A)supporting

confidence: 54%

Analysis of the Aspergillus fumigatus Biofilm Extracellular Matrix by Solid-State Nuclear Magnetic Resonance Spectroscopy

et al. 2015

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“…Firstly, it communicates with the polar region and exerts a possible interaction with ascorbic acid, and secondly, it interacts with unsaturated parts of the lipids and prevents hyperoxidation. A similar membrane location and phenolic hydroxyl function has been also proposed to account for the antioxidant neuroprotective activity of 17b-estradiol based on rotationalecho double-resonance NMR studies of interaction of the hormone and analogs thereof with DPPC phospholipid multilamellar vesicles (Cegelski et al 2006). Estradiol is thought to intercalate into the neuronal plasma and mitochondrial membranes with its phenolic ring positioned near the site of lipid peroxidation, thus preventing oxidative stress-induced collapse of ion gradients and mitochondrial energy production failure, known to result in damage of the organelle and cell death (reviewed by Simpkins et al 2010).…”

Section: Resultsmentioning

confidence: 99%

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

et al. 2011

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In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the headgroup, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC).Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the headgroup. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phasetransition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discussed.

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“…Despite advances in technology (19,(36)(37)(38)(39)(40)(41)(42)(43)(44)(45), there is an enduring thirst for new methods on account of the strengths and limitations inherent in existing biophysical techniques. This work is aimed at extending such investigations by using for the first time to our knowledge a combination of separated local-field (SLF) NMR spectroscopy (41,(46)(47)(48) and statistical mean-torque theory (35).…”

Section: Introductionmentioning

confidence: 98%

Area per Lipid and Cholesterol Interactions in Membranes from Separated Local-Field 13 C NMR Spectroscopy

Leftin

Molugu

Job

et al. 2014

Biophysical Journal

107

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Investigations of lipid membranes using NMR spectroscopy generally require isotopic labeling, often precluding structural studies of complex lipid systems. Solid-state (13)C magic-angle spinning NMR spectroscopy at natural isotopic abundance gives site-specific structural information that can aid in the characterization of complex biomembranes. Using the separated local-field experiment DROSS, we resolved (13)C-(1)H residual dipolar couplings that were interpreted with a statistical mean-torque model. Liquid-disordered and liquid-ordered phases were characterized according to membrane thickness and average cross-sectional area per lipid. Knowledge of such structural parameters is vital for molecular dynamics simulations, and provides information about the balance of forces in membrane lipid bilayers. Experiments were conducted with both phosphatidylcholine (dimyristoylphosphatidylcholine (DMPC) and palmitoyloleoylphosphatidylcholine (POPC)) and egg-yolk sphingomyelin (EYSM) lipids, and allowed us to extract segmental order parameters from the (13)C-(1)H residual dipolar couplings. Order parameters were used to calculate membrane structural quantities, including the area per lipid and bilayer thickness. Relative to POPC, EYSM is more ordered in the ld phase and experiences less structural perturbation upon adding 50% cholesterol to form the lo phase. The loss of configurational entropy is smaller for EYSM than for POPC, thus favoring its interaction with cholesterol in raftlike lipid systems. Our studies show that solid-state (13)C NMR spectroscopy is applicable to investigations of complex lipids and makes it possible to obtain structural parameters for biomembrane systems where isotope labeling may be prohibitive.

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Mapping the locations of estradiol and potent neuroprotective analogues in phospholipid bilayers by REDOR

Abstract: Estrogens are potent antioxidants and neuroprotectants. They have become the focus of drug development efforts aimed at treating and preventing neuronal damage in stroke-related brain damage, Alzheimer's disease, and Parkinson's disease.

Cited by 27 publications

References 46 publications

Analysis of the Aspergillus fumigatus Biofilm Extracellular Matrix by Solid-State Nuclear Magnetic Resonance Spectroscopy

Analysis of the Aspergillus fumigatus Biofilm Extracellular Matrix by Solid-State Nuclear Magnetic Resonance Spectroscopy

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

Area per Lipid and Cholesterol Interactions in Membranes from Separated Local-Field 13 C NMR Spectroscopy

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