SEARCH · Engineering Papers

Results for “ALBUMINS”

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.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5

All sources NASA NTRS DOE OSTI

NASA NTRS1987

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.↗

DOE OSTI2023

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↗

DOE OSTI2014

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↗

DOE OSTI2014

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↗

DOE OSTI2013

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↗

NASA NTRS1996

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↗

DOE OSTI2019

Development and validation of an imaging and clinical scoring system to predict early mortality in spontaneous ruptured hepatocellular carcinoma treated with transarterial embolization

Purpose: To develop and validate a scoring system using a combination of imaging and clinical parameters to predict 30-day mortality in ruptured HCC (rHCC) patients after transarterial embolization (TAE). Methods: 98 consecutive patients with rHCC who underwent abdominal CT and subsequent TAE between January 2007 and December 2016 were retrospectively reviewed. The CT scans were reviewed by two radiologists blinded to the patient outcome. Clinical parameters including serum bilirubin, albumin, INR, creatinine, and hemoglobin were recorded. Independent risk factors for 30-day mortality after TAE were identified using multivariate binary logistic regression, for development of a scoring system. The scoring system was then validated in 20 patients between January 2017 and May 2018. Results: In the development cohort, bilobar tumor distribution (OR = 29.6), clinical parameters of bilirubin > 2.5 mg/dL (OR = 5.9), and albumin < 30 g/L (OR = 4.1) were independent predictors for 30-day mortality. A 6-point score was derived and yielded area-under-the-receiver-operating-characteristic-curve (AUC) of 0.904. A score ≥ 4 resulted in sensitivity of 80.5% and specificity of 91.2% for 30-day mortality. In the validation cohort, AUC for 30-day mortality was 0.939. A score ≥ 4 resulted in sensitivity of 81.2% and specificity of 88.9%. In both development and validation cohorts, the proposed scoring system was better than biochemical components of Child–Pugh score and serum bilirubin to predict 30-day mortality. Conclusion: Imaging and clinical parameters can be combined into a scoring system to accurately predict 30-day mortality after TAE in rHCC patients. The score may help identify and counsel high-risk patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2018

Use of Fourier Transform IR Spectroscopy for the Study of Saliva Composition

The IR spectrum of saliva may be divided into groups of absorption bands corresponding to lipids, proteins, nucleic acids, and sugars. The finding of thiocyanate ion absorption bands is a characteristic feature of the spectra of saliva. In comparing a typical IR spectrum of saliva with the spectra of albumin, glucose, and lysozyme, a similarity is noted at 1100–1040 cm{sup –1} with the spectrum of albumin and at 1700–1400 cm{sup –1} with the spectra of glucose and lysozyme. It was shown that sugars are found in saliva in a form bound with proteins. Correlations were found between band intensities in the IR spectrum of saliva and its biochemical composition.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2018

Antibacterial and Drug Elution Performance of Thermoplastic Blends

Food preservatives or drug compounds can be eluted from polymer substrates to prevent the occurrence of hospital-acquired infections and food spoilage. We investigated the antimicrobial and drug-elution properties of the albumin and zein thermoplastic blends plasticized with glycerol and mixed with varying amounts of low-density polyethylene (LDPE), food preservatives (sodium benzoate or sodium nitrite), and drugs (ampicillin or ciprofloxacin). Bacillus subtilis and Escherichia coli were utilized as Gram (+) and Gram (−) species, respectively, for antimicrobial and drug-elution analyses, since these species are common in the human body and in food environments. The amount of contamination occurring in food and medical applications could be limited with usage of plastic blends made from thermomechanical molding of proteins (albumin from hen egg white and zein from corn), drug eluting compounds, and low-density polyethylene.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

Enhanced Therapeutic Potency of Nanoemulsified Garlic Oil Blend Towards Renal Abnormalities in Pre-diabetic Rats

The therapeutic potency of ultrasonic nanoemulsified garlic oil blend using a non-ionic surfactant (Tween 80) was assessed on pre-diabetic Wistar rats with microalbuminuria. The pre-diabetic condition was induced in male albino Wistar rats by supplementing high-fat diet. The prolonged period of the pre-diabetic state caused renal dysfunctioning, which was indicated by microalbuminuria. Treatment of pre-diabetic rats with nanoemulsified garlic oil blend significantly ameliorated the lipid profile (p < 0.001), urinary albumin (p < 0.01), microprotein (p < 0.001), urinary triglycerides (p < 0.01), serum triglycerides (p < 0.01), serum albumin (p < 0.05), and protein levels (p < 0.01) in comparison to treatment of pre-diabetic rats with garlic oil blend or atorvastatin. Similarly, histopathological investigations indicated a remarkable attenuation in the mesangial expansion and proliferation, glomerular and tubular basement membrane thickening, and the tubular lipid deposits on administering nanoemulsified garlic oil blend than garlic oil blend or atorvastatin. Moreover, nanoemulsified garlic oil blend significantly promoted renal podocin gene expression by 3.98-fold (p < 0.001) and attenuated increased urinary podocin level by 2.92-fold (p < 0.01). Thus, our study affirms that the efficacy of garlic oil blend was augmented upon nanoemulsification, which substantially ameliorated the renal abnormalities observed in the pre-diabetic condition than garlic oil blend or atorvastatin.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

Postoperative weight loss followed by radical cystectomy predicts poor prognosis in patients with muscle-invasive bladder cancer

We aimed to investigate the impact of postoperative weight loss following radical cystectomy (RC) on patients’ prognoses. RC and urinary diversion were performed in 512 consecutive patients with muscle-invasive bladder cancer at our hospitals between May 1996 and July 2018. Demographic clinical information, pre- and postoperative serum albumin, hemoglobin, and weight were evaluated retrospectively at 1 month. We also evaluated the association of weight loss with complications and overall survival (OS) as estimated using the Kaplan–Meier method and compared using the log-rank test. Risk factors for poor OS were determined by Inverse Probability of Treatment Weighted (IPTW)-adjusted Cox regression analysis. In 385 patients who met the study search criteria, median postoperative weight loss from baseline at 1 week and 1 month was 1.1 (− 1.8%) and 3.2 (− 5.4%) kg, respectively. Patients with significant weight loss (defined as ≥ 7.5% at 1 month) had higher-grade complications within 1 month and had significantly shorter OS than those with weight loss of < 7.5%. Type of urinary diversion, loss of serum albumin, and loss of hemoglobin were not significantly associated with weight loss. IPTW-adjusted Cox regression analysis showed that such significant weight loss was an independent risk factor for poor OS. Weight loss followed by radical cystectomy was significantly associated with poor prognosis in patients with muscle-invasive bladder cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

Effects of FoxO1 on podocyte injury in diabetic rats

Objective: This study was designed to investigate the protective effect of forkhead transcription factor O1 (FoxO1) on podocyte injury in rats with diabetic nephropathy. Methods: Streptozotocin-induced diabetic rats were served as DM group, while DM rats transfected with blank lentiviral vectors (LV-pSC-GFP) or lentiviral vectors carrying constitutively active FoxO1 (LV-CA-FoxO1) were served as LV-NC group or LV-CA group, respectively. The control group (NG) consisted of uninduced rats that received an injection of diluent buffer. At 2, 4, and 8 weeks after transfection, the levels of urine albumin, blood glucose, blood urea nitrogen, serum creatinine and urine podocalyxin were measured. Real-time PCR and western blotting were performed to measure mRNA and protein levels of FoxO1, podocalyxin, nephrin, and desmin in renal cortex. In addition, light and electron microscopy were used to detect structural changes in the glomerulus and podocytes. Results: Compared with the rats in LV-NC and DM groups, LV-CA rats showed a significant increase in FoxO1 mRNA and protein levels and a distinct decrease in urine albumin, blood urea nitrogen, and serum creatinine (except at the two-week time point) levels (p < 0.05). Podocalyxin and nephrin mRNA and protein levels increased (p < 0.05), whereas desmin mRNA and protein levels decreased (p < 0.05). Pathological changes in glomerulus were also ameliorated in LV-CA group. Conclusions: Upregulating expression of FoxO1 by transduction with recombinant lentivirus ameliorates podocyte injury in diabetic rats. - Highlights: • The structures and functions of podocytes were impaired in STZ-induced diabetic rats. • Constitutively active FoxO1 ameliorates structure injury and preserves function of podocytes in diabetic rats. • FoxO1 may alleviate the pathological changes associated with diabetic nephropathy.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

Diesel exhaust induced pulmonary and cardiovascular impairment: The role of hypertension intervention

Exposure to diesel exhaust (DE) and associated gases is linked to cardiovascular impairments; however, the susceptibility of hypertensive individuals is poorly understood. The objectives of this study were (1) to determine cardiopulmonary effects of gas-phase versus whole-DE and (2) to examine the contribution of systemic hypertension in pulmonary and cardiovascular effects. Male Wistar Kyoto (WKY) rats were treated with hydralazine to reduce blood pressure (BP) or L-NAME to increase BP. Spontaneously hypertensive (SH) rats were treated with hydralazine to reduce BP. Control and drug-pretreated rats were exposed to air, particle-filtered exhaust (gas), or whole DE (1500 μg/m{sup 3}), 4 h/day for 2 days or 5 days/week for 4 weeks. Acute and 4-week gas and DE exposures increased neutrophils and γ-glutamyl transferase (γ-GT) activity in lavage fluid of WKY and SH rats. DE (4 weeks) caused pulmonary albumin leakage and inflammation in SH rats. Two-day DE increased serum fatty acid binding protein-3 (FABP-3) in WKY. Marked increases occurred in aortic mRNA after 4-week DE in SH (eNOS, TF, tPA, TNF-α, MMP-2, RAGE, and HMGB-1). Hydralazine decreased BP in SH while L-NAME tended to increase BP in WKY; however, neither changed inflammation nor BALF γ-GT. DE-induced and baseline BALF albumin leakage was reduced by hydralazine in SH rats and increased by L-NAME in WKY rats. Hydralazine pretreatment reversed DE-induced TF, tPA, TNF-α, and MMP-2 expression but not eNOS, RAGE, and HMGB-1. ET-1 was decreased by HYD. In conclusion, antihypertensive drug treatment reduces gas and DE-induced pulmonary protein leakage and expression of vascular atherogenic markers. - Highlights: ► Acute diesel exhaust exposure induces pulmonary inflammation in healthy rats. ► In hypertensive rats diesel exhaust effects are seen only after long term exposure. ► Normalizing blood pressure reverses lung protein leakage caused by diesel exhaust. ► Normalizing blood pressure reverses atherogenic effects of diesel exhaust. ► Diesel exhaust and hydralazine cause similar aorta effect on vascular tone markers.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

The relationship between cadmium in kidney and cadmium in urine and blood in an environmentally exposed population

Introduction: Cadmium (Cd) is toxic to the kidney and a major part of the body burden occurs here. Cd in urine (U-Cd) and blood (B-Cd) are widely-used biomarkers for assessing Cd exposure or body burden. However, empirical general population data on the relationship between Cd in kidney (K-Cd), urine, and blood are scarce. Our objectives were to determine the relationship between cadmium in kidney, urine, and blood, and calculate the elimination half-time of Cd from the kidney. Methods: Kidney cortex biopsies, urine, and blood samples were collected from 109 living kidney donors. Cd concentrations were determined and the relationships between K-Cd, U-Cd, and B-Cd were investigated in regression models. The half-time of K-Cd was estimated from the elimination constant. Results: There was a strong association between K-Cd and U-Cd adjusted for creatinine (r{sub p} = 0.70, p < 0.001), while the association with B-Cd was weaker (r{sub p} = 0.44, p < 0.001). The relationship between K-Cd and U-Cd was nonlinear, with slower elimination of Cd at high K-Cd. Estimates of the K-Cd half-time varied between 18 and 44 years. A K-Cd of 25 μg/g corresponds to U-Cd of 0.42 μg/g creatinine in overnight urine (U-Cd/K-Cd ratio: about 1:60). Multivariate models showed Cd in blood and urinary albumin as determinants for U-Cd excretion. Discussion: In healthy individuals with low-level Cd exposure, there was a strong correlation between Cd in kidney and urine, especially after adjustment for creatinine. Urinary Cd was also affected by Cd in blood and urinary albumin. Previous estimates of the U-Cd/K-Cd ratio may underestimate K-Cd at low U-Cd. - Highlights: ► The first study of the relation between Cd in kidney, blood and urine at low U-Cd ► Simultaneous samples were collected from healthy kidney donors. ► There was a nonlinear relationship between cadmium in kidney and urine. ► Estimates of the kidney cadmium half-time were 18–44 years, depending on model used. ► Previous data seem to underestimate kidney cadmium at low urinary cadmium.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate

Perinatal exposure of rats and mice to the typically reported 4 mg/g bd wt dose of monosodium glutamate (MSG) results in a complete block in GH secretion as well as obesity, growth retardation and a profound suppression of several cytochrome P450s, including CYP2C11, the predominant male-specific isoform — all irreversible effects. In contrast, we have found that a lower dose of the food additive, 2 mg/g bd wt on alternate days for the first 9 days of life results in a transient neonatal depletion of plasma GH, a subsequent permanent overexpression of CYP2C11 as well as subnormal (mini) GH pulse amplitudes in an otherwise normal adult masculine episodic GH profile. The overexpressed CYP2C11 was characterized by a 250% increase in mRNA, but only a 40 to 50% increase in CYP2C11 protein and its catalytic activity. Using freshly isolated hepatocytes as well as primary cultures exposed to the masculine-like episodic GH profile, we observed normal induction, activation, nuclear translocation and binding to the CYP2C11 promoter of the GH-dependent signal transducers required for CYP2C11 transcription. The disproportionately lower expression levels of CYP2C11 protein were associated with dramatically high expression levels of an aberrant, presumably nontranslated CYP2C11 mRNA, a 200% increase in CYP2C11 ubiquitination and a 70–80% decline in miRNAs associated, at normal levels, with a suppression of CYP2C expression. Whereas the GH-responsiveness of CYP2C7 and CYP2C6 as well as albumin was normal in the MSG-derived hepatocytes, the abnormal expression of CYP2C11 was permanent and irreversible. - Highlights: • A “low” neonatal dose of MSG causes an immediate but transient growth hormone depletion. • Adult circulating growth hormone contains mini pulses in an otherwise male profile. • CYP2C11 is permanently overexpressed > 250%; CYP2C6, 2C7 and albumin remain normal. • The bulk of the overexpressed CYP2C11 mRNA consists of an intron-retained form. • SOCS2 and miRNAs are subnormal, ubiquitination is elevated but JAK2/STAT5b is normal.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice

High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100–300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK·MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein–acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1–5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10–20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity. - Graphical abstract: Cyclophosphamide (CY) treatment results in P450-mediated metabolic formation of phosphoramide mustard and acrolein (3-propenal). Acrolein is either metabolized and detoxified by glutathione S-transferase P (GSTP) via conjugation with GSH or acrolein can react with circulating and cardiac proteins to form protein–acrolein adducts that may contribute to cardiac injury, increased vascular permeability and edema and acute cardiotoxicity. Under low dose exposure, this event is reversible but at high levels of CY treatment and/or in susceptible individuals (e.g., hGSTP1 polymorphism), CY-induced cardiotoxicity is augmented and sudden death may occur. - Highlights: • Acute cardiotoxicity of cyclophosphamide (CY) is exacerbated in GSTP-null mice. • CY altered cardiac contractility, vascular leak and protein–acrolein adducts. • Cardiotoxicity of CY is recapitulated by acrolein only exposure. • Acrolein-induced cardiotoxicity and mortality is enhanced in male GSTP-null mice.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein

Acrolein is a highly toxic, volatile, unsaturated aldehyde generated during incomplete combustion as in tobacco smoke and indoor fires. Because the transient receptor potential ankyrin 1 (TRPA1) channel mediates tobacco smoke-induced lung injury, we assessed its role in high-level acrolein-induced toxicity in mice. Acrolein (100–275 ppm, 10–30 min) caused upper airway epithelial sloughing, bradypnea and oral gasping, hypothermia, cardiac depression and mortality. Male wild-type mice (WT, C57BL/6; 5–52 weeks) were significantly more sensitive to high-level acrolein than age-matched, female WT mice. Both male and female TRPA1-null mice were more sensitive to acrolein-induced mortality than age- and sex-matched WT mice. Acrolein exposure increased lung weight:body weight ratios and lung albumin and decreased plasma albumin to a greater extent in TRPA1-null than in WT mice. Lung and plasma protein-acrolein adducts were not increased in acrolein-exposed TRPA1-null mice compared with WT mice. To assess TRPA1-dependent protective mechanisms, respiratory parameters were monitored by telemetry. TRPA1-null mice had a slower onset of breathing rate suppression (‘respiratory braking’) than WT mice suggesting TRPA1 mediates this protective response. Surprisingly, WT male mice treated either with a TRPA1 antagonist (HC030031; 200 mg/kg) alone or with combined TRPA1 (100 mg/kg) and TRPV1 (capsazepine, 10 mg/kg) antagonists at 30 min post-acrolein exposure (i.e., “real world” delay in treatment) were significantly protected from acrolein-induced mortality. These data show TRPA1 protects against high-level acrolein-induced toxicity in a sex-dependent manner. Post-exposure TRPA1 antagonism also protected against acrolein-induced mortality attesting to a complex role of TRPA1 in cardiopulmonary injury. - Highlights: • TRPA1 protects mice against toxicity and mortality of inhaled high-level acrolein. • TRPA1 protection against inhaled high-level acrolein is sex-dependent in mice. • Age (5–52 weeks old) was not a determinant of acrolein-induced mortality in mice. • TRPA1 antagonist is protective after inhaled high-level acrolein in male mice.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

TH-C-17A-02: New Radioluminescence Strategies Based On CRET (Cerenkov Radiation Energy Transfer) for Imaging and Therapy

Purpose: Cerenkov photons are produced when charged particles, emitted from radionuclides, travel through a media with a speed greater than that of the light in the media. Cerenkov radiation is mostly in the UV/Blue region and, thus, readily absorbed by biological tissue. Cerenkov Radiation Energy Transfer (CRET) is a wavelength-shifting phenomenon from blue Cerenkov light to more penetrating red wavelengths. We demonstrate the feasibility of in-depth imaging of CRET light originating from radionuclides realized by down conversion of gold nanoclusters (AuNCs, a novel particle composed of few atoms of gold coated with serum proteins) in vivo. Methods: Bovine Serum Albumin, Human Serum Albumin and Transferrin conjugated gold nanoclusters were synthesized, characterized and examined for CRET. Three different clinically used radiotracers: 18F-FDG, 90Y and 99mTc were used. Optical spectrum (440–750 nm) was recorded by sensitive bioluminescence imaging system at physiological temperature. Dose dependence (activity range from 0.5 up to 800uCi) and concentration dependence (0.01 to 1uM) studies were carried out. The compound was also imaged in a xenograft mouse model. Results: Only β+ and β--emitting radionuclides (18F-FDG, 90Y) are capable of CRET; no signal was found in 99mTc (γ-emitter). The emission peak of CRET by AuNCs was found to be ∼700 nm and was ∼3 fold times of background. In vitro studies showed a linear dependency between luminescence intensity and dose and concentration. CRET by gold nanoclusters was observed in xenografted mice injected with 100uCi of 18F-FDG. Conclusion: The unique optical, transport and chemical properties of AuNCs (gold nanoclusters) make them ideal candidates for in-vivo imaging applications. Development of new molecular imaging probes will allow us to achieve substantially improved spatiotemporal resolution, sensitivity and specificity for tumor imaging and detection.

60 APPLIED LIFE SCIENCES↗