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991.
Y. Furuta M. Horiguchi E. Sugaru M. Ono‐Kishino M. Otani M. Sakai Y. Masui A. Tsuchida Y. Sato K. Takubo H. Hochigai H. Kimura H. Nakahira T. Nakagawa M. Taiji 《Diabetes, obesity & metabolism》2010,12(5):421-430
Aims: The purpose of this study is to assess the in vitro enzyme inhibition profile of DSP‐7238, a novel non‐cyanopyrrolidine dipeptidyl peptidase (DPP) IV inhibitor and to evaluate the acute and chronic effects of this compound on glucose metabolism in two different mouse models of type 2 diabetes. Methods: The in vitro enzyme inhibition profile of DSP‐7238 was assessed using plasma and recombinant enzymes including DPP IV, DPP II, DPP8, DPP9 and fibroblast activation protein α (FAPα) with fluorogenic substrates. The inhibition type was evaluated based on the Lineweaver–Burk plot. Substrate selectivity of DSP‐7238 and comparator DPP IV inhibitors (vildagliptin, sitagliptin, saxagliptin and linagliptin) was evaluated by mass spectrometry based on the changes in molecular weight of peptide substrates caused by release of N‐terminal dipeptides. In the in vivo experiments, high‐fat diet‐induced obese (DIO) mice were subjected to oral glucose tolerance test (OGTT) following a single oral administration of DSP‐7238. To assess the chronic effects of DSP‐7238 on glycaemic control and pancreatic β‐cell damage, DSP‐7238 was administered for 11 weeks to mice made diabetic by a combination of high‐fat diet (HFD) and a low‐dose of streptozotocin (STZ). After the dosing period, HbA1c was measured and pancreatic damage was evaluated by biological and histological analyses. Results: DSP‐7238 and sitagliptin both competitively inhibited recombinant human DPP IV (rhDPP IV) with Ki values of 0.60 and 2.1 nM respectively. Neither vildagliptin nor saxagliptin exhibited competitive inhibition of rhDPP IV. DSP‐7238 did not inhibit DPP IV‐related enzymes including DPP8, DPP9, DPP II and FAPα, whereas vildagliptin and saxagliptin showed inhibition of DPP8 and DPP9. Inhibition of glucagon‐like peptide‐1 (GLP‐1) degradation by DSP‐7238 was apparently more potent than its inhibition of chemokine (C‐X‐C motif) ligand 10 (IP‐10) or chemokine (C‐X‐C motif) ligand 12 (SDF‐1α) degradation. In contrast, vildagliptin and saxagliptin showed similar degree of inhibition of degradation for all the substrates tested. Compared to treatment with the vehicle, single oral administration of DSP‐7238 dose‐dependently decreased plasma DPP IV activity and improved glucose tolerance in DIO mice. In addition, DSP‐7238 significantly decreased HbA1c and ameliorated pancreatic damage following 11 weeks of chronic treatment in HFD/STZ mice. Conclusions: We have shown in this study that DSP‐7238 is a potent DPP IV inhibitor that has high specificity for DPP IV and substrate selectivity against GLP‐1. We have also found that chronic treatment with DSP‐7238 improves glycaemic control and ameliorates β‐cell damage in a mouse model with impaired insulin sensitivity and secretion. These findings indicate that DSP‐7238 may be a new therapeutic agent for the treatment of type 2 diabetes. 相似文献
992.
Yoshiyuki Yamagishi Hajime Higuchi Motoko Izumiya Gen Sakai Hideko Iizuka Shoko Nakamura Masayuki Adachi Sigenari Hozawa Hiromasa Takaishi Toshifumi Hibi 《Journal of gastroenterology》2010,45(11):1146-1154
Background
Gemcitabine (GEM) is the key drug for the chemotherapy of unresectable pancreatic cancer. However, the efficacy and safety of GEM has not been established in elderly patients. We retrospectively examined the prognosis of elderly pancreatic cancer patients treated with GEM. 相似文献993.
Naohisa Yoshida Yuji Naito Kyoko Sakai Yoshio Sumida Kazuyuki Kanemasa Ken Inoue Yasutaka Morimoto Hideyuki Konishi Naoki Wakabayashi Satoshi Kokura Nobuaki Yagi Akio Yanagisawa Toshikazu Yoshikawa 《International journal of colorectal disease》2010,25(4):455-461
Background
Endoscopic submucosal dissection (ESD) has been reported to be effective for the en bloc resection of large colorectal tumors. Our study investigated whether ESD was suitable for elderly people with large colorectal tumors in terms of its invasiveness.Patients and methods
We studied 119 colorectal tumors that were treated with ESD at Kyoto Prefectural University of Medicine or Nara City Hospital between 2006 and 2009. We classified each patient as either elderly, i.e., more than 75 years old, or non-elderly, i.e., less than 75 years old. Thirty-two of the cases were classified as elderly. Performance status, tumor size, operation time, rate of en bloc resection, histopathological diagnosis, complications, and hospital stay after ESD were analyzed retrospectively in both groups.Results
In the elderly group, the average tumor size was 32.6 mm; the average operation time, 96 min; the rate of en bloc resection, 81.2%; the rate of perforation, 3.1%; and hospital stay after ESD, 5.1 days. Histopathological diagnosis for 16 tumors was adenoma; for 13, carcinoma with invasion into the mucosa; and for three, carcinoma with invasion into the submucosa. There were no statistical differences between the two groups in any of these data. The case with perforation was treated conservatively without urgent surgery in the elderly group.Conclusions
ESD for colorectal tumors resulted in favorable rates of en bloc resection in elderly people. Perforation occurred in elderly people, but these patients were cured with conservative treatment. ESD is a safe and minimally invasive treatment for elderly people with colorectal tumors. 相似文献994.
Tomizawa M Tsuyuguchi T Sakai Y Sugiyama H Miyakawa K Ishihara T Yokosuka O 《Nihon Shokakibyo Gakkai zasshi》2010,107(12):1970-1977
A 72-year-old woman presented with epigastric discomfort. A low density tumor was found in the hilum and left liver by CT. Since she complained epigastralgia, upper gastrointestinal endoscopy was performed, showing an ulcer in the duodenal bulb, with poorly-differentiated adenocarcinoma seen on a biopsy specimen from the edge of the ulcer. After admission, poorly-differentiated adenocarcinoma cells were also obtained with ultrasound guided aspiration cytology of the liver tumor. We diagnosed intrahepatic cholangiocarcinoma (IHC), and treated with gemcitabine. During chemotherapy, the duodenal ulcer became a fistula, and the liver tumor diminished with bubbles inside it. It was suggested that liquid material of IHC, such as necrotic tissue and mucin, drained to the duodenal bulb during chemotherapy. 相似文献
995.
Masaki Takao Takashi Nishii Takashi Sakai Hideki Yoshikawa Nobuhiko Sugano 《Clinical rheumatology》2010,29(8):841-848
The purpose of this study was to evaluate retrospectively the progression of reparative changes in osteonecrosis of the femoral
head over a long period of time, using both serial plain films and magnetic resonance (MR) images. The subjects were 25 patients
with 33 hips affected by osteonecrosis, followed conservatively for more than 10 years (mean, 14.1; range, 10 to 23.4). At
the latest follow-up examination, there were 11 hips at the non-collapse stage, 17 hips at the collapse stage where collapse
has ceased, and five hips at the osteoarthritic stage. An increase in radiographic sclerosis of the lesion area was seen in
14 of 17 hips which showed cessation of collapse, 13 of which showed an intralesional area with intermediate signal intensity
on fat suppression MR images. Four of five hips at the osteoarthritic stage also showed an intralesional area with intermediate
signal intensity on fat suppression MR images. Ten of 11 hips at the non-collapse stage showed a normal fat signal intensity
area demarcated with a low-signal-intensity band on T1-weighted MR images. In the 24 hips followed for more than 5 years with
MR imaging (mean, 9.2; range, 5.9 to 13.8), changes of lesion size of abnormal signal intensity on T1-weighted MR images were
not observed. In conclusion, reparative process was limited to the periphery of osteonecrosis over a long period of time unless
collapse had occurred. If collapse had ceased minimally, the reconstructive repair process could be facilitated. 相似文献
996.
Fujita A Sakai R Matsuura S Yamamoto W Ohshima R Kuwabara H Okuda M Takahashi T Ishigatsubo Y Fujisawa S 《International journal of hematology》2010,92(3):463-467
Idiopathic thrombocytopenic purpura (ITP) commonly affects women of childbearing age. We studied the clinical characteristics
of pregnant women with ITP to estimate their risks of bleeding. A retrospective chart review was performed for all obstetric
patients with ITP who had delivery at our hospital, from 1 March 2000 to 31 March 2008. Twenty women with ITP delivered 24
children in 23 pregnancies. In all, eight women were treated with corticosteroid during their pregnancy period, and there
was only one non-responder. There was no correlation between the maternal platelet count and the amount of blood loss at delivery.
Two infants were revealed to have had platelet counts lower than 30 × 109/L, and were treated with high-dose IV IgG. One of them also received corticosteroid therapy. There was no relationship between
maternal platelet count at delivery and infant platelet count at birth. Overall, no serious bleeding event was seen in either
of the mothers or infants. For most women with ITP, pregnancy is uncomplicated, and even those with severe thrombocytopenia
during pregnancy have good outcomes when under the strict care of a hematologist and gynecologist. 相似文献
997.
Recently, physiologically based perfusion in vitro systems have been developed to provide cell culture environment close to in vivo cell environment (e.g., fluidic conditions, organ interactions). In this work, we model and compare the fate of a chemical, benzo[a]pyrene (B[a]P), in a perfusion and a standard (static well-plate) system. These in vitro systems are composed of Caco-2 and HepG2 cells so as to mimic absorption across the small intestine and intestinal and hepatic metabolism. Compartmental models were developed and calibrated with B[a]P kinetics data in the culture medium to estimate the apparent permeability of Caco-2 cells, the in vitro biotransformation of B[a]P, as well as the different routes of loss by non-specific adsorption. Our results show that non-specific binding is the main process responsible for the depletion of B[a]P in the culture media: at steady state, only 40% and 24% of the total concentration of B[a]P are bioavailable in the static and perfused systems, respectively. We also showed that Caco-2 permeability in the perfused culture system is closer to in vivo conditions than the one obtained in the static system and that higher cellular metabolic activities are observed in static conditions. Perfused in vitro systems combined with kinetic modelling are promising tools for studying in vitro the different processes involved in the toxicokinetics of xenobiotics. 相似文献
998.
The " Salvia phenomenon" is one of the most famous examples of allelopathic interaction between higher plants. The Salvia thickets are surrounded by zones of bare soil ("bare zone", 1-3 m in width), which merge into areas of inhibited grassland ("zone of inhibition") and finally undisturbed grassland at a distance of 3-9 m. This characteristic vegetation pattern was attributed to monoterpenes, especially 1,8-cineole and camphor, which volatilized from S. leucophylla leaves, got adsorbed in the soil around the Salvia thickets, and inhibited germination and seedling growth of annual herbs. Initially, continuity of hydrophobic environment (clay soil particles - cuticular waxes on the seed/seedling surfaces - plasmodesmata - plasma membrane) was regarded to be important for the lipophilic compounds to enter the target cells. However, monoterpenes can reach the target cells via aqueous route as well. Because monoterpenes produced by S. leucophylla all induce similar symptoms in the seedlings of target plants, their mode of action appears to be essentially common. They exert various deteriorating effects on the cells of target plants, which might be totally explained if the primary point of action resides in mitochondrial function (respiratory ATP synthesis) and/or generation of reactive oxygen species. In contrast to the previous belief that cuticular waxes act as the pathway of lipophilic monoterpene to enter the site of action or reservoir of the inhibitors, they may act as "adsorptive barrier" to prevent the entering of monoterpenes inside the cell wall. 相似文献
999.
Kiso K Ueno S Fukuda M Ichi I Kobayashi K Sakai T Fukui K Kojo S 《Biological & pharmaceutical bulletin》2012,35(6):980-983
Carbon tetrachloride (CCl(4))-induced acute hepatitis is assumed to involve two phases. The initial phase, initiated within 2 h after CCl(4) administration, involves the generation of reactive oxygen species. The second phase is assumed to start about 8 h subsequent to CCl(4) administration and involves the oxidant-induced activation of Kupffer cells, which release various pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We investigated the role of Kupffer cells during CCl(4) intoxication using Nucling-knockout mice (the KO group), in which the number of Kupffer cells is largely reduced. Plasma alanine transaminase and aspartate transaminase levels demonstrated that the liver necrosis during the second phase was significantly alleviated in the KO group compared with that in the wild-type mice (the WT group). Plasma TNF-α concentrations in the WT group significantly increased 24 h after CCl(4) intoxication, whereas those in the KO group did not significantly increase. Plasma IL-6 levels also significantly increased in the WT group 24 h after CCl(4) administration, but those in the KO group did not increase at any time point. These results indicated that excess reactions of Kupffer cells, once primed by oxidants, were involved in the exacerbation of oxidative stress and liver damage during the second phase of CCl(4) intoxication. 相似文献
1000.