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Articles by T Kondo
Total Records ( 23 ) for T Kondo
  H Adachi , T Kondo , R Ogawa , K Sasaki , S Morino Koga , M Sakakida , J Kawashima , H Motoshima , N Furukawa , K Tsuruzoe , N Miyamura , H Kai and E. Araki
 

Induction of heat shock protein (HSP)72 improves insulin resistance and obesity in diabetic animal models. Geranylgeranylacetone (GGA), known as an antiulcer drug, induces HSP72 and protects organs against several cellular stresses. This study investigated whether GGA administration would induce HSP72 in liver and render physiological protection against high-fat feeding in mice. A single and 4-wk oral administration of 200 mg/kg GGA was performed in high-fat diet (HFD)-fed mice. Metabolic parameters, cytokines, and gene expressions related to insulin signaling were evaluated. A single administration of GGA induced HSP72 in liver of normal chow-fed and HFD-fed mice. Insulin resistance after HFD was slightly ameliorated. Four weeks of GGA administration also increased HSP72 in liver and significantly improved insulin resistance and glucose homeostasis upon glucose challenge. Activation of c-jun NH2-terminal kinase (JNK) was attenuated, and insulin signaling was improved in the liver of HFD mice. Visceral adiposity was decreased in GGA-treated mice, accompanied by reduced leptin and increased adiponectin levels. GGA can be a novel therapeutic approach to treat metabolic syndrome as well as type 2 diabetes by improving insulin signaling and reducing adiposity. These beneficial effects of GGA could be mediated through HSP72 induction and JNK inactivation in the liver.

  A. K Stewart , A Yamamoto , M Nakakuki , T Kondo , S. L Alper and H. Ishiguro
 

Pancreatic ductal epithelium produces a HCO3-rich fluid. HCO3 transport across ductal apical membranes has been proposed to be mediated by both SLC26-mediated Cl/HCO3 exchange and CFTR-mediated HCO3 conductance, with proportional contributions determined in part by axial changes in gene expression and luminal anion composition. In this study we investigated the characteristics of apical Cl/HCO3 exchange and its functional interaction with Cftr activity in isolated interlobular ducts of guinea pig pancreas. BCECF-loaded epithelial cells of luminally microperfused ducts were alkalinized by acetate prepulse or by luminal Cl removal in the presence of HCO3-CO2. Intracellular pH recovery upon luminal Cl restoration (nominal Cl/HCO3 exchange) in cAMP-stimulated ducts was largely inhibited by luminal dihydro-DIDS (H2DIDS), accelerated by luminal CFTR inhibitor inh-172 (CFTRinh-172), and was insensitive to elevated bath K+ concentration. Luminal introduction of CFTRinh-172 into sealed duct lumens containing BCECF-dextran in HCO3-free, Cl-rich solution enhanced cAMP-stimulated HCO3 secretion, as calculated from changes in luminal pH and volume. Luminal Cl removal produced, after a transient small depolarization, sustained cell hyperpolarization of ~15 mV consistent with electrogenic Cl/HCO3 exchange. The hyperpolarization was inhibited by H2DIDS and potentiated by CFTRinh-172. Interlobular ducts expressed mRNAs encoding CFTR, Slc26a6, and Slc26a3, as detected by RT-PCR. Thus Cl-dependent apical HCO3 secretion in pancreatic duct is mediated predominantly by an Slc26a6-like Cl/HCO3 exchanger and is accelerated by inhibition of CFTR. This study demonstrates functional coupling between Cftr and Slc26a6-like Cl/HCO3 exchange activity in apical membrane of guinea pig pancreatic interlobular duct.

  T Watanabe , K Maeda , T Kondo , H Nakayama , S Horita , H Kusuhara and Y. Sugiyama
 

The clearance route and the absolute values for hepatic and renal clearance of drugs are important criteria for the selection of drug candidates. Based on pharmacokinetic theory, by assuming that uptake is the rate-determining process for the biliary excretion of drugs, organ intrinsic clearance should be simply estimated by the intrinsic uptake. In this study, to investigate whether organ clearance can be predicted from the in vitro uptake activity, we performed uptake experiments using isolated hepatocytes and kidney slices, integration plot analyses, and in vivo pharmacokinetic studies using 12 barely metabolized drugs in rats. The in vivo hepatic and renal clearance could be approximated by uptake clearance estimated from integration plot analyses, except for the renal clearance of some drugs that was relatively small. The comparison of intrinsic uptake clearance from in vitro experiments and integration plot studies revealed that in vivo hepatic uptake was well explained by uptake into isolated hepatocytes, whereas in kidney, in vivo uptake clearance was 10 to 100 times that in kidney slices and a scaling factor is required for its prediction from in vitro experiments. The organ clearance and the fraction excreted into urine could be predicted from in vitro studies except for drugs whose renal clearance was relatively small. This study suggests that the uptake process is the determining factor for organ clearance of minimally metabolized drugs, and uptake assays using isolated hepatocytes and kidney slices are useful for evaluating the uptake clearance.

  T Watanabe , K Maeda , T Kondo , H Nakayama , S Horita , H Kusuhara and Y. Sugiyama
 

The clearance route and the absolute values for hepatic and renal clearance of drugs are important criteria for the selection of drug candidates. Based on pharmacokinetic theory, by assuming that uptake is the rate-determining process for the biliary excretion of drugs, organ intrinsic clearance should be simply estimated by the intrinsic uptake. In this study, to investigate whether organ clearance can be predicted from the in vitro uptake activity, we performed uptake experiments using isolated hepatocytes and kidney slices, integration plot analyses, and in vivo pharmacokinetic studies using 12 barely metabolized drugs in rats. The in vivo hepatic and renal clearance could be approximated by uptake clearance estimated from integration plot analyses, except for the renal clearance of some drugs that was relatively small. The comparison of intrinsic uptake clearance from in vitro experiments and integration plot studies revealed that in vivo hepatic uptake was well explained by uptake into isolated hepatocytes, whereas in kidney, in vivo uptake clearance was 10 to 100 times that in kidney slices and a scaling factor is required for its prediction from in vitro experiments. The organ clearance and the fraction excreted into urine could be predicted from in vitro studies except for drugs whose renal clearance was relatively small. This study suggests that the uptake process is the determining factor for organ clearance of minimally metabolized drugs, and uptake assays using isolated hepatocytes and kidney slices are useful for evaluating the uptake clearance.

  T Kondo , Y Hashimoto , H Kobayashi , J Iizuka , T Nishikawa , M Nakano and K. Tanabe
  Objectives

We retrospectively analyzed our patients with advanced renal cell carcinoma who underwent presurgical targeted therapy with tyrosine kinase inhibitors to clarify the safety and clinical benefit. The histopathological effect of this treatment was also examined.

Methods

Between July 2005 and February 2010, nine patients with advanced renal cell carcinoma who were treated with tyrosine kinase inhibitors before surgery were the subjects of this study. Consolidative surgery was considered when these tumors showed clinical response or stable disease while on targeted therapy without evidence of disease progression at other sites.

Results

The agents used were sorafenib in seven patients and sunitinib in two. The median duration of presurgical therapy was 12.2 weeks, and seven patients had less than 4 months of treatment. Tumor reduction at 10–30% was obtained in all patients but one. Perioperative complications were observed in five of nine patients. Major complications occurred in two patients, including intraoperative excessive bleeding and delayed localized intraperitoneal abscess. Minor complications were found in three. The characteristics of the histopathological effect of tyrosine kinase inhibitors consisted of marked atrophy of the capillary sinus, confirming the pharmacological mechanisms of these agents. Other findings included nuclear pyknosis and degeneration of tumor cells.

Conclusions

Presurgical targeted therapy with tyrosine kinase inhibitors appears to be feasible in most patients with advanced renal cell carcinoma. However, the indications, the clinical benefit and the standard protocol still remain to be determined. Therapeutic effects in the histology were compatible to their pharmacological effects.

  H Hatta , K Tsuneyama , T Kondo and Y. Takano
 

Although intraoperative rapid diagnosis is conventionally performed using hematoxylin–eosin (HE)-stained specimens, the use of additional special staining, together with immunostaining techniques, has been examined in recent years to improve diagnostic accuracy. In intraoperative rapid diagnosis, immunostaining should be completed within 7–10 min, because the pathologist is typically presented with an HE-stained specimen within the same time period. We hypothesized that ultrasound may enhance antigen–antibody reactions and reduce the number of immunostaining steps. To clarify the ability of ultrasound to support immunostaining, we first created an ultrasonic generator specifically for immunostaining. Next, we explored the optimal conditions for immunostaining of formalin-fixed specimens to examine the utility of the ultrasonic generator. Finally, we tried immunostaining with the ultrasonic generator using frozen specimens to simulate intraoperative rapid diagnosis. We report herein that ultrasound enables immunostaining of frozen specimens in ~10 min. (J Histochem Cytochem 58:421–428, 2010)

  T Kondo , I. E Khattabi , W Nishimura , D. R Laybutt , P Geraldes , S Shah , G King , S Bonner Weir , G Weir and A. Sharma
 

Mammalian MafA/RIPE3b1 is an important glucose-responsive transcription factor that regulates function, maturation, and survival of β-cells. Increased expression of MafA results in improved glucose-stimulated insulin secretion and β-cell function. Because MafA is a highly phosphorylated protein, we examined whether regulating activity of protein kinases can increase MafA expression by enhancing its stability. We demonstrate that MafA protein stability in MIN6 cells and isolated mouse islets is regulated by both p38 MAPK and glycogen synthase kinase 3. Inhibiting p38 MAPK enhanced MafA stability in cells grown under both low and high concentrations of glucose. We also show that the N-terminal domain of MafA plays a major role in p38 MAPK-mediated degradation; simultaneous mutation of both threonines 57 and 134 into alanines in MafA was sufficient to prevent this degradation. Under oxidative stress, a condition detrimental to β-cell function, a decrease in MafA stability was associated with a concomitant increase in active p38 MAPK. Interestingly, inhibiting p38 MAPK but not glycogen synthase kinase 3 prevented oxidative stress-dependent degradation of MafA. These results suggest that the p38 MAPK pathway may represent a common mechanism for regulating MafA levels under oxidative stress and basal and stimulatory glucose concentrations. Therefore, preventing p38 MAPK-mediated degradation of MafA represents a novel approach to improve β-cell function.

  K Baba , Y. W Park , T Kaku , R Kaida , M Takeuchi , M Yoshida , Y Hosoo , Y Ojio , T Okuyama , T Taniguchi , Y Ohmiya , T Kondo , Z Shani , O Shoseyov , T Awano , S Serada , N Norioka , S Norioka and T. Hayashi
 

In response to environmental variation, angiosperm trees bend their stems by forming tension wood, which consists of a cellulose-rich G (gelatinous)-layer in the walls of fiber cells and generates abnormal tensile stress in the secondary xylem. We produced transgenic poplar plants overexpressing several endoglycanases to reduce each specific polysaccharide in the cell wall, as the secondary xylem consists of primary and secondary wall layers. When placed horizontally, the basal regions of stems of transgenic poplars overexpressing xyloglucanase alone could not bend upward due to low strain in the tension side of the xylem. In the wild-type plants, xyloglucan was found in the inner surface of G-layers during multiple layering. In situ xyloglucan endotransglucosylase (XET) activity showed that the incorporation of whole xyloglucan, potentially for wall tightening, began at the inner surface layers S1 and S2 and was retained throughout G-layer development, while the incorporation of xyloglucan heptasaccharide (XXXG) for wall loosening occurred in the primary wall of the expanding zone. We propose that the xyloglucan network is reinforced by XET to form a further connection between wall-bound and secreted xyloglucans in order to withstand the tensile stress created within the cellulose G-layer microfibrils.

  H Hirakawa , H Sawada , Y Yamahama , S. I Takikawa , H Shintaku , A Hara , K Mase , T Kondo and T. Iino
 

Tetrahydrobiopterin (BH4) acts as a cofactor of the aromatic amino-acid hydroxylases, and its deficiency may result in hyperphenylalaninemia (HPA) and decreased production of the neurotransmitters. BH4 is synthesized by sepiapterin reductase (SPR) from 6-pyruvoyl-tetrahydropterin (PPH4). A patient with SPR deficiency shows no HPA; however, an SPR knockout mouse exhibits HPA. We have reported on the SPR-unrelated novel biosynthetic pathway from PPH4 to BH4 (salvage pathway II) in which 3-hydroxysteroid dehydrogenase type 2 and aldose reductase work in concert. In this study, we performed the expression analysis of both proteins in humans and wild-type mice. The results of expression analysis indicated that salvage pathway II worked in human liver; however, it did not act in human brain or in mouse liver and brain. For this reason, a patient with SPR deficiency may show progressive neurological deterioration without HPA, and SPR knockout mice may exhibit HPA and abnormal locomotion activity.

 
 
 
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