KK mice and KK-Ay mice were examined for age related changes in blood and urinary biophysiological parameters. Blood hemoglobin A1c levels were significantly higher in KK-Ay and KK mice as compared to non-diabetic ddY mice. In both diabetic mice, especially KK-Ay mice, plasma insulin levels markedly increased at 2 to 4 months of age, and the urinary glucose and microalbumin levels and albumin-to-creatinine ratios increased dependent on age. Plasma thrombomodulin levels significantly increased at 2 to 4 months of age in both KK and KK-Ay mice. Mild enlargement of mesangial matrix and segmental proliferative glomerular nephritis were revealed in KK and KK-Ay mice, respectively, at 4 months of age. KK-Ay mice with insulin resistance and high urine mAlb level might be useful as models for the early stage of diabetic nephropathy.

Although several previous studies have been published on the effects of dipeptidase-4 (DPP-4) inhibitors in diabetic hemodialysis (HD) patients, the findings have yet to be reviewed comprehensively. Eyesight failure caused by diabetic retinopathy and aging-related dementia make multiple daily insulin injections difficult for HD patients. Therefore, we reviewed the effects of DPP-4 inhibitors with a focus on oral antidiabetic drugs as a new treatment strategy in HD patients with diabetes. The following 7 DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and saxagliptin. All of these are administered once daily with dose adjustments in HD patients. Four types of oral antidiabetic drugs can be administered for combination oral therapy with DPP-4 inhibitors, including sulfonylureas, meglitinide, thiazolidinediones, and alpha-glucosidase inhibitor. Nine studies examined the antidiabetic effects in HD patients. Treatments decreased hemoglobin A1c and glycated albumin levels by 0.3% to 1.3% and 1.7% to 4.9%, respectively. The efficacy of DPP-4 inhibitor treatment is high among HD patients, and no patients exhibited significant severe adverse effects such as hypoglycemia and liver dysfunction. DPP-4 inhibitors are key drugs in new treatment strategies for HD patients with diabetes and with limited choices for diabetes treatment.

Triple-negative breast cancer (TNBC), which does not show hormone sensitivity, is a poor prognosis disease without an established targeted treatment, so that establishing a therapeutic target for each subtype is desired. In addition, microRNA (miRNA), a non-cording RNA 19-25 nucleotide-longs in length, is known to be involved in regulating gene expression. We examined miRNA expression after exposure to eribulin, MDA-MB-231 cells, non-basal-like type of TNBC cell lines, and HCC1143 cells, basal-like type of TNBC cell lines. The activity of caspase-3 significantly increased compared to the control in MDA-MB-231, whereas no significant difference was observed in HCC1143. The expression level of 20-miRNAs significantly increased compared to the control in MDA-MB-231 after exposure to eribulin. The expression level of 6-miRNAs also significantly increased compared to the control in HCC1143. In these 2 cell types, miR-125b-1 and miR-195 were commonly expressed. While the expression level of miR-125b-1 decreased in both cells, the expression level of miR-195 increased in MDA-MB-231 and decreased in HCC1143. The expression level of miR-195 targeting Wnt3a significantly decreased compared to the control in MDA-MB-231, whereas it significantly increased in HCC1143. These results showed that exposure to eribulin highly increased the expression of miR-195 while it decreased the expression of Wnt3a in non-basal-like type of TNBC. Some miRNAs are known to regulate other signaling pathways involved in human pathogenesis by regulating the Wnt signaling pathway, and miRNA can act as a tumor-suppressing gene; therefore, miR-195 may serve as a therapeutic target in non-basal-like type of TNBC.

Several tea polyphenols, particularly those containing galloyl, have antitumor affects via strong antioxidant and antiangiogenic activities. Theaflavin-3,3'-digallate (TF3), a theaflavin derivative in black tea, has 2 galloyl groups. Matrix metalloproteinases (MMPs) are associated with extracellular matrix degradation, cellular migration, and angiogenesis, and (-)-epigallocatechin-3-gallate (EGCG) is an inhibitor of MMP activity and secretion; thus one of its major actions is the inhibition of angiogenesis. However, there are few studies of angiogenesis in theaflavin derivatives. We investigated the effects of TF3 on angiogenesis in vitro. Angiogenesis was assayed using cocultured human umbilical vein endothelial cells with fibroblasts. Cells were cultivated in various concentrations of TF3 and EGCG in the presence or absence of vascular endothelial growth factor-A. After 11 days, MMP-2 and MMP-9 activities and the pro-MMP-2 protein in the medium were measured by gelatin zymography and immunoassay, respectively. Tube formation was markedly inhibited by 100 umol/L TF3 or EGCG. Even at 10 iumolIL, TF3 or EGCG inhibited tube formation. The MMP-2 and MMP-9 activities were inhibited and pro-MMP-2 protein concentrations were reduced by TF3 or EGCG in a concentration-dependent manner, regardless of the presence of vascular endothelial growth factor. The effect of TF3 was similar to that of EGCG, indicating that the tube formation of endothelial cells was suppressed via decreased both MMP-2 and MMP-9 activities in vitro. Our results demonstrate antiangiogenic activity of TF3 in vitro, and suggest possible anti-tumor effects of TF3.

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The purpose of this investigation was to determine whether there were individual pharmacokinetic differences of a drug, pravastatin. Furthermore, the percentage of subjects who showed pharmacokinetic differences was determined. A single oral dose of pravastatin 10 mg was administered to 84 Japanese healthy male subjects. Serum concentrations of pravastatin were measured for 8 hours postdose. Area under the concentration-time curve (AUC) and peak concentration (Cmax) were determined as primary evaluation parameters. An outlier was defined as follows: Outlier 1 < Q1 - (Q3 - Q1) x 1.5 or Q3+(Q3-Q1) x 1.5 < Outlier 1, Outlier 2 < Q1 - (Q3 - Q1) x 3 or Q3+ (Q3-Q1) x 3 < Outlier 2. Subjects who were outliers were regarded as having an individual difference in pharmacokinetic behavior. In AUC and Cmax, 4 of 84 subjects (4.8%) were higher outliers. Of these 4 subjects, 2 were high outliers in both AUC and Cmax. No subjects were low outliers. It was concluded that a significant individual difference in the pharmacokinetics of pravastatin was observed in 4.8% of the subjects (4/84).

Glioblastoma is the most malignant central nervous system tumor. Patients with glioblastoma are treated with a combination of surgery, radiotherapy and chemotherapy; however, this effect is not satisfactory with regard to the prognosis. It is reported that the tumor stem cells affect recurrence, and radio- and chemotherapy resistance of the tumor, and that these cells play an important role in tumorigenesis and tumor progression. Using human glioblastoma cell lines (T98G and A172), irradiated (0, 30, 60 Gy) glioblastoma cells were prepared under the same conditions as clinical therapy. We analyzed cell proliferation rate, side population analysis by fluorescence-activated cell sorting and isolation of CD133⁺ cells, and performed genetic analysis (human stem cells) on these cells. We also investigated the difference in gene expression in the cells after radiation. The stem cell-related genes were highly expressed in the CD133⁺ cells compared with the CD133⁻ cells, suggesting that the cancer stem cells may be located in these CD133⁺ cells. In the T98G cell line, the cell proliferation rate of 30-Gy irradiated cells was higher than those of non-irradiated cells and 60-Gy irradiated cells. Stem cell-related genes were highly expressed in 30-Gy irradiated CD133⁺ T98G cells. In conclusion, we suggest that CD133⁺ cells may strongly affect tumor proliferation and the resistance against radiation therapy.

Osteoarthritis OA is a degenerative disease that occurs in joints throughout the body and includes various concomitant pathologies due to possible mechanical stress, such as destruction of cartilage, hyperplasic changes, and synovial in ammation. However, there have been few studies on the mechanical stress that is the basic cause of OA. Our goal was to establish an OA model at the cellular level, by measuring in ammatory cytokines and cartilage destruction markers that are induced after a mechanical stress load. Using a human synovial sarcoma cell line SW982 cells , we provided two types of mechanical stress load for 48 hr : shaking stress amplitude 2 mm, speed range 1,000 rpm , and the addition of hydroxyapatite 5 µg/ml into the culture medium. Then we measured the phosphorylation activity of nuclear factor NF -B transcription factor in the cell lysate, and the levels of tumor necrosis factor TNF -and interleukin IL -6 as in ammatory cytokines, and the level of matrix metalloproteinase MMP -3 as a cartilage destruction marker, released in the medium. Shaking stress signi cantly induced phosphorylation of NF-B and production of TNF-, compared with untreated controls. On the other hand, hydroxyapatite stress only increased production of TNF-. Both stresses together signi cantly induced phosphorylation of NF-B and production of TNF-, IL-6 and MMP-3 rather than a single stress load. In this study, markers related to in ammation and cartilage destruction IL-6, TNF-, and MMP-3 signi cantly increased. Therefore, we suggest that the mechanical stress load conditions used in this study might be useful as an OA model.