Biomedical subjects
Publications and source records attributed to H Yagi.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
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The time course of brain accumulation of radiolabelled human serum albumin ((125)I-HSA) injected intravenously and the transfer of (125)I-HSA from blood to brain were evaluated in DDD mice using a double isotope technique. The brain accumulation of (125)I-HSA at 3 and 9 h but not at 24 h postinjection and the brain transfer rates were significantly higher in 22-month-old DDD mice than in 4-month-old ones. The brain transfer rates of (125)I-HSA were measured also in senescence accelerated prone mice (SAM-P/8) with age-related deficits in learning and memory, and in senescence accelerated resistant mice (SAM-R/I) without these deficits. The brain transfer rates were significantly higher in 13-month-old SAM-P/8 and 22-month-old SAM-R/1 than in 3-month-old mice of the same strains, respectively. The mean brain transfer rates in five regions observed in 22-month-old DDD mice, 22-month-old SAM-R/1 and 13-month-old SAM-P/8 increased by 31%, 41% and 51% compared with corresponding values in 3- or 4-month-old mice of the same strains. DDD mice and SAM-R/1 mice with normal characteristics of aging showed similar age-related significant changes in brain transfer rates. Age-related increase in the brain transfer rate was manifested at the youngest age in SAM-P/8 among the three strains examined. These findings show that the transfer of human serum albumin into the mouse brain increases with aging and suggest that the barrier function in the mouse brain against macromolecules changes with aging.
Adenovirus-mediated gene transfer has been widely used in gene therapy for congenital metabolic, cardiovascular, and malignant diseases. It has been reported that a gene transfer technique into transplanted organs may suppress rejection reactions and inhibit preservation injury. However, the magnitude of transgene expression in organs preserved at a cold temperature remains to be determined. In this study, we compared the transgene expression using vascular endothelial growth factor receptor (VEGFR)-mediated adenoviral vector at cold versus warm temperatures alone and combined with hyperbaric oxygen in cold-preserved organs. The transgene expression by porcine endothelial cells transduced with adenoviral vector was significantly higher after a 24 hour-incubation at warm temperature than after a 1 hour-incubation with warm or cold temperature. Moreover, the transgene expression of after a 1-hour incubation at cold temperature was significantly lower than a 1-hour incubation at warm temperature. The VEGFR-mediated adenoviral vector augmented transgene expression during a 1-hour incubation at cold temperature compared to the control vector. A/J skin graft survival in C3H mice was significantly prolonged compared to control or standard vector with CTLA4Ig cDNA using VEGFR-mediated adenoviral vector with CTLA4Ig cDNA in a 1-hour cold preservation. Furthermore, combined use of VEGFR-mediated adenoviral vector with CTLA4Ig cDNA plus FK506 showed an augmented effect on graft prolongation. It is concluded that adenovirus-mediated gene transfer in 1-hour cold-preserved organ is difficult compared to that in the warm condition. However, VEGFR-mediated gene transfer can augment the transgene expression in 1-hour cold-preserved organs, followed by the effective suppression of rejection reactions in allogeneic transplantation.
This study examined age-dependent deficits in the learning and memory of fear conditioning, using a newly developed senescence-accelerated mouse (SAMP8) model of age-related brain dysfunction and its genetically related inbred strain (SAMR1). The mice were classically conditioned to tone by giving aversive foot shocks in a distinct experimental box (context). After conditioning, fear in response to the original context without the tone and to the tone in a different context were tested with no shocks. Freezing behavior was used as a reliable index of fear. At 4 and 8 months, contextual fear was weaker in the accelerated senescence-prone SAMP8 mice than in the accelerated senescence-resistant SAMR1 mice. However, at 1 and 2 months, both SAMP8 and SAMR1 mice showed significant contextual fear to equivalent levels. Aging did not affect the fear response to tone. These results indicate that SAMP8 mice have age-related learning and memory deficits in their fear response evoked by contextual but not explicit tone stimuli. Age-related hippocampal dysfunction is suggested to be the cause of these age-related deficits in contextual fear conditioning in SAMP8 mice.
In a series of inbred Senescence-Accelerated mice (SAM) strains, accelerated-senescence prone SAMP substrains show early onset and rapid advancement of senescence. SAMP8 and SAMP10, in particular, exhibit a significant age-related deterioration in memory and learning for passive and active avoidance tasks with, respectively, a low and high incidence of systemic senile amyloidosis. In the brains of both SAMP8 and SAMP10 strains, we have found numerous morphological alterations. Here we review the changes seen in both neuronal or glial components in SAMP8/P10 brains. They may serve as markers of the neuronal degeneration leading to the deficits in learning and memory.
The rates of reactions of the cis and trans (benzylic 7-hydroxyl group relative to epoxide oxygen) bay-region 7,8-diol 9,10-epoxides of benzo[a]pyrene (DE-1 and DE-2, respectively) in solutions containing human serum albumin (HSA) and a model system of micelles of the nonionic detergent Tween-80 have been determined as a function both of HSA or Tween-80 concentrations and of pH. The effect of increasing concentrations of both HSA and Tween-80 is to retard substantially the rates of reaction of DE-1 and DE-2 over the pH range 5-7. The rate data are consistent with a mechanism in which the diol epoxides physically associate with HSA or Tween-80, and the rates of reaction of the association complexes are reduced compared to those of free diol epoxides. The limiting rate constants for reaction of the diol epoxide.HSA and diol epoxide.Tween-80 complexes are dependent on pH. The rate data are best accommodated by a mechanism in which the complexes react by two competing pathways, one whose rate is proportional to hydronium ion activity, and the second whose rate is pH-independent. These reactions of the association complexes are therefore kinetically analogous to the acid-catalyzed and spontaneous reactions of free diol epoxide. The spontaneous reaction of the (DE-2).HSA complex results in approximately 10% covalent binding of diol epoxide to the protein, whereas the acid-catalyzed reaction of the complex results in significantly less covalent binding. The balance of the products consists of tetraols formed by hydrolysis of the diol epoxide.
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The restricted ability of deoxyribonuclease I/snake venom phosphodiesterase digestion to liberate deoxyadenosine (dA) nucleotide adducts of polycyclic aromatic hydrocarbons from DNA, first observed by Dipple and Pigott with the bay-region diol epoxide adducts of 7,12-dimethylbenz[a]anthracene, has been observed with the dA adducts of benz[a]anthracene and benzo[c]phenanthrene diol epoxides. The micrococcal nuclease/spleen phosphodiesterase digestion used in the original 32P postlabeling procedure developed by Randerath to determine DNA adducts also failed to liberate dA nucleotide adducts quantitatively. Thus either method can potentially lead to an underestimation of the extent to which dA has been modified in DNA. The two digestion procedures exhibit systematic and mostly opposite stereoselectivity in the pattern of which dA adducts are resistant to digestion, which suggest that these adducts may have preferred orientations within modified DNA that are determined by whether they have the R or S configuration at C-1, the point of attachment between the exocyclic amino group of dA and the hydrocarbon; this in turn is dictated by the configuration about the precursor benzylic epoxide carbon and the cis versus trans nature of epoxide opening during adduct formation.
Purine deoxyribonucleoside 3'-phosphates were reacted separately with the four configurational isomers of benzo[c]phenanthrene 3,4-dihydrodiol 1,2-epoxide. Products resulting from the cis and trans opening of the epoxide ring by the exocyclic amino groups of deoxyadenosine and deoxyguanosine 3'-phosphates were separated by high-pressure liquid chromatography and identified by comparison of the observed circular dichroism spectra with the known spectra for the corresponding nucleoside adducts. The 16 structurally identified benzo[c]phenanthrene-purine deoxyribonucleoside 3'-phosphate adducts were then separately postlabeled according to the Randerath method, and the positions of the individual bisphosphates were mapped by thin-layer chromatography. Chromatographic conditions were developed that allowed separation of the four adducts for 3 of the 4 dihydrodiol epoxide isomers.
P-Postlabeling assays were used to monitor the binding to epidermal DNA that resulted from the application of each of the four configurational isomers of benzo[c]phenanthrene 3,4-dihydrodiol 1,2-epoxide to mouse skin in vivo. For three of these configurational isomers, there was a reasonable correlation between the relative level of binding to epidermal DNA and the known tumorigenic effects of these compounds. However, for the 4(S),3(R)-dihydrodiol 2(S),1(R)-epoxide, the tumorigenic response was considerably greater in relation to the level of DNA modification than was the case for the other isomers. This greater tumorigenic response was consistent with previous observations indicating that this isomer was more mutagenic, at equivalent levels of DNA modification, than the other two tumorigenic dihydrodiol epoxides. Additionally, the 4(S),3(R)-dihydrodiol 2(S),1(R)-epoxide reacts with DNA to generate predominantly (approximately 80%) adducts on the amino group of adenine residues. These findings might imply a greater intrinsic biological effect of such adenine adducts with respect to the other major adduct formed on the amino group of guanine residues.
Reactions of diol epoxide metabolites of carcinogenic polycyclic aromatic hydrocarbons with DNA are thought to initiate the carcinogenic process. Although formation of a benzo[a]pyrene (BaP) diol epoxide-deoxyguanosine adduct has been held responsible for biological activity, the more potent carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA) binds extensively to deoxyadenosine residues in DNA, suggesting that hydrocarbon carcinogen-deoxyadenosine adducts may be instrumental in tumour initiation. Because the bay region diol epoxides of benzo[c]phenanthrene (BcPh) are very active tumour initiators, and the relative activities of the four configurationally isomeric 3,4-diol 1,2-epoxides (Fig. 1) are known, we examined their reactions with DNA. Each BcPh diol epoxide isomer exhibits a remarkable preference for covalent binding to DNA over hydrolysis, each yields a unique distribution of products with the nucleosides of DNA and each reacts extensively with deoxyadenosine residues in DNA. The relative tumour initiating activities of these stereoisomers is best reflected by the relative yields of one of the deoxyadenosine adducts formed.
OBJECTIVE: The enhancement of ascites following intravenous administration of Gd-DTPA on MRI was investigated. MATERIALS AND METHODS: Magnetic resonance imaging was performed in 20 patients with ascites (8 peritoneal carcinomatosis, 2 tuberculous peritonitis, 8 liver cirrhosis, 1 nephrotic syndrome, 1 peritoneal adhesion), and T1-weighted SE images were obtained before and 15-20 min following intravenous administration of Gd-DTPA (0.1 mmol/kg). RESULTS: There were 10 exudative ascites and 10 transudative ascites. Eight of 10 exudative ascites showed enhancement, in contrast to none of 10 transudative ascites. The precontrast signal intensity ratios (SIRs) of exudative ascites were significantly higher (p < 0.05) than those of transudative ascites, and the postcontrast SIRs of exudative ascites were significantly higher (p < 0.01) than those of transudative ascites. This difference was thought to be caused by increased peritoneal permeability and higher protein concentration in the cases with exudative ascites in this study. CONCLUSION: It is concluded that enhancement of ascites on MRI obtained 15-20 min after intravenous administration of Gd-DTPA is not an uncommon finding in exudative ascites (especially associated with peritoneal carcinomatosis).
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