- Methionine sulfoxides in serum proteins as potential clinical biomarkers of oxidative stress. [Journal Article]
- SRSci Rep 2016 Dec 08; 6:38299
- Oxidative stress contributes to the pathophysiology of a variety of diseases, and circulating biomarkers of its severity remains a topic of great interest for researchers. Our peptidomic strategy ena...
Oxidative stress contributes to the pathophysiology of a variety of diseases, and circulating biomarkers of its severity remains a topic of great interest for researchers. Our peptidomic strategy enables accurate and reproducible analysis of circulating proteins/peptides with or without post-translational modifications. Conventional wisdom holds that hydrophobic methionines exposed to an aqueous environment or experimental handling procedures are vulnerable to oxidation. However, we show that the mass spectra intensity ratio of oxidized to non-oxidized methionine residues in serum tryptic proteins can be accurately quantified using a single drop of human serum and give stable and reproducible results. Our data demonstrate that two methionine residues in serum albumin (Met-111 and Met-147) are highly oxidized to methionine sulfoxide in patients with diabetes and renal failure and in healthy smokers versus non-smoker controls. This label-free mass spectrometry approach to quantify redox changes in methionine residues should facilitate the identification of additional circulating biomarkers suitable for predicting the development or progression of human diseases.
- Renin-Angiotensin System Transgenic Mouse Model Recapitulates Pathophysiology Similar to Human Preeclampsia with Renal Injury that may be Mediated through VEGF. [Journal Article]
- AJAm J Physiol Renal Physiol 2016 Dec 07; :ajprenal.00108.2016
- Using a transgenic cross, we evaluated features of preeclampsia, renal injury and the sFlt1/VEGF changes. Transgenic hAGT and hREN, or wild type (WT) C57Bl/6 mice were cross-bred: ♀hAGT x ♂hREN for p...
Using a transgenic cross, we evaluated features of preeclampsia, renal injury and the sFlt1/VEGF changes. Transgenic hAGT and hREN, or wild type (WT) C57Bl/6 mice were cross-bred: ♀hAGT x ♂hREN for preeclampsia (PRE) model and ♀WT x ♂WT for pregnant controls (WTP). Samples were collected for plasma VEGF, sFlt1 and urine albumin. Blood pressures (BP) were monitored by telemetry. Vascular reactivity was investigated by wire myography. Kidneys and placenta were immunostained for sFlt1 and VEGF. Eleven PRE and 9 WTP mice were compared. PRE more frequently demonstrated albuminuria, glomerular endotheliosis (80% vs. 11%; p=0.02), and placental necrosis (60% vs. 0%; p<0.01). PRE group demonstrated declining BPs with advancing gestation. Plasma sFlt1 increased across pregnancy in PRE, VEGF did not vary. IHC demonstrated the presence of sFlt1 in glomeruli, lymphatics and collecting tubules of PRE kidneys suggesting excretion. VEGF immunostaining was increased specifically in the glomeruli of PRE kidneys. Placenta in PRE showed marked immunostaining for sFlt1. We conclude that this transgenic model of preeclampsia recapitulates human preeclamptic state with high fidelity, and that, vascular adaptation to pregnancy is suggested by declining BPs and reduced vascular response to PE and increased response to Ach. Placental damage with resultant increased release of sFlt1, proteinuria, deficient spiral artery remodeling and glomerular endotheliosis were observed in this model of PRE. Increased VEGF binding to glomerular endothelial cells in this model of PRE is similar to human PRE and leads us to hypothesize that renal injury in preeclampsia may be mediated through local VEGF.
- From the Journals. [Journal Article]
- JWJ Wound Care 1995 Apr 02; 4(4):158-160
- Standardised assessment and evaluation of wounds Nutritional support in wound healing Pressure sores, a review of the literature Gene therapy in skin grafts Surgical techniques in pilonidal disease P...
Standardised assessment and evaluation of wounds Nutritional support in wound healing Pressure sores, a review of the literature Gene therapy in skin grafts Surgical techniques in pilonidal disease Prognostic usefulness of serum albumin for pressure ulcer healing.
- Allosteric effects of gold nanoparticles on human serum albumin. [Journal Article]
- NNanoscale 2016 Dec 07
- The ability of nanoparticles to alter protein structure and dynamics plays an important role in their medical and biological applications. We investigate allosteric effects of gold nanoparticles on h...
The ability of nanoparticles to alter protein structure and dynamics plays an important role in their medical and biological applications. We investigate allosteric effects of gold nanoparticles on human serum albumin protein using molecular simulations. The extent to which bound nanoparticles influence the structure and dynamics of residues distant from the binding site is analyzed. The root mean square deviation, root mean square fluctuation and variation in the secondary structure of individual residues on a human serum albumin protein are calculated for four protein-gold nanoparticle binding complexes. The complexes are identified in a brute-force search process using an implicit-solvent coarse-grained model for proteins and nanoparticles. They are then converted to atomic resolution and their structural and dynamic properties are investigated using explicit-solvent atomistic molecular dynamics simulations. The results show that even though the albumin protein remains in a folded structure, the presence of a gold nanoparticle can cause more than 50% of the residues to decrease their flexibility significantly, and approximately 10% of the residues to change their secondary structure. These affected residues are distributed on the whole protein, even on regions that are distant from the nanoparticle. We analyze the changes in structure and flexibility of amino acid residues on a variety of binding sites on albumin and confirm that nanoparticles could allosterically affect the ability of albumin to bind fatty acids, thyroxin and metals. Our simulations suggest that allosteric effects must be considered when designing and deploying nanoparticles in medical and biological applications that depend on protein-nanoparticle interactions.
- The Chemical Basis of Thiol Addition to Nitro-Conjugated Linoleic Acid, a Protective Cell-Signaling Lipid. [Journal Article]
- JBJ Biol Chem 2016 Dec 06
- Nitroalkene fatty acids are formed in vivo and exert protective and anti-inflammatory effects via reversible Michael addition to thiol-containing proteins in key signaling pathways. Nitro-conjugated ...
Nitroalkene fatty acids are formed in vivo and exert protective and anti-inflammatory effects via reversible Michael addition to thiol-containing proteins in key signaling pathways. Nitro-conjugated linoleic acid (NO2-CLA) is preferentially formed, constitutes the most abundant nitrated fatty acid in humans and contains two carbons that could potentially react with thiols, modulating signaling actions and levels. In this work, we examined the reactions of NO2-CLA with low molecular weight thiols (glutathione, cysteine, homocysteine, cysteinylglycine and β mercaptoethanol) and human serum albumin (HSA). Reactions followed reversible biphasic kinetics, consistent with the presence of two electrophilic centers in NO2-CLA located on the β- and δ-carbons with respect to the nitro group. The differential reactivity was confirmed by computational modeling of the electronic structure. The rates (kon and koff) and equilibrium constants for both reactions were determined for different thiols. LC-UV-Vis and LC MS analyses showed that the fast reaction corresponds to β-adduct formation (the kinetic product) while the slow reaction corresponds to the δ-adduct (the thermodynamic product). The pH dependencies of the rate constants, the correlations between intrinsic reactivity and thiol pKa and the absence of deuterium solvent kinetic isotope effects suggested stepwise mechanisms with thiolate attack on NO2-CLA as rate-controlling steps. Computational modeling supported the mechanism and revealed additional features of the transition states, anionic intermediates and final neutral products. Importantly, the detection of cysteine-δ-adducts in human urine provided evidence for the biological relevance of this reaction. Finally, HSA was found to bind NO2-CLA non-covalently and to form covalent adducts at Cys34, suggesting potential modes for systemic distribution. These results provide new insights into the chemical basis of NO2-CLA signaling actions.
- The importance of albumin infusion rate for plasma volume expansion following major abdominal surgery - AIR: study protocol for a randomised controlled trial. [Journal Article]
- TTrials 2016 Dec 07; 17(1):578
- CONCLUSIONS: The present study is the first clinical investigation of the importance of infusion rate for the plasma volume-expanding effect of a resuscitation fluid.
- Monolayers of immunoglobulin G on polystyrene microparticles and their interactions with human serum albumin. [Journal Article]
- JCJ Colloid Interface Sci 2016 Nov 27; 490:587-597
- The adsorption of mouse monoclonal immunoglobulin G (IgG) on negatively charged polystyrene microparticles was studied by the laser Doppler velocimetry (LDV) electrophoretic mobility measurements. Th...
The adsorption of mouse monoclonal immunoglobulin G (IgG) on negatively charged polystyrene microparticles was studied by the laser Doppler velocimetry (LDV) electrophoretic mobility measurements. The dependence of the electrophoretic mobility of microparticles on the IgG concentration in the suspension was determined for different ionic strengths and pHs (3.5, 7.4). The increase in the electrophoretic mobility was quantitatively interpreted in terms of the 3D electrokinetic model. The maximum coverage of IgG on latex was determined by the depletion method aided by AFM imaging. It was shown by monitoring the electrophoretic mobility and hydrodynamic dimeter of IgG covered microparticles over prolonged time periods that IgG adsorption was irreversible. The acid-base properties of the IgG monolayers were also determined in pH cycling experiments. It was also confirmed that the adsorption of human serum albumin (HSA) on saturated IgG monolayers, often referred to as blocking, was negligible at pH 7.4.
- A meta-analysis of the association of serum ischemia-modified albumin levels with human hypothyroidism and hyperthyroidism. [Journal Article]
- BRBiosci Rep 2016 Dec 05
- CONCLUSIONS: This meta-analysis showing increased IMA level in both HT and HYT patients and its association with thyroid profile suggests that serum IMA could be used as a simple measure of increased OXS in thyroid dysfunction.
- Phase I Study of Triweekly Nab-Paclitaxel Combined with S-1 in Patients with HER2-negative Metastatic Breast Cancer. [Journal Article]
- ARAnticancer Res 2016; 36(12):6515-6519
- CONCLUSIONS: The response rate was 66.7%. The clinical benefit rate was 77.8%. Our study shows the efficacy and the feasibility of this combination therapy.
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- Attenuation of amyloid fibrillation in presence of Warfarin: A biophysical investigation. [Journal Article]
- IJInt J Biol Macromol 2016 Dec 02
- Protein misfolding and aggregation are associated with more than twenty diseases, such as neurodegenerative diseases. The amyloid oligomers and fibrils may induce cell membrane disruption and lead to...
Protein misfolding and aggregation are associated with more than twenty diseases, such as neurodegenerative diseases. The amyloid oligomers and fibrils may induce cell membrane disruption and lead to cell apoptosis. A great number of studies have focused on discovery of amyloid inhibitors which may prevent or treat amyloidosis. In this study, we used human serum albumin (HSA) as an amyloid model to test the anti-amyloid effects of warfarin (WFN), a very well-known drug for treatment of thrombosis and also used by biophysicists to characterize the specific binding site on HSA (site I of subdomain IIA). We have used a combination of different biophysical, spectroscopic and imaging techniques to prove the anti-amyloidogenic behavior of WFN. Our results demonstrated that WFN is capable enough to inhibit the HSA fibrillation. Exposed HSA surface hydrophobicity was decreased by 50% as judged by ANS analysis. Moreover, anti-amyloidegenic behavior of WFN was found to be concentration dependent as supported by decreased ThT fluorescence by 22.4% and 46% at WFN concentrations of 500 and 1000μM, respectively. Circular dichroism technique showed the change in secondary structure of native HSA as well as in presence of WFN. These results suggests that WFN is capable of inhibiting amyloid aggregation, hence, WFN related compounds may thus be further explored for designing effective anti-amyloidosis compounds.