Circulatory zinc transport is controlled by distinct interdomain sites on mammalian albumins
Abstract not provided
Handing, Katarzyna B.↗
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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.
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Organism-specific differences in the binding of ketoprofen to serum albumin
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Czub, Mateusz P.↗
Serum tryptophan level after carbohydrate ingestion - Selective decline in non-albumin-bound tryptophan coincident with reduction in serum free fatty acids.
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Lipsett, D.↗
Serum tryptophan level after carbohydrate ingestion - Selective decline in non-albumin-bound tryptophan coincident with reduction in serum free fatty acids.
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Lipsett, D.↗
Exercise training-induced hypervolemia - Role of plasma albumin, renin, and vasopressin
The purpose of the present study was twofold: (1) to determine the rate of induction and decay of exercise-training hypervolemia with a short-duration high-intensity training regimen; and (2) to assess the protein, osmotic, and endocrine responses that contribute to that mechanism. The test subjects were eight volunteer, healthy, trained college men (20-22 yr) engaged in isotonic exercise on a bicycle ergometer. Factors associated with plasma hypervolemia during training are identified. The results suggest that an efficient procedure for increasing plasma volume is the daily performance of high-intensity isotonic leg exercise for 2 h/day.
Convertino, V. A.↗
Albumin, oral contraceptives, and venous thromboembolism risk in astronauts
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Sara R. Zwart↗
Site specific modification of the human plasma proteome by methylglyoxal
Increasing evidence identifies dicarbonyl stress from reactive glucose metabolites, such as methylglyoxal (MG), as a major pathogenic link between hyperglycemia and complications of diabetes. MG covalently modifies arginine residues, yet the site specificity of this modification has not been thoroughly investigated. Sites of MG adduction in the plasma proteome were identified using LC–MS/MS analysis in vitro following incubation of plasma proteins with MG. Treatment of plasma proteins with MG yielded 14 putative MG hotspots from five plasma proteins (albumin [nine hotspots], serotransferrin, haptoglobin [2 hotspots], hemopexin, and Ig lambda-2 chain C regions). The search results revealed two versions of MG-arginine modification, dihydroxyimidazolidine (R + 72) and hydroimidazolone (R + 54) adducts. One of the sites identified was R257 in human serum albumin, which is a critical residue located in drug binding site I. This site was validated as a target for MG modification by a fluorescent probe displacement assay, which revealed significant drug dissociation at 300 μM MG from a prodan–HSA complex (75 μM). Moreover, twelve human plasma samples (six male, six female, with two type 2 diabetic subjects from both genders) were analyzed using multiple reaction monitoring (MRM) tandem mass spectrometry and revealed the presence of the MG-modified albumin R257 peptide. These data provide insights into the nature of the site-specificity of MG modification of arginine, which may be useful for therapeutic treatments that aim to prevent MG-mediated adverse responses in patients. - Highlights: • Methylglyoxal (MG) selectively modifies arginine sites in human plasma proteome. • Dihydroxyimidazolidine and hydroimidazolone adducts on serum albumin identified • MG modification on albumin R257 associated with loss of drug site I binding capacity • MRM-tandem mass spectrometry enables sensitive detection of albumin MG-R257. • Site-specific MG modification may represent a useful monitor of effective therapy of T2DM.
60 APPLIED LIFE SCIENCES↗
Protein Innovations Advance Drug Treatments, Skin Care
Dan Carter carefully layered the sheets of tracing paper on the light box. On each sheet were renderings of the atomic components of an essential human protein, one whose structure had long been a mystery. With each layer Carter laid down, a never-before-seen image became clearer. Carter joined NASA s Marshall Space Flight Center in 1985 and began exploring processes of protein crystal growth in space. By bouncing intense X-rays off the crystals, researchers can determine the electron densities around the thousands of atoms forming the protein molecules, unveiling their atomic structures. Cultivating crystals of sufficient quality on Earth was problematic; the microgravity conditions of space were far more accommodating. At the time, only a few hundred protein structures had been mapped, and the methods were time consuming and tedious. Carter hoped his work would help reveal the structure of human serum albumin, a major protein in the human circulatory system responsible for ferrying numerous small molecules in the blood. More was at stake than scientific curiosity. Albumin has a high affinity for most of the world s pharmaceuticals, Carter explains, and its interaction with drugs can change their safety and efficacy. When a medication enters the bloodstream a cancer chemotherapy drug, for example a majority of it can bind with albumin, leaving only a small percentage active for treatment. How a drug interacts with albumin can influence considerations like the necessary effective dosage, playing a significant role in the design and application of therapeutic measures. In spite of numerous difficulties, including having no access to microgravity following the 1986 Space Shuttle Challenger disaster, the image Carter had hoped to see was finally clarifying. In 1988, his lab had acquired specialized X-ray and detection equipment a tipping point. Carter and his colleagues began to piece together albumin s portrait, the formation of its electron densities coalescing on the sheets of tracing paper he arranged on the light box. While space-grown crystals were ultimately not involved in the achievement, a year later, Carter says, we were on the cover of Science magazine, having determined the atomic structure of albumin.
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Atrial natriuretic factor increases vascular permeability
An increase in central blood volume in microgravity may result in increased plasma levels of atrial natriuretic factor (ANF). In this study, it was determined whether ANF increases capillary permeability to plasma protein. Conscious, bilaterally nephrectomized male rats were infused with either saline, ANF + saline, or hexamethonium + saline over 2 h following bolus injections of (I-125)-albumin and (C-14)-dextran of similar molecular size. Blood pressure was monitored, and serial determinations of hematocrits were made. Animals infused with 1.0 microg/kg per min ANF had significantly higher hematocrits than animals infused with saline vehicle. Infusion of ANF increased the extravasation of (I-125)-albumin, but not (C-14)-dextran from the intravascular compartment. ANF also induced a depressor response in rats, but the change in blood pressure did not account for changes in capillary permeability to albumin; similar depressor responses induced by hexamethonium were not accompanied by increased extravasation of albumin from the intravascular compartment. ANF may decrease plasma volume by increasing permeability to albumin, and this effect of ANF may account for some of the signs and symptoms of space motion sickness.
Lockette, Warren↗
Characterization of Plasma Protein Alterations in Pregnant and Postpartum Individuals Living With HIV to Support Physiologically-Based Pharmacokinetic Model Development
Alterations in plasma protein concentrations in pregnant and postpartum individuals can influence antiretroviral (ARV) pharmacokinetics. Physiologically-based pharmacokinetic (PBPK) models can serve to inform drug dosing decisions in understudied populations. However, development of such models requires quantitative physiological information (e.g., changes in plasma protein concentration) from the population of interest. Objective: To quantitatively describe the time-course of albumin and α1-acid glycoprotein (AAG) concentrations in pregnant and postpartum women living with HIV. Serum and plasma protein concentrations procured from the International Maternal Pediatric Adolescent AIDS Clinical Trial Protocol 1026s (P1026s) were analyzed using a generalized additive modeling approach. Separate non-parametric smoothing splines were fit to albumin and AAG concentrations as functions of gestational age or postpartum duration. The analysis included 871 and 757 serum albumin concentrations collected from 380 pregnant (~20 to 42 wks gestation) and 354 postpartum (0 to 46 wks postpartum) women, respectively. Thirty-six and 32 plasma AAG concentrations from 31 pregnant (~24 to 38 wks gestation) and 30 postpartum women (~2–13 wks postpartum), respectively, were available for analysis. Estimated mean albumin concentrations remained stable from 20 wks gestation to term (33.4 to 34.3 g/L); whereas, concentrations rapidly increased postpartum until stabilizing at ~42.3 g/L 15 wk after delivery. Estimated AAG concentrations slightly decreased from 24 wks gestation to term (53.6 and 44.9 mg/dL) while postpartum levels were elevated at two wks after delivery (126.1 mg/dL) and subsequently declined thereafter. Computational functions were developed to quantitatively communicate study results in a form that can be readily utilized for PBPK model development. By characterizing the trajectory of plasma protein concentrations in pregnant and postpartum women living with HIV, our analysis can increase confidence in PBPK model predictions for HIV antiretrovirals and better inform drug dosing decisions in this understudied population.
60 APPLIED LIFE SCIENCES↗
Pioglitazone induces hypoxia-inducible factor 1 activation in human renal proximal tubular epithelial cell line HK-2
We previously reported that fatty acid-bearing albumin but not fatty acid-depleted albumin induces hypoxia-inducible factor-1 (HIF-1) activation in human renal proximal tubular epithelial cell line HK-2. Then, an increase in mRNA expression of peroxisome proliferator-activated receptor gamma (PPARγ) was observed on treatment with fatty acid-bearing albumin but not fatty acid-depleted albumin. The aim of this study was to determine whether a PPARγ agonist, pioglitazone, induces HIF-1 activation or not. Treatment with pioglitazone induced HIF-1α mRNA as well as PPARγ mRNA expression in a concentration dependent manner. In addition, pioglitazone increased HIF-1 target genes such as the mRNAs of glucose transporter 1 (GLUT1) and breast cancer resistance protein (BCRP/ABCG2), in a concentration-dependent manner. Consistent with the increases in GLUT1 and ABCG2 mRNAs, protein expression of GLUT1 and BCRP was increased by pioglitazone. In addition, GLUT inhibitor phloretin-sensitive D-[{sup 3}H]glucose uptake activity and BCRP inhibitor Ko143-sensitive accumulation of Hoecsht33342, a BCRP substrate, were significantly enhanced by treatment with pioglitazone. These findings suggest that PPARγ activation by pioglitazone leads to HIF-1 protein expression induction followed by changes in HIF-1 target gene expression and protein product activity.
60 APPLIED LIFE SCIENCES↗
Assessing Structural, Thermal, and Functional Characteristics of Marigold Flower Protein as a Sustainable Food Ingredient
The demand for sustainable and alternative protein sources has been on the rise, driving interest in the valorization of underutilized plants. This study evaluated Calendula officinalis (marigold), a common floral waste, as a sustainable alternative protein source for the food industry. The primary objective of this study was to investigate the physicochemical properties of protein fractions from Calendula officinalis flower to evaluate their potential as a novel protein ingredient. Extraction of the Calendula officinalis flower yielded 92.17% of the crude protein. A sequential extraction of albumin, globulin, glutelin, and prolamin from marigold flower revealed albumin as the dominant fraction (65.47%) and exhibited the highest protein functionality, including water-holding capacity (2.37 g/g), oil-holding capacity (2.49 g/g), and emulsifying capacity (65.22 mL/g). Compared with other protein fractions, glutelin showed a relatively high emulsifying and foaming capacity (EC: 59.13 mL/g; FC: 16.23%). Differential scanning calorimetry revealed high thermal stability for albumin (T p = 105.28 °C) and glutelin (T p = 97.6 °C). Sodium Dodecyl Sulfate–Polyacrylamide Gel Electrophoresis (SDS-PAGE) and Liquid Chromatography–Mass Spectrometry (LC-MS) confirmed the presence of abundant low-molecular-weight polypeptides (<37 kDa), which enhanced emulsification, while scanning electron microscopy revealed porous structures aligned with hydration properties. Antioxidant activity was higher in albumin and glutelin, linked to surface hydrophobicity. LC-MS/MS identified 33 short-chain proteins, including oxidoreductase proteins and lipid-transfer proteins. Findings highlight marigold flower proteins as a sustainable, functional ingredient for a diverse range of food applications.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Early Fluid and Protein Shifts in Men During Water Immersion
High precision blood and plasma densitometry was used to measure transvascular fluid shifts during water immersion to the neck. Six men (28-49 years) undertook 30 min of standing immersion in water at 35.0 +/- 0.2 C; immersion was preceded by 30 min control standing in air at 28 +/- 1 C. Blood was sampled from an antecubital catheter for determination of Blood Density (BD), Plasma Density (PD), Haematocrit (Ht), total Plasma Protein Concentration (PPC), and Plasma Albumin Concentration (PAC). Compared to control, significant decreases (p less than 0.01) in all these measures were observed after 20 min immersion. At 30 min, plasma volume had increased by 11.0 +/- 2.8%; the average density of the fluid shifted from extravascular fluid into the vascular compartment was 1006.3 g/l; albumin moved with the fluid and its albumin concentration was about one-third of the plasma protein concentration during early immersion. These calculations are based on the assumption that the F-cell ratio remained unchanged. No changes in erythrocyte water content during immersion were found. Thus, immersion-induced haemodilution is probably accompanied by protein (mainly albumin) augmentation which accompanies the intra-vascular fluid shift.
Hinghofer-Szalkay, H.↗
High-Performance Hemofiltration via Molecular Sieving and Ultra-Low Friction in Carbon Nanotube Capillary Membranes
Conventional dialyzer membranes typically comprise of unevenly distributed polydisperse, tortuous, rough pores, embedded in relatively thick ≈20–50 µm polymer layers wherein separation occurs via size exclusion as well as differences in diffusivity of the permeating species. However, transport in such polymeric pores is increasingly hindered as the molecule size approaches the pore dimension, resulting in significant retention of undesirable middle molecules (≥15–60 kDa) and uremic toxins. Enhanced removal of middle molecules is usually accompanied by high albumin loss (≈66 kDa) causing hypoalbuminemia. Here, the scalable bottom-up fabrication of wafer-scale carbon nanotube (CNT) membranes with highly aligned, low-friction, straight-channels/capillaries and narrow pore-diameter distributions (≈0.5–4.5 nm) is demonstrated, to overcome persistent challenges in hemofiltration/hemodialysis. Using fluorescein isothiocyanate (FITC)-Ficoll 70 and albumin in phosphate buffered saline (PBS) as well as in bovine blood plasma, it is shown that CNT membranes can allow for significantly higher hydraulic permeability (more than an order of magnitude when normalized to pore area) than commercial high-flux hemofiltration/hemodialysis membranes (HF 400), as well as greatly enhance removal of middle molecules while maintaining comparable albumin retention. These findings are rationalized via an N-pore transport model that highlights the critical role of molecular flexing and deformation during size-selective transport within nanoscale confinements of the CNTs. In conclusion, the unique transport characteristics of CNTs coupled with size-exclusion and wafer-scale fabrication offer transformative advances for hemofiltration, and the obtained insight into molecular transport can aid advancements in several other bio-systems/applications beyond hemofiltration/hemodialysis.
36 MATERIALS SCIENCE↗
Low serum zinc is associated with elevated risk of cadmium nephrotoxicity
Background: Despite animal evidence suggests that zinc modulates cadmium nephrotoxicity, limited human data are available. Objective: To test the hypothesis that low serum zinc concentrations may increase the risk of cadmium-mediated renal dysfunction in humans. Methods: Data from 1545 subjects aged 20 or older in the National Health and Nutrition Examination Survey (NHANES), 2011–2012 were analyzed. Renal function was defined as impaired when estimated glomerular filtration rate (eGFR) fell below 60 ml/min/1.73 m{sup 2} and/or the urinary albumin-to-creatinine ratio surpassed 2.5 in men and 3.5 mg/mmol in women. Results: Within the study cohort, 117 subjects had reduced eGFR and 214 had elevated urinary albumin. After adjusting for potential confounders, subjects with elevated blood cadmium (>0.53 μg/L) were more likely to have a reduced eGFR (odds ratio [OR]=2.21, 95% confidence interval [CI]: 1.09–4.50) and a higher urinary albumin (OR=2.04, 95% CI: 1.13–3.69) than their low cadmium (<0.18 μg/L) peers. In addition, for any given cadmium exposure, low serum zinc is associated with elevated risk of reduced eGFR (OR=3.38, 95% CI: 1.39–8.28). A similar increase in the odds ratio was observed between declining serum zinc and albuminuria but failed to reach statistical significance. Those with lower serum zinc/blood cadmium ratios were likewise at a greater risk of renal dysfunction (p<0.01). Conclusions: This study results suggest that low serum zinc concentrations are associated with an increased risk of cadmium nephrotoxicity. Elevated cadmium exposure is global public health issue and the assessment of zinc nutritional status may be an important covariate in determining its effective renal toxicity. - Highlights: • Blood cadmium was associated with increased risk of nephrotoxicity. • Low serum zinc may exacerbate risk of cadmium-mediated renal dysfunction. • Both zinc deficiency and elevated cadmium exposure are global public health issues. • Nutritional status is important in the assessment of cadmium nephrotoxicity.
54 ENVIRONMENTAL SCIENCES↗
Cadmium, type 2 diabetes, and kidney damage in a cohort of middle-aged women
Background: It has been proposed that diabetic patients are more sensitive to the nephrotoxicity of cadmium (Cd) compared to non-diabetics, but few studies have examined this in humans, and results are inconsistent. Aim: To test the hypothesis that women with type 2 diabetes mellitus (DM) or impaired glucose tolerance (IGT) have higher risk of kidney damage from cadmium compared to women with normal glucose tolerance (NGT). Methods: All 64-year-old women in Gothenburg, Sweden, were invited to a screening examination including repeated oral glucose tolerance tests. Random samples of women with DM, IGT, and NGT were recruited for further clinical examinations. Serum creatinine was measured and used to calculate estimated glomerular filtration rate (eGFR). Albumin (Alb) and retinol-binding protein (RBP) were analyzed in a 12 h urine sample. Cadmium in blood (B-Cd) and urine (U-Cd) was determined using inductively coupled plasma mass spectrometry. Associations between markers of kidney function (eGFR, Alb, and RBP) and quartiles of B-Cd and U-Cd were evaluated in models, including also blood pressure and smoking habits. Results: The mean B-Cd (n=590) was 0.53 µg/L (median 0.34 µg/L). In multivariable models, a significant interaction was seen between high B-Cd (upper quartile, >0.56 µg/L) and DM (point estimate +0.40 mg Alb/12 h, P=0.04). In stratified analyzes, the effect of high B-Cd on Alb excretion was significant in women with DM (53% higher Alb/12 h, P=0.03), but not in women with IGT or NGT. Models with urinary albumin adjusted for creatinine showed similar results. In women with DM, the multivariable odds ratio (OR) for microalbuminuria (>15 mg/12 h) was increased in the highest quartile of B-Cd vs. B-Cd quartiles 1–3 in women with DM (OR 4.2, 95% confidence interval 1.1–12). No such effect was found in women with IGT or NGT. There were no associations between B-Cd and eGFR or excretion of RBP, and no differences between women with DM, IGT, or NGT regarding effect of B-Cd on eGFR or RBP. Conclusion: The present study provides support for the hypothesis that women with DM have higher risk of renal glomerular damage from cadmium exposure compared to women without DM. - Highlights: • Cadmium in blood, kidney function, and glucose tolerance was examined in 590 women. • Blood cadmium was associated with albumin excretion in women with type 2 diabetes. • No such associations with cadmium were found in women without diabetes. • Women with type 2 diabetes have increased sensitivity to kidney damage from cadmium.
60 APPLIED LIFE SCIENCES↗
Protein tyrosine adduct in humans self-poisoned by chlorpyrifos
Studies of human cases of self-inflicted poisoning suggest that chlorpyrifos oxon reacts not only with acetylcholinesterase and butyrylcholinesterase but also with other blood proteins. A favored candidate is albumin because in vitro and animal studies have identified tyrosine 411 of albumin as a site covalently modified by organophosphorus poisons. Our goal was to test this proposal in humans by determining whether plasma from humans poisoned by chlorpyrifos has adducts on tyrosine. Plasma samples from 5 self-poisoned humans were drawn at various time intervals after ingestion of chlorpyrifos for a total of 34 samples. All 34 samples were analyzed for plasma levels of chlorpyrifos and chlorpyrifos oxon (CPO) as a function of time post-ingestion. Eleven samples were analyzed for the presence of diethoxyphosphorylated tyrosine by mass spectrometry. Six samples yielded diethoxyphosphorylated tyrosine in pronase digests. Blood collected as late as 5 days after chlorpyrifos ingestion was positive for CPO-tyrosine, consistent with the 20-day half-life of albumin. High plasma CPO levels did not predict detectable levels of CPO-tyrosine. CPO-tyrosine was identified in pralidoxime treated patients as well as in patients not treated with pralidoxime, indicating that pralidoxime does not reverse CPO binding to tyrosine in humans. Plasma butyrylcholinesterase was a more sensitive biomarker of exposure than adducts on tyrosine. In conclusion, chlorpyrifos oxon makes a stable covalent adduct on the tyrosine residue of blood proteins in humans who ingested chlorpyrifos. - Highlights: • Chlorpyrifos-poisoned patients have adducts on protein tyrosine. • Diethoxyphosphate-tyrosine does not lose an alkyl group. • Proteins in addition to AChE and BChE are modified by organophosphates.
60 APPLIED LIFE SCIENCES↗
Protein crystallization studies
The Structural Biology laboratory at NASA Marshall Spaceflight Center uses x-ray crystallographic techniques to conduct research into the three-dimensional structure of a wide variety of proteins. A major effort in the laboratory involves an ongoing study of human serum albumin (the principal protein in human plasma) and its interaction with various endogenous substances and pharmaceutical agents. Another focus is on antigenic and functional proteins from several pathogenic organisms including the human immunodeficiency virus (HIV) and the widespread parasitic genus, Schistosoma. My efforts this summer have been twofold: first, to identify clinically significant drug interactions involving albumin binding displacement and to initiate studies of the three-dimensional structure of albumin complexed with these agents, and secondly, to establish collaborative efforts to extend the lab's work on human pathogens.
Lyne, James Evans↗