Features of T-cell subset composition in a D-galactose-induced senescence mouse model.

Long-term administration of D-galactose induces oxidative stress and accelerates normal age-related changes. Hence, the D-galactose-treated rodent model has been widely used for aging research. In this study, we examined the immunological characteristics, especially CD4+ T-cell subset composition, of D-galactose-induced aging model mice to evaluate the model's utility in immunosenescence studies. The spleens of aging model mice subjected to repeated subcutaneous injections of D-galactose exhibited significant increases in T cells with the memory phenotype (CD62Llow CD44high) and individual T-cell subsets (Th1, Th2, Th17 and Treg). Furthermore, cells with the phenotype of T follicular helper (Tfh) cells were spontaneously increased. The features of T-cell subset composition in D-galactose-treated mice were in close agreement with those observed in normal aged mice and appeared to mimic the currently known normal aging processes associated with T-cell homeostasis. Our results suggest that D-galactose-induced aging models would be useful for immunosenescence studies focusing on T-cell homeostasis and give valuable insight into age-related immune system dysregulation.

Different sensitivity to the suppressive effects of isoflurane anesthesia on cardiorespiratory function in SHR/Izm, WKY/Izm, and Crl:CD (SD) rats.

Isoflurane is a widely used anesthetic, but its effects with increase in inspired concentration on cardiovascular function have not yet been clarified in rodents. Additionally, there are only a few studies comparing isoflurane-induced cardiorespiratory effects between rat strains. Thus, we investigated the differences in cardiorespiratory responsiveness to increasing concentration of inspired isoflurane in SHR/Izm, WKY/Izm and Crl:CD (SD) rats, by increasing the setting values of vaporizer's dial indicator. The rats were anesthetized with 1.5% isoflurane, and electrocardiograms, blood pressure, and respiratory rate were recorded simultaneously. Thereafter, the inspired concentration was increased stepwise to 2%, 3%, 4%, and 5%, and cardiorespiratory parameters were obtained at each concentration. Under anesthesia at more than 4%, although prolongation of the RR and PR intervals was observed in all strains, shortening of the QTC interval was found only in SHR/Izm rats. From frequency domain analysis of heart rate variability, an increase in LF/HF ratio and a decrease of HF components were observed in SHR/Izm and WKY/Izm rats, respectively, with 5% isoflurane anesthesia. Blood pressure and heart rate were remarkably reduced in SHR/Izm rats at higher concentrations, whereas the reduction was smallest in WKY/Izm rats among the three strains examined. Respiratory rate was inspired concentration-dependently decreased in all strains. These results suggested that SHR/Izm rats are more sensitive to suppressive effects of isoflurane anesthesia on cardiovascular function among these rat strains.

Pulmonary inflammation in brown Norway rats: possible association of environmental particles in the animal room environment.

Brown Norway (BN) rats have been found to develop granulomatous pneumonia with high spontaneous incidence under normal husbandry conditions. In our laboratory, ambient particles from the animal housing environment were suspected to be involved in the pathogenesis of these pulmonary lesions. In the present study, we correlated the histopathology of spontaneous granulomatous pneumonia with the cytology of bronchoalveolar lavage fluid (BALF) analysis and animal room particle counts. The results show that the sum of the macroscopic lesion score in the lung correlated with the number of eosinophils in the BALF. Microscopically, the severity of granulomatous lesions was significantly correlated with both pulmonary eosinophils and the number of eosinophils in the BALF, but not with those of neutrophils or lymphocytes. In addition, the histological features of the lesions were not influenced by housing conditions or sensitization with ovalbumin. Ambient particles (0.3-1.0 microm in diameter) in the animal room environment were measured and compared with the number of eosinophils in BALF. Interestingly, there was a significant correlation between them, suggesting a possible relationship between environmental particles and the pathogenesis of granulomatous pneumonia in BN rats. However, further study is needed to clarify the pathogenic mechanism.

The evaluation of whole-body plethysmography as a semiautomated method for analysis of emesis in the house musk shrew (Suncus murinus).

We analyzed the cisplatin-induced emetic responses of Suncus murinus by observation of both videorecorded behavior and changes in peak expiratory flow (PEF) as monitored by whole-body plethysmography. Analysis of the PEF data by use of a macro program revealed emesis-related changes in PEF. Cisplatin dose-response curves obtained by both methods showed similar emesis profiles. In addition, our PEF-based analytical method could be used to assess emesis changes induced by various other emetogens (veratrine hydrochloride, nicotine bitartrate, and copper sulfate) and confirmed the efficacy of the antiemetic drugs ondansetron, metoclopramide, and GR205171 in the cisplatin-induced emesis model. These results demonstrate that the use of whole-body plethysmography to follow changes in PEF was an effective semiautomated method of assessing emetic responses in Suncus murinus. This novel semiautomated method may provide an objective, sensitive, and efficient way to study emesis in animal models.

Orally active 4-amino-5-diarylurea-furo[2,3-d]pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2.

During our effort to develop dual VEGFR2 and Tie-2 inhibitors as anti-angiogenic agents for cancer therapy, we discovered 4-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)- aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (8a) possessing strong inhibitory activity at both the enzyme and cellular level against VEGFR2 and Tie-2. Compound 8a demonstrated high pharmacokinetic exposure through oral administration, and showed marked tumor growth inhibition and anti-angiogenic activity in mouse HT-29 xenograft model via once-daily oral administration.