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Acrolein, a highly reactive α,β-unsaturated aldehyde, is a compound to which humans are exposed in many different situations and often causes various human diseases. This paper ...summarizes the reports over the past twenty-five years regarding disease-associated acrolein detected in clinical patients and the role acrolein plays in various diseases. In several diseases, it was found that the increased acrolein acts as a pathogenetic factor. Thus, we propose the utility of over-produced acrolein as a substrate for a promising therapeutic or diagnostic method applicable to a wide range of diseases based on an in vivo synthetic chemistry strategy.
Efflux transport systems are essential to suppress the absorption of xenobiotics from the intestinal lumen and protect the critical tissues at the blood-tissue barriers, such as the blood–brain ...barrier. The function of drug efflux transport is dominated by various transporters. Accumulated clinical evidences have revealed that genetic variations of the transporters, together with coadministered drugs, affect the expression and/or function of transporters and subsequently the pharmacokinetics of substrate drugs. Thus, in the preclinical stage of drug development, quantitative prediction of the impact of efflux transporters as well as that of uptake transporters and metabolic enzymes on the pharmacokinetics of drugs in humans has been performed using various in vitro experimental tools. Various kinds of human-derived cell systems can be applied to the precise prediction of drug transport in humans. Mathematical modeling consisting of each intrinsic metabolic or transport process enables us to understand the disposition of drugs both at the organ level and at the level of the whole body by integrating a variety of experimental results into model parameters. This review focuses on the role of efflux transporters in the intestinal absorption and brain distribution of drugs, in addition to recent advances in predictive tools and methodologies.
Intestinal permeability is a critical factor for orally administered drugs. It can be facilitated by uptake transporters or limited by efflux transporters and metabolic enzymes in the intestine. The ...present study aimed to characterize the Ussing chamber system incorporating human intestinal tissue as an in vitro model for investigating the impact of intestinal uptake/efflux transporters on the intestinal absorption of substrate drugs in humans. We confirmed the functions of major intestinal uptake/efflux drug transporters in freshly isolated human jejunum sections by demonstrating a significant decrease in the mucosal uptake of cefadroxil (peptide transporter 1) and methotrexate (proton-coupled folate transporter), mucosal-to-serosal permeability of ribavirin (concentrative nucleoside transporters/equilibrative nucleoside transporters), and serosal-to-mucosal permeability of P-glycoprotein and breast cancer resistance protein substrates in the presence of their typical inhibitors. The mucosal-to-serosal apparent permeability coefficients (P
) of 19 drugs, including substrates of drug transporters and cytochrome P450 3A, ranged from 0.60 × 10
to 29 × 10
cm/s and showed a good correlation with reported fraction of an oral dose that enters the gut wall and passes into the portal circulation with escaping intestinal metabolism (FaFg) values in humans. Furthermore, the P
values for cefadroxil, methotrexate, and ribavirin in the presence of the corresponding transporter inhibitors underestimated the FaFg of these drugs, which clearly showed that intestinal uptake transporters facilitate their intestinal absorption in humans. In conclusion, the functions of major intestinal uptake/efflux drug transporters could be maintained in freshly isolated human jejunum sections. The Ussing chamber system incorporating human intestinal tissue would be useful for evaluating the impact of intestinal uptake/efflux transporters on the intestinal absorption of various types of drugs in humans. SIGNIFICANCE STATEMENT: Although previous studies have predicted the intestinal absorption of drugs in humans using the Ussing chamber system incorporating human intestinal tissue, there is little systematic information about drug transport mediated by multiple transporters in this system. We confirmed the functions of major intestinal uptake/efflux transporters in freshly isolated human jejunum sections and demonstrated that the mucosal-to-serosal apparent permeability coefficient of various types of drugs showed a good correlation with reported human FaFg values.
It was clarified that strength mis-match induces a significant effect on stable crack growth resistance in the previous paper. Extensive experimental and numerical works should be done for ...establishing a method for assessing a defect in heterogeneous material such as weld joints. This paper describes the effects of strength mis-match and plastic restraint on equivalent plastic strain at the stable crack tip. The CTOD-R curves are experimentally obtained using homogeneous and bimaterial compact specimens produced by diffusion bonding. In the under-matched bimaterial specimens, the ratios of the width of low strength region including a notch to the thickness (H/t) are 1/4 and 1/2. The shallow (a/W=0.15) and deep (a/W=0.5) notched specimens are tested to study the effect of plastic restraint on ductile crack behavior. A 3-dimensional analysis is carried out to get the strain near the crack tip using the results of performed experiments. The equivalent platic strain is expected to be a characteristic value independent of the existence of strength mis-match in the ductile fracture process. In the range of stress triaxiality obtained in the present works, the equivalent plastic strain does not change during the stable crack growth irrespectively of the difference in stress triaxiality. The load-load displacement curve obtained from the stable crack growth simulation using the equivalent plastic strain agrees well with the data obtained from the compact test.
Stable crack resistance (R) curves were frequently used for assessing the integrity of structures containing defects in loading regimes. In that case, R curves are treated as characteristics of ...materials, but it is known that R curves are actually affected by various factors. The effect of strength mis-match on stable crack growth resistance is discussed in this paper. In order to compare the R curve of bimaterial materials with that of homogeneous ones, compact type tests are carried out. 3-dimensional FEM analyses taking into account the stable crack growth are also executed using the result of performed experiments. In the case of over-matched specimens (high strength region including a notch are surrounded with low strength region), dCTOD/da apparently increases comparing with homogeneity. In the case of under-matched specimens (opposite of the previous case), dCTOD/da apparently decreases comparing with homogeneity. Strength mis-match affects on CTOD(J)-R curves. On the other hand, the equivalent plastic strain at stable crack tip obtained from 3D analyses may be generally independent of the strength mis-match during ductile fracture process.
The numerical results of stable crack growth simulation (3D FE analysis) using equivalent plastic strain showed good agreement with the experimental results irrespective of the heterogeneous specimen ...presented in the previous papers. From the results, it can be seen that the equivalent plastic strain is a characteristic value that is independent of the existence of strength mis-match in ductile fracture process. However, in order to obtain the equivalent plastic strain, it is needed to perform 3D FE calculation. On the other hand, the local displacement obtained from the experimental measurement is beneficial regardless of numerical simulation. The local displacement is influenced by the measurement distance from the initial crack tip. The value of local displacement measured at the shifted location of crack tip does not change with an increase in stable crack growth. A similar relation between equivalent plastic strain and stable crack growth was also observed in the previous publication of authors. The local displacement measured at the mid-thickness is independent of the existence of strength mis-match. While, in practice, the local displacement is measured on the surface, discussion is about the effect of the strength mis-match on the ratio of local displacement at the surface to its value at the mid-thickness. The strain estimated by the local displacement can be used as a substitute for the equivalent plastic strain. Moreover, it is expected to express the stable crack growth resistance of mis-matched joint in terms of the local displacement measured at the surface of specimen.
A failure assessment diagram (FAD) approach is strongly expected to be useful for the simplified fracture assessment. The applicability of FAD approach to ductile fracture strength analysis was ...verified using a heavy section 9%Ni steel plate and its weld joints, in use for large scale LNG storage tank, in this paper. Various ductile fracture tests using compact and center cracked panel specimens were carried out in order to observe stable crack extension behavior and to estimate failure strength. The obtained results are summarized as follows : (1) When the assessment by means of Option 2 FADs is considered, an appropriate failure assessment curve (FAC) which takes account of actual fracture behavior should be selected. (2) The accuracy of assessment by FAD approach was strongly affected by the precision of estimation of limit load for Lr. (3) In case of 9%Ni steel, stable crack behavior agreed well with FAC regardless the specimen thickness. (4) Maximum load measured in experiments and its prediction by FAD were in good agreement regardless the specimen configuration. In case of 9%Ni weld joints, however, FAD approach showed a poor accuracy in the ductile tearing analysis and the maximum load prediction.
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