These findings suggest that 521T>C, existing commonly in SLCO1B1*5, *15 and *15+C1007G, is the key single nucleotide polymorphism (SNP) that determines the functional properties of SLCO1B1*5, *15 and *15+C1007G allelic proteins and that decreased activities of these variant proteins are mainly caused by a sorting error produced by this SNP.
To address the issue of excess polyethylene glycol (PEG)-lipid degradation observed when PEG-modified liposomes are prepared using the pH-gradient method, a concept using a novel PEG-modification method, called the post-modification method, was proposed and evaluated. To assess the proof concept, a preservation-stability study and a pharmacokinetic study were performed that compared the conventional PEG-modification method, called the pre-modification method, with the post-modification method. The results show that PEG-lipid degradation could be markedly inhibited in the post-modification method. Furthermore, the post-modification method could be used without any manufacturing process difficulties, especially with high PEG-lipid content. In addition, a higher blood circulation capability was observed in the post-modification method. Through comparative studies, it was found that the post-modification method was advantageous compared to the pre-modification method. In conclusion, the post-modification method has the potential to be a novel PEG-modification method that can achieve a higher preservation stability of PEG-lipid, a greater ease of manufacturing, and a higher blood circulation capability, especially in the manufacturing of pH-gradient liposomal products.
Abstract-Diltiazem, a new 1,5-benzothiazepine derivative, antagonized calcium ion and thus caused a reduction in the contractile force of isolated papillary muscle. The antagonistic ratio of diltiazem to calcium ion was estimated to be approx. 1 : 100. A lower concentration of diltiazem (2.2 yX 10-13 M) decreased the contractile force without affecting significantly the intracellularly recorded resting and action potentials. When the concentration of the compound was increased to 2.2 x 10-5 M, only the maximum rate of rise of the action potential was reduced, while the other parameters of the ac tion potential were also affected at 1
In the present study, we analyzed the function of a novel mutation (c.1628T4G, p.Leu543Trp) in the solute carrier organic anion transporter (SLCO) 1B1 gene, encoding organic anion transporting polypeptide (OATP) 1B1, which was identified in a patient with pravastatin-induced myopathy. OATP1B1 variants carrying the mutation (OATP1B1*1a þ c.1628T4G or *1b þ c.1628T4G) showed a reduced transporting activity toward typical substrates and pravastatin compared with the activity of the references (OATP1B1*1a or *1b). This was due to reduction in V max values of the variants, not due to change in their K m values. OATP1B1*1b þ c.1628T4G was normally expressed on the plasma membrane of HEK293 cells at the same level as that of OATP1B1*1b. Taken together, our results suggest that the mutation c.1628T4G (p.Leu543Trp) reduced the function of OATP1B1 probably due to decrease in turnover rate of one OATP1B1 molecule rather than impairment of protein sorting to the plasma membrane.
Isotactic (it) and syndiotactic (st) poly(methyl methacrylate)s (PMMAs) were assembled on a poly(ethylene terephthalate) cell disk (as a solid substrate), which is normally used for cell culture, to produce ultrathin stereocomplex films. Static contact angles of the films using air bubbles in aqueous phase revealed the stepwise assembly of both polymers. More L929 fibroblast cells adhered and were flattened on the ultrathin stereocomplex films, compared to homogeneous PMMA films and to spin-coated films comprised of a mixed solution of it- and st-PMMAs with a molar ratio of 1 : 2, which is the stoichiometry of a stereocomplex. The difference in the number of adherent cells was greatest after the first 3 h of incubation. Pre-adsorption of proteins, which are related to cell adhesion, onto the stereocomplex film potentially modulated the cell-adhesive properties. Fresh whole human blood did not coagulate on the complex film for 20 min, although blood coagulated after 15 min on the homogeneous films and on the 1 : 2 mixed film. Platelets did not adhere onto the complex films after 15 min of incubation, which was consistent with the results of blood coagulation. These observations indicate that the stereocomplex formation of PMMAs on the surface of films strongly affects the bioactivity of these films.
Stereoregular poly(methyl methacrylate)s (PMMAs) were stepwise assembled on a quartz crystal microbalance (QCM) substrate after the immersion of the QCM into alternating acetonitrile solutions at ambient temperature. A quantitative QCM analysis at each step showed stereocomplex formation on the substrate surface. The adsorption of bovine serum albumin (BSA) onto stereocomplex films with a molecularly regulated nanostructure was analyzed quantitatively. The adsorption constant and the maximum adsorption amount, calculated by the assumption of Langmuir-type adsorption, showed that BSA adsorbed with a relatively weak interaction onto the stereocomplex films. The BSA adsorption onto the stereocomplex films occurred in an end-on manner, with a smaller adsorption constant than for that onto individual spin-coated films. The amount of BSA adsorbed was significantly affected by the molecular weight of syndiotactic PMMA. Attenuated total reflection spectra indicated that BSA adsorbed onto the films with or without denaturing.
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