UMLS:C0344329 - FACTA Search

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The incorporation of cholesterol into unilamellar liposomes greatly increased the transmembranous movement of hydrophobic ionophores such as nigericin. In reconstituted liposomes containing rhodopsin as the only protein, the presence of cholesterol lowers by 10-fold or more the amount of negericin required to eliminate the light-driven proton gradient. These effects are seen both above and below the transition temperature of the phospholipid used for reconstitution. Cholesterol similarly increases the ability of A-23187, 1799, or NH4SCN to collapse the proton gradient of bacteriorhodopsin vesicles. Cholesterol also lowers the concentration of nigericin or valinomycin required for a rapid translocation of Rb+ into protein-free liposomes. It also lowers the concentration of A-23187 required for the release of Ca45 trapped in protein-free liposomes. In contrast to these observations and in confirmation of previous findings, we observed that cholesterol decreased the permeability of liposomes for glucose. Thus the effects of cholesterol on the permeability of the membrane vary with the chemical nature of the permeating compounds. We have also confirmed that in multilamellar liposomes cholesterol decreases the permeability of Rb+ in the presence of valinomycin. It therefore appears that the effect of cholesterol changes with the size and structural features of the model membranes.
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PMID:Cholesterol Stimulation of Penetration of Unilamellar Liposomes by Hydrophobic Compounds. 32 87

Cholesterol is a substantial component of pulmonary surfactant (approximately 8 wt % or approximately 14 mol % of surfactant lipids). This study investigated the effect of cholesterol on the way in which hydrophobic SP-B and SP-C modulated the adsorption of lipid into the air-water interface and their respreading from collapsed phase produced on overcompression of the surface film. The properties of binary spread monolayers of SP-B or SP-C plus cholesterol (CH) were consistent with miscibility between the hydrophobic proteins and the sterol. Results from surface pressure versus area measurements at 23 degrees C on spread monolayers of dipalmitoylphosphatidylcholine (DPPC) plus SP-B in the presence of 8 wt % cholesterol implied that CH did not significantly affect the properties of the films of SP-B/(DPPC/CH) compared to those of binary SP-B/DPPC monolayers. In contrast, CH appeared to enhance the mixing of SP-C with DPPC/CH in ternary SP-C/(DPPC/CH) films compared to the miscibility of SP-C with DPPC in the SP-C/DPPC films. It is estimated that about 10 wt % SP-C might remain in the SP-C/(DPPC/CH) monolayers compressed to high surface pressures of about 72 mN/m, whereas SP-C at concentrations of > or = 5 wt % was squeezed out at pi approximately 50 mN/m from SP-C/DPPC films without cholesterol. Cholesterol reduced the stability of the films of SP-B/(DPPC/CH) and SP-C/(DPPC/CH) when they had been compressed to pi approximately 72 mN/m, in contrast to films of SP-B/DPPC and SP-C/DPPC which exhibited a relatively slow relaxation from the collapse pressure of 72 mN/m. Dynamic cyclic compression beyond collapse of SP-B/(DPPC/CH) and SP-C/(DPPC/CH) monolayers showed that cholesterol diminished their postcollapse respreading compared to the respreading of the protein/DPPC films without cholesterol. Cholesterol, at 8 wt %, inhibited the rate of adsorption to the air-water interface at 35 degrees C of aqueous dispersions of DPPC containing 2.5 or 5 wt % SP-B or SP-C. The results suggest that cholesterol has an apparent negative influence on the surfactant surface properties, which are generally considered to be important in surfactant function, although increasing protein concentrations can counteract some of the negative influences.
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PMID:Cholesterol modifies the properties of surface films of dipalmitoylphosphatidylcholine plus pulmonary surfactant-associated protein B or C spread or adsorbed at the air-water interface. 902 Jul 91

To better characterize the heavy proteinuria occasionally described in cholesterol atheroembolic renal disease (CAE), we reviewed the clinical features and histological findings of 24 patients found at renal biopsy to have CAE. Twelve (50%) had a typical clinical presentation soon after an invasive vascular procedure. Eight (33%) underwent biopsies to evaluate proteinuria and four (17%) with insidiously developing renal failure to exclude rapidly progressive glomerulonephritis. All had usual and similar risk factors for CAE; 71% were male, 96% had peripheral vascular disease, 79% had recently undergone an invasive vascular procedure, 74% were hypercholesterolemic, and all were hypertensive. Proteinuria was higher and serum creatinine lower in the proteinuria group. In the nine (38%) nephrotic patients, serum creatinine measurements were lower (2.7 +/- 1.2 v 5.6 +/- 2.4 mg/dL), duration of renal disease to biopsy longer, and time from biopsy to dialysis greater (23.5 +/- 14.8 v 0.03 +/- 0.098 mo, P < 0.05 for all). Focal segmental glomerulosclerosis (FSGS) was observed in 15 (63%) of the biopsy specimens. Although FSGS itself did not occur more commonly in nephrotic patients, these patients did have a higher fraction of segmentally sclerosed glomeruli (0.158 +/- 0.097 v 0.026 +/- 0.050, P < 0.01). A variant of FSGS, the cellular lesion with epithelial cell prominence and capillary loop collapse, was observed in 7 of 9 (78%) patients with nephrotic-range proteinuria, but in only 3 of 12 (25%) patients with lesser degrees of protein excretion (P < 0.05). The cellular lesion was accompanied by higher mean proteinuria, 7.6 +/- 4.3 versus 2.1 +/- 2.4 g/24 hr (P < 0.01). In a larger group of patients with a similar age range as the CAE group who were identified by search of a computerized biopsy database, membranous nephropathy was the only other form of idiopathic glomerulonephritis that occurred with CAE. One of 82 (1.2%) patients with membranous nephropathy also had CAE, compared with 20 of 102 (19.6%) with FSGS (P < 0.0002, chi2). Thus, the finding of FSGS with CAE was not coincidence. Mean follow-up was 20 +/- 26 months (range, 0 to 103 months). Six patients (25%) were followed-up at least 3 years after renal biopsy. These findings indicate that extended survival in CAE is not rare and that heavy proteinuria occurs as part of a chronic disorder with distinctive histological features. Cholesterol atheroembolism with FSGS should be considered in the differential diagnosis of nephrotic syndrome in elderly patients with advanced atherosclerosis.
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PMID:Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: clinicopathological correlations. 904 Dec 8

Interaction of pulmonary surfactant protein A (SP-A) with pure and binary mixed dipalmitoylphosphatidylcholine (DPPC) and cholesterol (3.5 wt%) at the air/saline, 1.5 mM CaCl2 interface was investigated using a rhomboid surface balance at 37 degrees C. Surface tension-area isotherms were measured to access the surface active properties of the monolayers. The organization of DPPC and cholesterol in DPPC and DPPC/cholesterol mixed monolayers with or without SP-A at equilibrium surface tension (approximately 23 mN/N) was revealed by autoradiographs of Langmuir-Blodgett (L-B) films deposited from [14C]DPPC or [14C]cholesterol-labeled monolayers. The results showed that SP-A can interact with the polar head groups of DPPC monolayers and aggregate DPPC molecules. SP-A decreased the surface area reduction required for DPPC monolayers to achieve near zero surface tension from 30 to 25% of the area at equilibrium. SP-A also reduced the collapse surface tension of pure cholesterol from 27 to 23 mN/m. DPPC and cholesterol formed homogeneous mixed monolayers when both were dissolved in the spreading solvent prior to spreading, while separate cholesterol-rich domains appeared when DPPC and cholesterol were spread successively. Cholesterol resisted squeeze-out from either mixed monolayer through compression. Although SP-A could not promote the squeeze-out of cholesterol from homogeneous mixed monolayers, it facilitated that of cholesterol domains especially when SP-A had first interacted with DPPC. These results indicate that pulmonary surfactant protein A facilitates the squeeze-out of cholesterol domains from mixed monolayers by condensing DPPC and limiting lateral interactions of DPPC with cholesterol domains.
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PMID:Interaction of pulmonary surfactant protein A with dipalmitoylphosphatidylcholine and cholesterol at the air/water interface. 954 88

Surfactant occurs in cyclically inflating and deflating, gas-holding structures of vertebrates to reduce the surface tension of the inner fluid lining, thereby preventing collapse and decreasing the work of inflation. Here we determined the presence of surfactant in material lavaged from the airspace in the gas mantle of the pulmonate snail Helix aspersa. Surfactant is characterized by the presence of disaturated phospholipid (DSP), especially disaturated phosphatidylcholine (PC), lavaged from the airspace, by the presence of lamellated osmiophilic bodies (LBs) in the airspaces and epithelial tissue, and by the ability of the lavage to reduce surface tension of fluid in a surface balance. Lavage had a DSP/phospholipid (PL) ratio of 0.085, compared to 0.011 in membranes, with the major PL being PC (45.3%). Cholesterol, the primary fluidizer for pulmonary surfactant, was similar in lavage and in lipids extracted from cell homogenates (cholesterol/PL: 0.04 and 0. 03, respectively). LBs were found in the tissues and airspaces. The surface activity of the lavage material is defined as the ability to reduce surface tension under compression to values much lower than that of water. In addition, surface-active lipids will vary surface tension, increasing it upon inspiration as the surface area expands. By these criteria, the surface activity of lavaged material was poor and most similar to that shown by pulmonary lavage of fish and toads. Snail surfactant displays structures, a biochemical PL profile, and biophysical properties similar to surfactant obtained from primitive fish, teleost swim bladders, the lung of the Dipnoan Neoceratodus forsteri, and the amphibian Bufo marinus. However, the cholesterol/PL and cholesterol/DSP ratios are more similar to the amphibian B. marinus than to the fish, and this similarity may indicate a crucial physicochemical relationship for these lipids.
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PMID:Surfactant in the gas mantle of the snail Helix aspersa. 1060 32

This study reports the isolation and characterization of a Triton X-100-resistant membrane fraction from homogenates of rod outer segment (ROS) disk membranes purified free of the surrounding plasma membrane. A portion of the ROS disk membrane was found to be resistant to Triton X-100 extraction at 4 degrees C. This detergent-resistant fraction was isolated as a low buoyant density band on sucrose density gradients and exhibited an increase in light scattering detected at 600 nm. Biochemical analysis of the Triton X-100-resistant fraction showed it to be enriched in cholesterol and sphingomyelin relative to phospholipid and in phospholipid relative to protein compared with the soluble fraction. The Triton X-100-resistant membranes described herein did not arise simply from partial solubilization of the ROS disk membranes because detergent-treated low buoyant density fractions isolated from homogenates with octyl glucopyranoside had cholesterol and sphingomyelin content indistinguishable from that of solubilized ROS disk homogenates. Analysis of proteins associated with the Triton X-100-resistant fraction showed it to be enriched in the rim-specific protein ROM-1 and caveolin; surprisingly, the fusion protein peripherin/rds (where rds is retinal degeneration slow), also localized to the disk rim, was entirely absent from the membrane raft domain. The lipid profiles of the Triton X-100-resistant membranes were virtually identical in preparations homogenized in either the light or dark. Slightly more ROM-1 was recovered from samples prepared in the light (23%) than from samples prepared in the dark (13%), but peripherin/rds could not be detected in either preparation. When the Triton X-100-resistant membranes were treated with methyl-beta-cyclodextran to deplete membrane cholesterol, the resultant membranes contained slightly lower levels of ROM-1, specifically in the dimeric form. Cholesterol depletion also resulted in the collapse of the large caveolin complex to monomeric caveolae. The results presented herein characterize a pool of ROM-1, a photoreceptor tetraspanin protein, that may play a regulatory role in peripherin/rds-dependent fusion.
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PMID:Association of a photoreceptor-specific tetraspanin protein, ROM-1, with triton X-100-resistant membrane rafts from rod outer segment disk membranes. 1219 38

This report presents the scientific rationale and hypothesis for the investigator-initiated, double-blind, placebo-controlled Alzheimer's Disease Cholesterol-Lowering Treatment Trial. As part of the supporting preclinical data, accumulation of neuronal beta-amyloid immunoreactivity was investigated in 12-month-old male spontaneously hypercholesterolemic Watanabe rabbits, female Watanabe rabbits between 3 and >36 months of age, and untreated female New Zealand white rabbits between 6 and 12 months of age. Prior evidence suggests that there are significant accumulations of neuronal beta-amyloid immunoreactivity in the cholesterol-fed New Zealand white rabbit. At 3 months of age, abundant beta-amyloid immunoreactive neurons are also found in female hypercholesterolemic Watanabe rabbits. By 6 months of age, as female Watanabe rabbits are approaching sexual maturity, the number of beta-amyloid immunoreactive neurons was somewhat reduced, but the intensity of the immunoreactivity was clearly and consistently diminished. Very few neurons expressing beta-amyloid immunoreactivity were identifiable among the 12-month-old Watanabe female rabbits. Variably increased numbers of intensely stained beta-amyloid immunoreactive neurons were observed in retired breeder female animals over 3 years of age. Twelve-month-old male Watanabe rabbits exhibited levels of neuronal beta-amyloid immunoreactivity consistent with younger and older female animals, but greater than the adult 12-month-old females. Cholesterol levels in the blood were not noticeably different among females over the age range investigated or compared to 12-month-old males. Estrogen levels varied with age in female Watanabe rabbits in an apparent inverse relationship with neuronal beta-amyloid immunoreactivity. However, there was no evidence of increased neuronal beta-amyloid immunoreactivity in untreated female New Zealand white rabbits with "normal" circulating cholesterol levels at any age investigated. Therefore, under conditions of stable, but elevated, circulating cholesterol levels, pathologic accumulation of neuronal beta-amyloid immunoreactivity was similar in male Watanabe rabbits and female animals prior and subsequent to estrus. The intensity of observable neuronal beta-amyloid immunoreactivity accumulation decreases in female animals as circulating estrogen levels increased with sexual maturity. These data suggest that a loss of circulating estrogen could mark the collapse of a system previously protecting a female from conditions conducive to production of beta-amyloid as a putative neurotoxin in AD. This may, in part, explain the epidemiological evidence for "protective" effects of estrogen in AD.
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PMID:Cholesterol and cognition: rationale for the AD cholesterol-lowering treatment trial and sex-related Differences in beta-amyloid accumulation in the brains of spontaneously hypercholesterolemic Watanabe rabbits. 1248 Jul 73

The chemokine receptor, CCR5, acts as a co-receptor for human immunodeficiency virus entry into cells. CCR5 has been shown to be targeted to cholesterol- and sphingolipid-rich membrane microdomains termed lipid rafts or caveolae. Cholesterol is essential for CCL4 binding to CCR5 and for keeping the conformational integrity of the receptor. Filipin treatment leads to loss of caveolin-1 from the membrane and therefore to a collapse of the caveolae. We have found here that sequestration of membrane cholesterol with filipin did not affect receptor signalling, however a loss of ligand-induced internalisation of CCR5 was observed. Cholesterol extraction with methyl-beta-cyclodextrin (MCD) reduced signalling through CCR5 as measured by release of intracellular Ca(2+) and completely abolished the inhibition of forskolin-stimulated cAMP accumulation with no effect on internalisation. Pertussis toxin (PTX) treatment inhibited the intracellular release of calcium that is transduced via Galphai G-proteins. Depletion of cholesterol destroyed microdomains in the membrane and switched CCR5/G-protein coupling to a PTX-independent G-protein. We conclude that cholesterol in the membrane is essential for CCR5 signalling via the Galphai G-protein subunit, and that integrity of lipid rafts is not essential for effective CCR5 internalisation however it is crucial for proper CCR5 signal transduction via Galphai G-proteins.
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PMID:CCR5 internalisation and signalling have different dependence on membrane lipid raft integrity. 1857 34

The feasibility of a method based on mass preservation [G. Schwarz, J. Zhang, Chem. Phys. Lipids, 110 (2001) 35-45] to determine the solubility of Cholesterol in water from monomolecular films on air/water interface was investigated. Using a mass balance equation, it was found that Cholesterol undergoes an exponential desorption at very low surface pressures followed by an almost linear desorption into the subphase at higher surface pressures until monolayer collapse. Processing of the surface pressure measurements as a function of trough area in accord with the theory, enabled the accurate determination of the molecular dimensions of Cholesterol as a function of surface pressure. Slight modification of the theory enabled accurate quantification of the surface pressure-independent apparent solubility of Cholesterol and the amount of Cholesterol desorbed into the subphase as a function of surface pressure, in the nanomolar range.
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PMID:The Conventional Langmuir Trough Technique as a Convenient Means to Determine the Solubility of Sparingly Soluble Surface Active Molecules: Case Study Cholesterol. 1960 37

Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC) disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) and murine double minute (Mdm2) E3 ligase. Growth cone collapse induced by genetic (npc1-/-) or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK)-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1-/- mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism.
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PMID:Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation. 2038 95

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