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Results: 1 to 10 of 38

Publication Record


Gal8 Visualization of Endosome Disruption Predicts Carrier-Mediated Biologic Drug Intracellular Bioavailability.
Kilchrist KV, Dimobi SC, Jackson MA, Evans BC, Werfel TA, Dailing EA, Bedingfield SK, Kelly IB, Duvall CL
(2019) ACS Nano 13: 1136-1152
MeSH Terms: Biological Availability, Biological Products, Drug Carriers, Drug Delivery Systems, Endosomes, Galectins, High-Throughput Screening Assays, Humans
Show Abstract · Added April 10, 2019
Endolysosome entrapment is one of the key barriers to the therapeutic use of biologic drugs that act intracellularly. The screening of prospective nanoscale endosome-disrupting delivery technologies is currently limited by methods that are indirect and cumbersome. Here, we statistically validate Galectin 8 (Gal8) intracellular tracking as a superior approach that is direct, quantitative, and predictive of therapeutic cargo intracellular bioactivity through in vitro high-throughput screening and in vivo validation. Gal8 is a cytosolically dispersed protein that, when endosomes are disrupted, redistributes by binding to glycosylation moieties selectively located on the inner face of endosomal membranes. The quantitative redistribution of a Gal8 fluorescent fusion protein from the cytosol into endosomes is demonstrated as a real-time, live-cell assessment of endosomal integrity that does not require labeling or modification of either the carrier or the biologic drug and that allows quantitative distinction between closely related, endosome-disruptive drug carriers. Through screening two families of siRNA polymeric carrier compositions at varying dosages, we show that Gal8 endosomal recruitment correlates strongly ( r = 0.95 and p < 10) with intracellular siRNA bioactivity. Through this screen, we gathered insights into how composition and molecular weight affect endosome disruption activity of poly[(ethylene glycol)- b-[(2-(dimethylamino)ethyl methacrylate)- co-(butyl methacrylate)]] [PEG-(DMAEMA- co-BMA)] siRNA delivery systems. Additional studies showed that Gal8 recruitment predicts intracellular bioactivity better than current standard methods such as Lysotracker colocalization ( r = 0.35, not significant), pH-dependent hemolysis (not significant), or cellular uptake ( r = 0.73 and p < 10). Importantly, the Gal8 recruitment method is also amenable to fully objective high-throughput screening using automated image acquisition and quantitative image analysis, with a robust estimated Z' of 0.6 (whereas assays with Z' > 0 have high-throughput screening utility). Finally, we also provide measurements of in vivo endosomal disruption based on Gal8 visualization ( p < 0.03) of a nanocarrier formulation confirmed to produce significant cytosolic delivery and bioactivity of siRNA within tumors ( p < 0.02). In sum, this report establishes the utility of Gal8 subcellular tracking for the rapid optimization and high-throughput screening of the endosome disruption potency of intracellular delivery technologies.
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8 MeSH Terms
Lipopolysaccharide Induced Opening of the Blood Brain Barrier on Aging 5XFAD Mouse Model.
Barton SM, Janve VA, McClure R, Anderson A, Matsubara JA, Gore JC, Pham W
(2019) J Alzheimers Dis 67: 503-513
MeSH Terms: Aging, Alzheimer Disease, Amyloid beta-Peptides, Animals, Benzothiazoles, Biological Availability, Blood-Brain Barrier, Ferric Compounds, Humans, Inflammation, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nanoparticles, Permeability, Plaque, Amyloid
Show Abstract · Added March 26, 2019
The development of neurotherapeutics for many neurodegenerative diseases has largely been hindered by limited pharmacologic penetration across the blood-brain barrier (BBB). Previous attempts to target and clear amyloid-β (Aβ) plaques, a key mediator of neurodegenerative changes in Alzheimer's disease (AD), have had limited clinical success due to low bioavailability in the brain because of the BBB. Here we test the effects of inducing an inflammatory response to disrupt the BBB in the 5XFAD transgenic mouse model of AD. Lipopolysaccharide (LPS), a bacterial endotoxin recognized by the innate immune system, was injected at varying doses. 24 hours later, mice were injected with either thioflavin S, a fluorescent Aβ-binding small molecule or 30 nm superparamagnetic iron oxide (SPIO) nanoparticles, both of which are unable to penetrate the BBB under normal physiologic conditions. Our results showed that when pretreated with 3.0 mg/kg LPS, thioflavin S can be found in the brain bound to Aβ plaques in aged 5XFAD transgenic mice. Following the same LPS pretreatment, SPIO nanoparticles could also be found in the brain. However, when done on wild type or young 5XFAD mice, limited SPIO was detected. Our results suggest that the BBB in aged 5XFAD mouse model is susceptible to increased permeability mediated by LPS, allowing for improved delivery of the small molecule thioflavin S to target Aβ plaques and SPIO nanoparticles, which are significantly larger than antibodies used in clinical trials for immunotherapy of AD. Although this approach demonstrated efficacy for improved delivery to the brain, LPS treatment resulted in significant weight loss even at low doses, resulting from the induced inflammatory response. These findings suggest inducing inflammation can improve delivery of small and large materials to the brain for improved therapeutic or diagnostic efficacy. However, this approach must be balanced with the risks of systemic inflammation.
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2 Members
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17 MeSH Terms
Associations of Vitamin D-Binding Globulin and Bioavailable Vitamin D Concentrations With Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA).
Robinson-Cohen C, Zelnick LR, Hoofnagle AN, Lutsey PL, Burke G, Michos ED, Shea SJC, Tracy R, Siscovick DS, Psaty B, Kestenbaum B, de Boer IH
(2017) J Clin Endocrinol Metab 102: 3075-3084
MeSH Terms: African Americans, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Biological Availability, Case-Control Studies, Coronary Disease, European Continental Ancestry Group, Female, Hispanic Americans, Humans, Male, Mass Spectrometry, Middle Aged, Proportional Hazards Models, Protein Isoforms, Risk Factors, United States, Vitamin D, Vitamin D-Binding Protein
Show Abstract · Added September 19, 2017
Context - Low 25-hydroxyvitamin D [25(OH)D] is associated with coronary heart disease (CHD) in people who are white and Chinese but not black or Hispanic. Vitamin D binding globulin (VDBG) avidly binds 25(OH)D, reducing its bioavailability, and differs in isoform and concentration by race.
Objective - Evaluate associations of VDBG with CHD and whether accounting for VDBG or estimating bioavailable 25(OH)D explains the heterogeneity of the association of 25(OH)D with CHD.
Design and Setting - We conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis. Participants with an incident CHD event over 12 years of follow-up (n = 538) and a randomly assigned subcohort (n = 999) were included. We measured baseline 25(OH)D, VDBG, and isoforms using mass spectrometry and estimated bioavailable 25(OH)D from published equations.
Results - VDBG was associated with an increased risk of CHD [hazard ratio, 1.77 (95% confidence interval, 1.46 to 2.14) per standard deviation increment, P < 0.0001], without evidence of heterogeneity by race or isoform (each P for interaction > 0.1). Low total 25(OH)D was differentially associated with CHD events, by race, with or without adjustment for VDBG (P for interaction = 0.04 or 0.05, respectively). Associations of 25(OH)D with CHD were strengthened with adjustment for VDBG among participants who were white or Chinese, and bioavailable 25(OH)D was associated with CHD events only among white participants.
Conclusions - High VDBG concentration was associated with CHD events in all racial and ethnic groups. Incorporation of VDBG strengthened existing associations of 25(OH)D with CHD but did not explain racial heterogeneity in associations of 25(OH)D with CHD.
Copyright © 2017 Endocrine Society
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1 Members
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20 MeSH Terms
Associations between dopamine D2 receptor availability and BMI depend on age.
Dang LC, Samanez-Larkin GR, Castrellon JJ, Perkins SF, Cowan RL, Zald DH
(2016) Neuroimage 138: 176-183
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Aging, Benzamides, Biological Availability, Body Mass Index, Brain, Female, Humans, Male, Middle Aged, Molecular Imaging, Positron-Emission Tomography, Pyrrolidines, Radiopharmaceuticals, Receptors, Dopamine D2, Receptors, Dopamine D3, Reproducibility of Results, Sensitivity and Specificity, Statistics as Topic, Tissue Distribution, Young Adult
Show Abstract · Added April 6, 2017
OBJECTIVE - The dopamine D2/3 receptor subtypes (DRD2/3) are the most widely studied neurotransmitter biomarker in research on obesity, but results to date have been inconsistent, have typically involved small samples, and have rarely accounted for subjects' ages despite the large impact of age on DRD2/3 levels. We aimed to clarify the relation between DRD2/3 availability and BMI by examining this association in a large sample of subjects with BMI spanning the continuum from underweight to extremely obese.
SUBJECTS - 130 healthy subjects between 18 and 81years old underwent PET with [18F]fallypride, a high affinity DRD2/3 ligand.
RESULTS - As expected, DRD2/3 availability declined with age. Critically, age significantly interacted with DRD2/3 availability in predicting BMI in the midbrain and striatal regions (caudate, putamen, and ventral striatum). Among subjects under 30years old, BMI was not associated with DRD2/3 availability. By contrast, among subjects over 30years old, BMI was positively associated with DRD2/3 availability in the midbrain, putamen, and ventral striatum.
CONCLUSION - The present results are incompatible with the prominent dopaminergic hypofunction hypothesis that proposes that a reduction in DRD2/3 availability is associated with increased BMI, and highlights the importance of age in assessing correlates of DRD2/3 function.
Copyright © 2016 Elsevier Inc. All rights reserved.
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1 Members
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24 MeSH Terms
L-Arginine Availability and Metabolism Is Altered in Ulcerative Colitis.
Coburn LA, Horst SN, Allaman MM, Brown CT, Williams CS, Hodges ME, Druce JP, Beaulieu DB, Schwartz DA, Wilson KT
(2016) Inflamm Bowel Dis 22: 1847-58
MeSH Terms: Amino Acid Transport Systems, Basic, Amino Acids, Arginase, Arginine, Biological Availability, Case-Control Studies, Citrulline, Clinical Trials as Topic, Colitis, Ulcerative, Colon, Crohn Disease, Diet Records, Humans, Nitric Oxide Synthase Type II, Prospective Studies, RNA, Messenger, Severity of Illness Index
Show Abstract · Added April 24, 2016
BACKGROUND - L-arginine (L-Arg) is the substrate for both inducible nitric oxide (NO) synthase (NOS2) and arginase (ARG) enzymes. L-Arg is actively transported into cells by means of cationic amino acid transporter (SLC7) proteins. We have linked L-Arg and arginase 1 activity to epithelial restitution. Our aim was to determine if L-Arg, related amino acids, and metabolic enzymes are altered in ulcerative colitis (UC).
METHODS - Serum and colonic tissues were prospectively collected from 38 control subjects and 137 UC patients. Dietary intake, histologic injury, and clinical disease activity were assessed. Amino acid levels were measured by high-performance liquid chromatography. Messenger RNA (mRNA) levels were measured by real-time PCR. Colon tissue samples from 12 Crohn's disease patients were obtained for comparison.
RESULTS - Dietary intake of arginine and serum L-Arg levels were not different in UC patients versus control subjects. In active UC, tissue L-Arg was decreased, whereas L-citrulline (L-Cit) and the L-Cit/L-Arg ratio were increased. This pattern was also seen when paired involved (left) versus uninvolved (right) colon tissues in UC were assessed. In active UC, SLC7A2 and ARG1 mRNA levels were decreased, whereas ARG2 and NOS2 were increased. Similar alterations in mRNA expression occurred in tissues from Crohn's disease patients. In involved UC, SLC7A2 and ARG1 mRNA levels were decreased, and NOS2 and ARG2 increased, when compared with uninvolved tissues.
CONCLUSIONS - Patients with UC exhibit diminished tissue L-Arg, likely attributable to decreased cellular uptake and increased consumption by NOS2. These findings combined with decreased ARG1 expression indicate a pattern of dysregulated L-Arg availability and metabolism in UC.
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2 Members
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17 MeSH Terms
Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges.
Lockhart JN, Stevens DM, Beezer DB, Kravitz A, Harth E
(2015) J Control Release 220: 751-7
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Biological Availability, Biotransformation, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Chemistry, Pharmaceutical, Cross-Linking Reagents, Cytochrome P-450 CYP3A, Delayed-Action Preparations, Dose-Response Relationship, Drug, Drug Carriers, Drug Stability, Female, Gastric Juice, Glucuronosyltransferase, Intestinal Secretions, Kinetics, Mice, Nanomedicine, Nanoparticles, Particle Size, Polyesters, Quercetin, Solubility, Tamoxifen
Show Abstract · Added February 15, 2016
We report the synthesis and encapsulation of polyester nanosponge particles (NPs) co-loaded with tamoxifen (TAM) and quercetin (QT) to investigate the loading, release and in vitro metabolism of a dual drug formulation. The NPs are made in two variations, 4% and 8% crosslinking densities, to evaluate the effects on metabolism and release kinetics. The NP-4% formulation with a particle size of 89.3 ± 14.8 nm was found to have loading percentages of 6.91 ± 0.13% TAM and 7.72 ± 0.15% QT after targeting 10% (w/w) each. The NP-8% formulation with a particle size of 91.5 ± 9.8 nm was found to have loading percentages of 7.26 ± 0.10% TAM and 7.80 ± 0.12% QT. The stability of the formulation was established in simulated gastrointestinal fluids, and the metabolism of TAM was shown to be reduced 2-fold and 3-fold for NP-4%s and NP-8%s, respectively, while QT metabolism was reduced 3 and 4-fold. The implications for improved bioavailability of the NP formulations were supported by cytotoxicity results that showed a similar efficacy to free dual drug formulations and even enhanced anti-cancer effects in the recovery condition. This work demonstrates the suitability of the nanosponges not only as a dual release drug delivery system but also enabling a regulated metabolism through the capacity of a nanonetwork. The variation in crosslinking enables a dual release with tailored release kinetics and suggests improved bioavailability aided by a reduced metabolism.
Copyright © 2015 Elsevier B.V. All rights reserved.
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1 Members
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27 MeSH Terms
Regulation of Selenium Metabolism and Transport.
Burk RF, Hill KE
(2015) Annu Rev Nutr 35: 109-34
MeSH Terms: Animals, Biological Availability, Biological Transport, Biomarkers, Diet, Dietary Supplements, Health Status, Homeostasis, Humans, Kidney Tubules, Proximal, LDL-Receptor Related Proteins, Liver, Low Density Lipoprotein Receptor-Related Protein-2, Nutritional Requirements, Organ Specificity, Selenium, Selenocysteine, Selenomethionine, Selenoprotein P, Selenoproteins
Show Abstract · Added September 28, 2015
Selenium is regulated in the body to maintain vital selenoproteins and to avoid toxicity. When selenium is limiting, cells utilize it to synthesize the selenoproteins most important to them, creating a selenoprotein hierarchy in the cell. The liver is the central organ for selenium regulation and produces excretory selenium forms to regulate whole-body selenium. It responds to selenium deficiency by curtailing excretion and secreting selenoprotein P (Sepp1) into the plasma at the expense of its intracellular selenoproteins. Plasma Sepp1 is distributed to tissues in relation to their expression of the Sepp1 receptor apolipoprotein E receptor-2, creating a tissue selenium hierarchy. N-terminal Sepp1 forms are taken up in the renal proximal tubule by another receptor, megalin. Thus, the regulated whole-body pool of selenium is shifted to needy cells and then to vital selenoproteins in them to supply selenium where it is needed, creating a whole-body selenoprotein hierarchy.
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1 Members
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20 MeSH Terms
Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling.
Bhushan S, Kondo K, Polhemus DJ, Otsuka H, Nicholson CK, Tao YX, Huang H, Georgiopoulou VV, Murohara T, Calvert JW, Butler J, Lefer DJ
(2014) Circ Res 114: 1281-91
MeSH Terms: Aged, Animals, Biological Availability, Cyclic GMP, Cytoprotection, Disease Models, Animal, Female, Heart Failure, Hemodynamics, Humans, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Middle Aged, Nitric Oxide, Signal Transduction, Sodium Nitrite, Stroke Volume, Ventricular Dysfunction, Left
Show Abstract · Added January 29, 2016
RATIONALE - Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury.
OBJECTIVE - No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy.
METHODS AND RESULTS - Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.
CONCLUSIONS - These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.
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20 MeSH Terms
Antimicrobial dosing in acute renal replacement.
Fissell WH
(2013) Adv Chronic Kidney Dis 20: 85-93
MeSH Terms: Acute Kidney Injury, Anti-Bacterial Agents, Antifungal Agents, Biological Availability, Critical Care, Critical Illness, Drug Administration Schedule, Drug Dosage Calculations, Humans, Inactivation, Metabolic, Metabolic Clearance Rate, Piperacillin, Practice Guidelines as Topic, Renal Replacement Therapy, Tissue Distribution
Show Abstract · Added August 21, 2013
Acute kidney injury (AKI) is a common problem in hospitalized patients and is associated with significant morbidity and mortality. Two large trials showed no benefit from increased doses of renal replacement therapy (RRT) despite previous clinical data suggesting that increased clearance from RRT has beneficial effects. Since infection is the leading cause of death in AKI, my group and others hypothesized that increased RRT antibiotic clearance might create a competing morbidity. The data from my group, as well as those of other groups, show that many patients are underdosed when routine "1 size fits all" antibiotic dosing is used in patients with AKI receiving continuous RRT (CRRT). Here, concepts of drug distribution and clearance in AKI are briefly discussed and then 1 antibiotic (piperacillin) is discussed in depth to illustrate the challenges in applying the medical literature to clinical practice. The fact that published data on drug dosing in AKI and dialysis reflect the evolution of practice patterns and often do not apply to present prescribing habits is also discussed. A more general approach to drug dosing facilitates situation-specific prescribing by the nephrologist and critical care specialist.
Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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15 MeSH Terms
Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model.
Jones CK, Engers DW, Thompson AD, Field JR, Blobaum AL, Lindsley SR, Zhou Y, Gogliotti RD, Jadhav S, Zamorano R, Bogenpohl J, Smith Y, Morrison R, Daniels JS, Weaver CD, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR
(2011) J Med Chem 54: 7639-47
MeSH Terms: Administration, Oral, Allosteric Regulation, Animals, Antiparkinson Agents, Biological Availability, CHO Cells, Catalepsy, Cricetinae, Cricetulus, Haloperidol, Humans, In Vitro Techniques, Isoindoles, Microsomes, Liver, Picolinic Acids, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added February 16, 2015
There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.
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4 Members
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18 MeSH Terms