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Query: UNIPROT:P06889 (Mol)
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The endothelial glycocalyx is believed to play a major role in capillary permeability by functioning as a macromolecular barrier overlying the intercellular junction. Little is known about the functional attributes of the glycocalyx (i.e., porosity and permeability) or which constituents contribute to its overall structure-function relationship. In this report, we demonstrate the utility of fluorescence correlation spectroscopy (FCS) to measure albumin diffusion rates and concentration profiles above the cell surface and overlying the intercellular junctions of lung capillary endothelial cells. Albumin diffusion rates and concentration profiles were obtained before and after enzymatic digestion of the glycocalyx with pronase, heparanase, or hyaluronidase. The results suggest a structure interacting with albumin located from 1.0 to 2.0 microm above the cell membrane capable of reducing albumin diffusion by 30% while simultaneously increasing albumin concentration fivefold. Digestion of the glycocalyx with pronase or heparanase resulted in only modest changes in albumin diffusion and concentration profiles. Hyaluronidase digestion completely eliminated albumin-glycocalyx interactions. These data also suggest that hyaluronan is a major determinant for albumin interactions with the lung endothelial glycocalyx. Confocal images of heparan sulfate and hyaluronan confirm a cell-surface layer 2-3 mum in thickness, thus supporting FCS measurements. In summary, we report the first use of FCS to probe extracellular structures and further our understanding of the structure-function relationship of the lung microvascular endothelial glycocalyx.
Am J Physiol Lung Cell Mol Physiol 2007 Aug
PMID:Fluorescence correlation spectroscopy can probe albumin dynamics inside lung endothelial glycocalyx. 1748 94

Hematology and clinical blood chemistry (HCBC) profiles in free-living bottlenose dolphins from Sarasota Bay, Florida have been monitored over a 14-year period. This long-term dataset includes samples from recaptured dolphins, enabling individual variation to be accounted for when investigating seasonal and annual variability. Four different laboratories carried out the assays and inter-laboratory comparisons found significant differences in 31 of 39 parameters measured. However, variability in comparable HCBCs by sex, age, condition, season and year could be investigated. Significant relationships with the independent variables were found for the majority of the HCBCs. Notable consistent seasonal differences included significantly elevated glucose and significantly lower creatinine concentrations in winter compared to summer. These differences may be due to energetic or thermoregulatory fluctuations in the animals by season and do not necessarily have any clinical significance. Erythrocyte counts were significantly lower in the winter, possibly also due to nutritional differences. Albumin and calcium levels in this population have increased significantly over the years of monitoring and consistently across seasons, being higher in the winter than the summer. Again, nutritional and thermal constraints seem to be the most likely environmental factors influencing these patterns.
Comp Biochem Physiol A Mol Integr Physiol 2007 Oct
PMID:Annual, seasonal and individual variation in hematology and clinical blood chemistry profiles in bottlenose dolphins (Tursiops truncatus) from Sarasota Bay, Florida. 1752 92

Interaction of charge transfer fluorophore N,N-dimethylaminonaphthyl-(acrylo)-nitrile (DMANAN) with globular proteins Human Serum Albumin (HSA) and Bovine Serum Albumin (BSA) brings forth a marked change in the position and intensity of band maxima both in case of absorption and fluorescence spectra. Spectroscopic approach has been elaborately implemented to explore the binding phenomena of the probe with HSA and BSA and it is found that the extent of binding of the probe to both serum albumins is similar in nature. Steady state fluorescence anisotropy values, fluorescence quenching study using acrylamide quencher and Red Edge Excitation Shift (REES) help in drawing reliable conclusions regarding the location of the probe molecule within the hydrophobic cavity of the proteins. An increase in fluorescence lifetime of the probe molecule solubilized in both the proteinous media also indicate that the probe is located at the motionally restricted environment inside the hydrophobic cavity of proteins and hence non-radiative channels are less operative than in the bulk water. Similarly, the variation of position and intensity of the emission maxima of DMANAN solubilized in micellar medium of Sodium Dodecyl Sulphate (SDS) also predicts well the critical micellar concentration (CMC) and polarity of micellar microenvironment.
Spectrochim Acta A Mol Biomol Spectrosc 2009 Jun
PMID:Study of proteinous and micellar microenvironment using donor acceptor charge transfer fluorosensor N,N-dimethylaminonaphthyl-(acrylo)-nitrile. 1923 Jul 49

The study was performed to investigate the effect of combination therapy with aminoguanidine (AG) and dexamethasone (DEX) on the compression spinal cord injury (SCI) in rat. Compared to the control group, the combination therapy group with AG (75 mg/kg) and DEX (0.025 mg/kg) significantly reduced the degree of (1) spinal cord edema, (2) the permeability of blood spinal cord barrier (measured by (99m)Tc-Albumin), (3) infiltration of neutrophils (MPO evaluation), (4) cytokines expression (tumor necrosis factor-alpha and interleukin-1 beta), and (5) apoptosis (measured by Bax and Bcl-2 expression). In addition, we have also clearly demonstrated that the combination therapy significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly indicated for the first time that strategies targeting multiple proinflammatory pathways may be more effective than a single effector molecule for the treatment of SCI.
Cell Mol Neurobiol 2009 Jul
PMID:Combination of dexamethasone and aminoguanidine reduces secondary damage in compression spinal cord injury. 1937 50

Inflammation in patients defined as frail by Fried's phenotypic definition may be related to sarcopenia. This study aimed to investigate inflammation in older patients across different frailty criteria. Frailty status was determined in 110 patients aged over 75 years (mean 83.9 years) according to function (dependent, intermediate, independent); Fried (three or more items of exhaustion, weight loss, slow walking speed, low handgrip strength, low physical activity) and Frailty Index (a measure of accumulated deficits). With increasing patient frailty as defined by function and by Fried phenotype, tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and C-reactive protein (CRP) increased significantly. Albumin was lowest in the frailest subjects by each definition. The greatest differences were seen between intermediate and dependent groups and between the pre-frail and frail. Adjustment for multiple covariates (age, sex, BMI category, smoking status, number of co-morbidities and number of prescribed medications) did not account for any of the observed differences in levels of inflammatory markers. The Frailty Index correlated significantly with log-transformed CRP (r= 0.221, P < 0.05), log-transformed IL-6 (r= 0.369, P < 0.01), TNF-alpha (r= 0.379, P < 0.01) and inversely with albumin (r=- 0.545, P < 0.01). This study provides further evidence linking inflammation and frailty in older people, an association that seems consistent across different frailty measures.
J Cell Mol Med 2009 Sep
PMID:Inflammation and frailty measures in older people. 1943 6

Human serum albumin (HSA) inhibits endothelial apoptosis in a highly specific manner. CNBr fragmentation greatly increases the effectiveness of this activity, suggesting that this type of protection is mediated by a partially cryptic albumin domain which is transiently exposed by intramolecular movement. Advanced glycation end-product (AGE) formation in HSA greatly reduces its intra-molecular movement. This study aimed to determine if this inhibits the anti-apoptotic activity of HSA, and if such inactivation could be reversed by CNBr fragmentation. HSA-AGE was prepared by incubating HSA with glucose, and assessed using the fructosamine assay, mass spectrometry, SDS-PAGE and fluorometry. Low levels of AGE in the HSA had little effect upon its anti-apoptotic activity, but when the levels of AGE were high and the intra-molecular movement was reduced, endothelial cell survival was also found to be reduced to levels equivalent to those in cultures without HSA or serum (p > 0.001). Survival was restored by the inclusion of native HSA, despite the presence of HSA with high levels of AGE. Also, CNBr fragmentation of otherwise inactive HSA-AGE restored the anti-apoptotic activity for endothelium. Apoptosis was confirmed by DNA gel electrophoresis, transmission electron microscopy and fluorescence-activated cell sorting analysis, and there was no evidence for direct toxicity in the HSA-AGE preparations. The results are consistent with the proposed role of intra-molecular movement in exposing the anti-apoptotic domain in HSA for endothelium. The levels of AGE formation required to inhibit the anti-apoptotic activity of HSA exceeded those reported for diabetes. Nonetheless, the data from this study seems to be the first example of reduced protein function due to AGE-restricted intra-molecular movement.
Cell Mol Biol Lett 2009
PMID:The anti-apoptotic activity of albumin for endothelium is inhibited by advanced glycation end products restricting intramolecular movement. 1948 97

Preeclampsia (PE) is characterized by widespread endothelial damage with hypertension, proteinuria, glomeruloendotheliosis and elevated soluble Flt-1 (sFlt-1), a natural occurring antagonist of vascular endothelial growth factor (VEGF). Cancer patients receiving anti-VEGF therapy exhibit similar symptoms. We suggested that a decrease in circulating sFlt-1 would alleviate the symptoms associated with PE. Adenoviral (Adv) overexpression of sFlt-1 induced proteinuria, caused glomerular damage and increase in blood pressure in female Balb/c mice. Circulating level of sFlt-1 above 50 ng/ml plasma induced severe vascular damage and glomerular endotheliosis. Albumin concentration in urine was elevated up to 30-fold, compared to control AdvGFP-treated animals. The threshold of kidney damage was in the range of 20-30 ng/ml sFlt-1 in plasma (8-15 ng/ml in urine). Co-administration of AdvsFlt-1 with AdvVEGF to neutralize circulating sFlt-1 resulted in more than a 70% reduction in free sFlt-1 in plasma, more than 80% reduction in urine and rescued the damaging effect of sFlt-1 on the kidneys. This demonstrates that below a critical threshold sFlt-1 fails to elicit damage to the fenestrated endothelium and that co-expression of VEGF is able to rescue effects mediated by sFlt-1 overexpression.
J Cell Mol Med 2010 Jun
PMID:Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. 1953 65

Neutrophil recruitment to the alveolar space is associated with increased epithelial permeability. The present study investigated in mice whether neutrophil recruitment to the lung leads to accumulation of plasma-derived host defense proteins in the alveolar space and whether respiratory burst contributes to this increase in permeability. Albumin, complement C1q, and IgM were increased in bronchoalveolar lavage (BAL) fluid 6 h after intratracheal LPS challenge. Neutrophil depletion before LPS treatment completely prevented this increase in BAL fluid protein concentration. Respiratory burst was not detected in neutrophils isolated from BAL fluid, and BAL proteins were increased in mice deficient in a key subunit of the respiratory burst apparatus, gp91(phox), similar to wild-type mice. Neutrophil recruitment elicited by intratracheal instillation of the chemokines macrophage inflammatory protein-2 and keratinocyte-derived chemokine was also accompanied by accumulation of albumin, C1q, and IgM. During neutrophil recruitment to the alveolar space, epithelial permeability facilitates delivery of host defense proteins. The observed increase in epithelial permeability requires recruitment of neutrophils, but not activation of the respiratory burst, and occurs with chemokine-induced neutrophil migration independent of LPS exposure.
Am J Physiol Lung Cell Mol Physiol 2009 Oct
PMID:Neutrophil-mediated lung permeability and host defense proteins. 1964 88

Human serum albumin (HSA)-coated liposomal formulations were synthesized and evaluated for the delivery of antisense oligodeoxyribonucleotide (ODN) G3139 in KB human oral carcinoma cells. Liposomes composed of dimethyldioctadecyl ammonium bromide/egg phosphatidylcholine/alpha-tocopheryl polyethylene glycol 1000 succinate (58:40:2 molar ratio) complexed with G3139 and coated with HSA were investigated for Bcl-2 downregulating activity. Cellular uptake of HSA-coated liposome-ODN complexes was more efficient than the uncoated liposome-ODN complexes. Treatment of the cells with HSA-coated liposome-ODN complexes resulted in efficient Bcl-2 mRNA downregulation that was approximately 3-fold greater than with uncoated liposomes (p < 0.05) and 6-fold greater than with free ODN. The transfection efficiency of liposome-ODN complexes coated with HSA was dependent on the concentration of HSA used and on the contents of alpha-helix and beta-strand in HSA. HSA-coated liposomes are effective delivery vehicles for antisense ODN.
Mol Pharm
PMID:Efficient delivery of antisense oligodeoxyribonucleotide g3139 by human serum albumin-coated liposomes. 1972 64

Human serum albumin (HSA), the most abundant protein found in blood plasma, transports many drugs and ligands in the circulatory system. The drug binding ability of HSA strongly influences free drug concentrations in plasma, and is directly related to the effectiveness of clinical therapy. In current work, binding of HSA to angiotensin II receptor blockers (ARBs) are investigated using docking and molecular dynamics (MD) simulations. Docking results demonstrate that the main HSA-ARB binding site is subdomain IIIA of HSA. Simulation results reveal clearly how HSA binds with valsartan and telmisartan. Interestingly, electrostatic interactions appear to be more important than hydrophobic interactions in stabilizing binding of valsartan to HSA, and vice versa for HSA-telmisartan. The molecular distance between HSA Trp214 (donor) and the drug (acceptor) can be measured by fluorescence resonance energy transfer (FRET) in experimental studies. The average distances between Trp-214 and ARBs are estimated here based on our MD simulations, which could be valuable to future FRET studies. This work will be useful in the design of new ARB drugs with desired HSA binding affinity.
J Mol Model 2010 Apr
PMID:Characterization of the binding of angiotensin II receptor blockers to human serum albumin using docking and molecular dynamics simulation. 1990 72


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