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81.
Eriko Kikuchi Takayasu Mori Moko Zeniya Kiyoshi Isobe Mari Ishigami-Yuasa Shinya Fujii Hiroyuki Kagechika Tomoaki Ishihara Tohru Mizushima Sei Sasaki Eisei Sohara Tatemitsu Rai Shinichi Uchida 《Journal of the American Society of Nephrology : JASN》2015,26(7):1525-1536
Upon activation by with-no-lysine kinases, STE20/SPS1-related proline–alanine-rich protein kinase (SPAK) phosphorylates and activates SLC12A transporters such as the Na+-Cl− cotransporter (NCC) and Na+-K+-2Cl− cotransporter type 1 (NKCC1) and type 2 (NKCC2); these transporters have important roles in regulating BP through NaCl reabsorption and vasoconstriction. SPAK knockout mice are viable and display hypotension with decreased activity (phosphorylation) of NCC and NKCC1 in the kidneys and aorta, respectively. Therefore, agents that inhibit SPAK activity could be a new class of antihypertensive drugs with dual actions (i.e., NaCl diuresis and vasodilation). In this study, we developed a new ELISA-based screening system to find novel SPAK inhibitors and screened >20,000 small-molecule compounds. Furthermore, we used a drug repositioning strategy to identify existing drugs that inhibit SPAK activity. As a result, we discovered one small-molecule compound (Stock 1S-14279) and an antiparasitic agent (Closantel) that inhibited SPAK-regulated phosphorylation and activation of NCC and NKCC1 in vitro and in mice. Notably, these compounds had structural similarity and inhibited SPAK in an ATP-insensitive manner. We propose that the two compounds found in this study may have great potential as novel antihypertensive drugs. 相似文献
82.
Isao Taguchi Tomoaki Kanaya Toru Toi Shichirou Abe Hiroyuki Sugimura Toshiyasu Hoshi Akitsugu Oida Hidehiko Araki Kenichi Ogawa Noboru Kaneko 《Circulation journal》2005,69(1):49-54
BACKGROUND: The beneficial effect of percutaneous coronary intervention (PCI) using stents for acute myocardial infarction (AMI) has already been demonstrated, but there is the problem that mechanical microvascular occlusion can occur because of thrombus/atheroma embolization when the PCI was performed. The aim of the present study was to retrospectively test and compare the effects of an aspiration catheter or distal embolic protection with a distal occlusion balloon catheter to prevent peripheral vascular embolization. METHODS AND RESULTS: The subjects consisted of 135 patients who underwent PCI with stenting within 12 h of the onset of chest pain caused by their first AMI. They were divided into 2 groups; the aspiration group, consisted of 81 consecutively seen patients who underwent aspiration catheter treatment between January 2001 and May 2002, and the distal protection group was the next group of 54 consecutively seen patients treated with a distal protection device between June 2002 and February 2003. The results were as follows. Thrombolysis in Myocardial Infarction (TIMI) score of 3 was obtained significantly more frequently in the distal protection group (94.4%) than in the aspiration group (79.0%). Additionally, the intensity of the cardiac muscle stain (blush score) was evaluated on coronary angiography and the rate of cases showing a blush score of 3, which indicates favorable blood perfusion at the tissue level, in the distal protection group (56.6%) was significantly greater than in the aspiration group (33.3%, p<0.01). The time to peak blood concentration of creatinine kinase was also significantly shorter in the distal protection group. CONCLUSIONS: The distal embolism protection method is superior to the aspiration method for prevention of embolization after PCI with stenting for AMI, in terms of tissue level reperfusion in myocardial recanalization therapy. 相似文献
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Aya Taniguchi Tetsuhiro Ishikawa Masayuki Miyagi Hiroto Kamoda Yoshihiro Sakuma Yasuhiro Oikawa Go Kubota Kazuhide Inage Takeshi Sainoh Junichi Nakamura Yasuchika Aoki Tomoaki Toyone Gen Inoue Miyako Suzuki Kazuyo Yamauchi Takane Suzuki Kazuhisa Takahashi Seiji Ohtori Sumihisa Orita 《International journal of clinical and experimental pathology》2015,8(10):12967-12971
Background: The detailed mechanisms of knee osteoarthritis (OA) pain have not been clarified, but involvement of inflammatory cytokines such as tumor necrosis factor-alpha (TNF) has been suggested. The present study aimed to investigate the more detailed neurological involvement of TNF in joint pain using a TNF-knockout mouse OA model. Methods: The right knees of twelve-week-old C57BL/6J wild and TNF-deficient knockout (TNF-ko) mice (n=15, each group) were given a single intra-articular injection of 10 µg monoiodoacetate in 10 mL sterile saline. The left knees were only punctured as the control. Evaluations were performed immediately after the injection (baseline) and at 7, 14, and 28 days after the injection with a subsequent intra-articular injection of neurotracer into both knees. The animals were evaluated for immunofluorescence of the lumbar dorsal root ganglia (DRG) innervating the knee joints. The injected knees were observed macroscopically and mouse pain-related behaviors were scored. Results: Macroscopic observation showed similar knee OA development in both wild and TNF-ko mice. Calcitonin gene-related peptide (CGRP, a neuropeptide identified as a inflammatory pain-related biomarker) was significantly increased in DRG neurons innervating OA-induced knee joints with significantly less CGRP expression in TNF-ko animals. Pain-related behavior scoring showed a significant increase in pain in OA-induced joints, but there was no significant difference in pain observed between the wild and TNF-ko mice. Conclusions: The result of the present study indicates the possible association of TNF-alpha in OA pain but not OA development. 相似文献
85.
Nobutoshi Komatsu Utaroh Motosugi Shinya Maekawa Kuniaki Shindo Minoru Sakamoto Mitsuaki Sato Akihisa Tatsumi Mika Miura Fumitake Amemiya Yasuhiro Nakayama Taisuke Inoue Mitsuharu Fukasawa Tomoyoshi Uetake Masahiko Ohtaka Tadashi Sato Yasuhiro Asahina Masayuki Kurosaki Namiki Izumi Tomoaki Ichikawa Tsutomu Araki Nobuyuki Enomoto 《Hepatology research》2014,44(13):1339-1346
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89.
Tomoaki Nakamura Yushi Hirota Naoko Hashimoto Tomokazu Matsuda Michinori Takabe Kazuhiko Sakaguchi Wataru Ogawa Susumu Seino 《Journal of diabetes investigation.》2014,5(1):48-50
To estimate the carbohydrate‐to‐insulin ratio (CIR), a formula dividing a constant, usually 300–500, by the total daily dose (TDD) of insulin, is widely utilized. An appropriate CIR varies for each meal of the day, however. Here, we investigate diurnal variation of CIR in hospitalized Japanese type 1 diabetic patients treated with continuous subcutaneous insulin infusion. After optimization of the insulin dose, TDD and total basal insulin dose (TBD) were 34.9 ± 10.2 and 9.3 ± 2.8 units, respectively, with a percentage of TBD to TDD of 27.3 ± 6.0%. The products of CIR and TDD at breakfast, lunch and dinner were 311 ± 63, 530 ± 161, and 396 ± 63, respectively, suggesting that in the formula estimating CIR using TDD, the constant should vary for each meal of the day, and that 300, 500, and 400 are appropriate for breakfast, lunch, and dinner, respectively. 相似文献
90.
Tomomi Fujisawa Chisato Tawada Yoko Mizutani Tomoaki Doi Shozo Yoshida Shinji Ogura Mariko Seishima 《Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy》2014,18(3):238-243
Palmoplantar pustulosis (PPP) is characterized by neutrophilic pustules with erythema, which are limited to the hands and feet. Although granulocyte and monocyte adsorption apheresis (GMA) has shown remarkable effects on generalized pustular psoriasis, there are few reports of PPP treated with GMA. We treated three refractory PPP patients using GMA weekly for 5 weeks. The skin eruptions were assessed by a 5‐grade score for scales, pustules, and erythema. GMA decreased the total grade from 9 to 2 in patients 1 and 2, and from 7 to 3 in patient 3. The GMA effects were estimated to be excellent in all three patients. Pustule formation and pain disappeared in all cases. The treatment effect lasted for at least 5 months after GMA. GMA was also effective for relieving the arthralgia in one patient, but it recurred at 6 weeks. Based on these findings, GMA could be an effective therapy for refractory PPP. 相似文献