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albumin human [keywords]
- Effects of mycophenolate mofetil on kidney function and phosphorylation status of renal proteins in Alport COL4A3-deficient mice. [Journal Article]
- Proteome Sci 2014; 12(1):56.
We investigated the effects of mycophenolate mofetil (MMF) on kidney function and on protein phosphorylation in a mouse model for the human Alport syndrome.COL4A3-deficient (COL4A3-/-) mice were randomly allocated to receive a placebo (PLC COL4A3-/-) or MMF treatment (MMF COL4A3-/-). Wild type mice (WT) were used as controls. Changes in serum creatinine, total protein and blood urea nitrogen (BUN), concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG), serum protein electrophoresis, urine dipstick chemistry and sediment were measured. Changes in the phosphorylation status of renal proteins and histology were analyzed.MMF influenced kidney function and protein phosphorylation. Serum creatinine and BUN were lower in MMF treated compared to PLC treated COL4A3-/- mice. Serum albumin and alpha-1 globulins were significantly decreased while serum creatinine, alpha-2 globulins, urine dipstick protein, leukocyte esterase, hemoglobin and red blood cells were all increased in both COL4A3-/- groups compared to WT. Differential 2DE-gel analysis identified six phosphorylated kidney protein spots that were significantly altered by MMF.These data suggest that the MMF treatment in this murine model moderately improved kidney function and reversed the phosphorylation status of six renal phosphoprotein spots to that seen in WT mice.
- Effect of polymer molecular weight on chitosan-protein interaction. [JOURNAL ARTICLE]
- Colloids Surf B Biointerfaces 2014 Dec 2.
We present a comprehensive study of the interactions between chitosan nanoparticles (15, 100 and 200kDa with the same degree of deacetylation 90%) and two model proteins, i.e., bovine (BSA) and human serum albumins (HSA), with the aim of correlating chitosan molecular weight (Mw) and the binding affinity of these naturally occurring polymers to protein. The effect of chitosan on the protein secondary structure and the influence of protein complexation on the shape of chitosan nanoparticles are discussed. A combination of multiple spectroscopic methods, transmission electron microscopy (TEM) and thermodynamic analysis were used to assess the polymer-protein complex formation. Results revealed that the three chitosan nanoparticles interact with BSA to form chitosan-BSA complexes, mainly through hydrophobic contacts with the affinity order: 200>100>15kDa. However, HSA-chitosan complexation is mainly via electrostatic interactions with the stability order: 100>200>15kDa. Furthermore, the association between polymer and protein causes a partial protein conformational change by a major reduction of α-helix from 63% (free BSA) to 57% (chitosan-BSA) and 57% (free HSA) to 51% (chitosan-HSA). Finally, TEM micrographs clearly revealed that the binding of serum albumins with chitosan nanoparticles induces a significant change in protein morphology and the shape of the polymer.
- Safety, pharmacokinetics and pharmacodynamics of TV-1380, a novel mutated butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects. [JOURNAL ARTICLE]
- J Clin Pharmacol 2014 Dec 18.
Human plasma butyrylcholinesterase (BChE) contributes to cocaine metabolism and has been considered for use in treating cocaine addiction and cocaine overdose. TV-1380 is a recombinant protein composed of the mature form of human serum albumin fused at its amino terminus to the carboxy-terminus of a truncated and mutated BChE. In preclinical studies, TV-1380 has been shown to rapidly eliminate cocaine in the plasma thus forestalling entry of cocaine into the brain and heart. Two randomized, blinded phase I studies were conducted to evaluate the safety, pharmacokinetics and pharmacodynamics of TV-1380, following single and multiple administration in healthy subjects. TV-1380 was found to be safe and well tolerated with a long half-life (43 to 77 hours) and showed a dose-proportional increase in systemic exposure. Consistent with pre-clinical results, the ex vivo cocaine hydrolysis, TV-1380 activity clearly increased upon treatment in a dose-dependent manner. In addition, there was a direct relationship between ex vivo cocaine hydrolysis (kel ) and TV-1380 serum concentrations. There was no evidence that TV-1380 affected heart rate, the uncorrected QT interval or the heart-rate-corrected QTcF interval. TV-1380 therefore offers a safe once-weekly therapy to increase cocaine hydrolysis. This article is protected by copyright. All rights reserved.
- Phosphorescent biscyclometallated iridium(iii) ethylenediamine complexes functionalised with polar ester or carboxylate groups as bioimaging and visualisation reagents. [JOURNAL ARTICLE]
- Dalton Trans 2014 Dec 18.
We report the synthesis, characterisation and photophysical properties of new phosphorescent biscyclometallated iridium(iii) ethylenediamine (en) complexes functionalised with polar ester or carboxylate groups [Ir(N^C)2(en)](n)(X) (n = +1, X = Cl(-), HN^C = methyl 4-(2-pyridyl)benzoate Hppy-COOMe (), methyl 2-phenyl-4-quinolinecarboxylate Hpq-COOMe (); n = -1, X = Li(+), HN^C = 4-(2-pyridyl)benzoate Hppy-COO(-) (), 2-phenyl-4-quinolinecarboxylate Hpq-COO(-) ()). In aqueous solutions, the carboxylate complexes and displayed emission quenching (ca. 7 and 74 fold, respectively) and lifetime shortening upon protonation, and their pKa values were determined to be 5.13 and 3.46, respectively. The pq complexes and exhibited hypsochromic shifts in their emission maxima and a significant increase in emission intensity (ca. 84 and 15 fold, respectively) upon nonspecific binding to the protein bovine serum albumin (BSA). Inductively coupled plasma-mass spectroscopy (ICP-MS) and laser-scanning confocal microscopy (LSCM) results revealed that the ester complexes and were efficiently internalised by the human cervix epithelioid carcinoma (HeLa) cells through energy-requiring pathways and subsequently localised in endosomes and mitochondria, respectively. They showed good biocompatibility in the dark, but became significantly cytotoxic upon photoirradiation due to the generation of singlet oxygen. In contrast, in aqueous solutions of physiological pH, the carboxylate complexes and existed as the anionic form and hardly entered cells due to limited membrane permeability, as evidenced by the intense emission surrounding the plasma membrane of the cells. They showed negligible cytotoxicity and the cell viability remained over 95% for an incubation period of 24 hours. In view of the low cytotoxicity and strongly emissive nature of the hydrophilic ppy-COO(-) complex in an aqueous medium, the potential application of the complex as a visualisation reagent has been demonstrated using zebrafish (Danio rerio) as an animal model.
- A comparative study of capillary electrophoresis and isothermal titration calorimetry for the determination of binding constant of human serum albumin to monoclonal antibody. [JOURNAL ARTICLE]
- Electrophoresis 2014 Dec 17.
This paper focuses on the investigation of the interactions between the anti-HSA-mAb and its protein antigen using CZE, ACE and isothermal titration calorimetry. The CZE revealed the formation of the anti-HSA-mAb·HSA and anti-HSA-mAb·(HSA)2 complexes and the binding constants determined by plotting the amount of the bound anti-HSA-mAb as a function of the concentration of HSA. The ACE provided information on the binding strength from the change in effective electrophoretic mobility of the anti-HSA-mAb. These two separation techniques estimated the presence of two binding sites. The equilibrium dissociation constant values obtained by CZE and ACE were found to be 2.26·10(-6) M for anti-HSA-mAb·HSA, 1.22·10(-6) M for anti-HSA-mAb·(HSA)2 and 4.45·10(-8) M for anti-HSA-mAb·HSA, 1.08·10(-7) M for anti-HSA-mAb·(HSA)2 , respectively. The dissociation constant data obtained by ACE were in congruence with the values obtained by ITC (2.74·10(-8) M, 1.04·10(-7) M). This article is protected by copyright. All rights reserved.
- Anti-glycative effects of asiatic acid in human keratinocyte cells. [JOURNAL ARTICLE]
- Biomedicine (Taipei) 2014.:19.
Background: Human skin keratinocyte (HaCaT) cells served to examine effects of asiatic acid (AA) at 1, 2, 4 and 8 μM against advanced glycative endproduct (AGE)-modified bovine serum albumin (BSA) induced glycative stress. Results: AGE-BSA treatment reduced cell viability; and increased reactive oxygen species, nitric oxide, protein carbonyl, interleukin (IL)-1beta and tumor necrosis factor-alpha levels in HaCaT cells. Yet AA pretreatments decreased these oxidative and inflammatory factors, dose-dependently lowering nitric oxide synthase activity and expression. AGE-BSA raised activity and expression of caspase-3 and caspase-8. AA pretreatments at 2-8 μM decreased activity and expression of these two caspases. AGE-BSA declined collagen I expression, but enhanced matrix metalloproteinase (MMP)-1, MMP-8 and MMP-9 protein expression. AA pretreatments at 2-8 μM maintained collagen I expression, and reduced three MMPs expression. AGE-BSA also up-regulated RAGE (receptor of AGE), p-p38 and p-JNK expression. AA pretreatments at 2-8 μM suppressed RAGE expression, and at 1-8 μM down-regulated p-p38 and p-JNK expression. Conclusion: Asiatic acid, via its anti-glycative activity, could protect skin. Thus, this compound could be developed as an external agent and applied for personalized medicine.
- A comparative analysis on the binding characteristics of various mammalian albumins towards a multitherapeutic agent, pinostrobin. [JOURNAL ARTICLE]
- Exp Anim 2014 Dec 16.
The interaction of pinostrobin (PS), a multitherapeutic agent with serum albumins of various mammalian species namely, goat, bovine, human, porcine, rabbit, sheep and dog was investigated using fluorescence quench titration and competitive drug displacement experiments. Analysis of the intrinsic fluorescence quenching data revealed values of the association constant, Ka in the range of 1.49 - 6.12 × 10(4) M(-1), with 1:1 binding stoichiometry. Based on the PS-albumin binding characteristics, these albumins were grouped into two classes. Ligand displacement studies using warfarin as the site I marker ligand correlated well with the binding data. Albumins from goat and bovine were found to be closely similar to human albumin on the basis of PS binding characteristics.
- Serum albumin and α-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor Imatinib. [Journal Article]
- Int J Parasitol Drugs Drug Resist 2014 Dec; 4(3):287-95.
In the search for new drugs and drug targets to treat the flatworm disease schistosomiasis, protein kinases (PKs) have come under particular scrutiny because of their essential roles in developmental and physiological processes in schistosome parasites. In this context the application of the anti-cancer Abl tyrosine kinase (TK) inhibitor Imatinib (Gleevec/Glivec; STI-571) to adult Schistosoma mansoni in vitro has indicated negative effects on diverse physiological processes including survival. Motivated by these in vitro findings, we performed in vivo experiments in rodent models of S. mansoni infection. Unexpectedly, Imatinib had no effect on worm burden or egg-production. We found that the blood components serum albumin (SA) and alpha-1 acid glycoprotein (AGP or orosomucoid) negated Imatinib's deleterious effects on adult S. mansoni and schistosomula (post-infective larvae) in vitro. This negative effect was partially reversed by erythromycin. AGP synthesis can increase as a consequence of inflammatory processes or infection; in addition upon infection AGP levels are 6-8 times higher in mice compared to humans. Therefore, mice and probably other rodents are poor infection models for measuring the effects of Imatinib in vivo. Accordingly, we suggest the routine evaluation of the ability of AGP and SA to block in vitro anti-schistosomal effects of small molecules like Imatinib prior to laborious and expensive animal experiments.
- Hybrid bioartificial liver support in cynomolgus monkeys with D-galactosamine-induced acute liver failure. [Journal Article]
- World J Gastroenterol 2014 Dec 14; 20(46):17399-406.
To evaluate a hybrid bioartificial liver support system (HBALSS) in cynomolgus monkeys with acute liver failure.To establish a model of acute liver failure, 0.3 g/kg of D-galactosamine was injected intravenously into cynomolgus monkeys. Chinese human liver cells were introduced into a perfusion bioreactor to carry out hybrid bioartificial liver support treatment. Forty-eight hours after the injection, one group of cynomolgus monkeys received HBALSS care, and a second experimental group received no treatment. Clinical manifestations of all animals, survival time, liver and kidney functions and serum biochemistry changes were recorded. Simultaneous detection of the number, viability and function of hepatocytes in the hybrid bioartificial liver were also performed.Forty-eight hours after the injection of D-galactosamine, serum biochemistry levels were significantly increased, whereas albumin levels and the Fischer index were significantly reduced compared to baseline (all Ps < 0.05). Of the ten monkeys in the HBALSS treatment group, five survived, with an average duration of survival of 128 ± 3 h. All cynomolgus monkeys in the control group died, with a duration of survival of 112 ± 2 h. Survival time was significantly longer with HBALSS treatment (P < 0.05). Moreover, the number, viability and function of hepatocytes were maintained at a high level with HBALSS.The novel hybrid bioartificial liver plays a significant role in liver support by significantly reducing serum biochemistry levels and extending animal survival time.
- Simultaneous targeting of two ligand-binding sites on VEGFR2 using biparatopic Affibody molecules results in dramatically improved affinity. [JOURNAL ARTICLE]
- Sci Rep 2014.:7518.
Angiogenesis plays an important role in cancer and ophthalmic disorders such as age-related macular degeneration and diabetic retinopathy. The vascular endothelial growth factor (VEGF) family and corresponding receptors are regulators of angiogenesis and have been much investigated as therapeutic targets. The aim of this work was to generate antagonistic VEGFR2-specific affinity proteins having adjustable pharmacokinetic properties allowing for either therapy or molecular imaging. Two antagonistic Affibody molecules that were cross-reactive for human and murine VEGFR2 were selected by phage and bacterial display. Surprisingly, although both binders independently blocked VEGF-A binding, competition assays revealed interaction with non-overlapping epitopes on the receptor. Biparatopic molecules, comprising the two Affibody domains, were hence engineered to potentially increase affinity even further through avidity. Moreover, an albumin-binding domain was included for half-life extension in future in vivo experiments. The best-performing of the biparatopic constructs demonstrated up to 180-fold slower dissociation than the monomers. The new Affibody constructs were also able to specifically target VEGFR2 on human cells, while simultaneously binding to albumin, as well as inhibit VEGF-induced signaling. In summary, we have generated small antagonistic biparatopic Affibody molecules with high affinity for VEGFR2, which have potential for both future therapeutic and diagnostic purposes in angiogenesis-related diseases.