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91.
92.
Hiroyuki Watanabe Masahiro Ono Ryoichi Ikeoka Mamoru Haratake Hideo Saji Morio Nakayama 《Bioorganic & medicinal chemistry》2009,17(17):6402-6406
This paper describes the synthesis and biological evaluation of a new series of 2,5-diphenyl-1,3,4-oxadiazole (1,3,4-DPOD) derivatives for detecting β-amyloid plaques in Alzheimer’s brains. The affinity for β-amyloid plaques was assessed by an in vitro binding assay using pre-formed synthetic Aβ42 aggregates. The new series of 1,3,4-DPOD derivatives showed affinity for Aβ42 aggregates with Ki values ranging from 20 to 349 nM. The 1,3,4-DPOD derivatives clearly stained β-amyloid plaques in an animal model of Alzheimer’s disease, reflecting the affinity for Aβ42 aggregates in vitro. Compared to 3,5-diphenyl-1,2,4-oxadiazole (1,2,4-DPOD) derivatives, they displayed good penetration of and fast washout from the brain in biodistribution experiments using normal mice. The novel radioiodinated 1,3,4-DPOD derivatives may be useful probes for detecting β-amyloid plaques in the Alzheimer’s brain. 相似文献
93.
94.
Ryoichi Shibuya Hideo Kawai Kouji Yamamoto 《Journal of brachial plexus and peripheral nerve injury》2009,4(1):1-7
The purpose of this study is to evaluate prospectively the sensitivities of conventional and new electrophysiological techniques and to investigate their relationship with the body mass index (BMI) in a population of patients suspected of having carpal tunnel syndrome (CTS). In this study, 165 hands of 92 consecutive patients (81 female, 11 male) with clinical diagnosis of CTS were compared to reference population of 60 hands of 30 healthy subjects (26 female and 4 male). Extensive sensory and motor nerve conduction studies (NCSs) were performed in the diagnosis of subtle CTS patients. Also, the patients were divided into subgroups and sensitivities were determined according to BMI. The mean BMI was found to be significantly higher in the CTS than in the control group (p < 0.001). The sensitivity of the median sensory nerve latency (mSDL) and median motor distal latency (mMDL) were 75.8% and 68.5%, respectively. The most sensitive parameters of sensory and motor NCSs were the difference between median and ulnar sensory distal latencies to the fourth digit [(D4M-D4U), (77%)] and the median motor terminal latency index [(mTLI), (70.3%)], while the median-to-ulnar sensory action potential amplitude ratio (27%) and the median-thenar to ulnar-hypothenar motor action potential amplitude ratio (15%) were least sensitive tests. Sensory tests were more sensitive than motor NCSs. Combining mSDL with D4M-D4U, and mMDL with mTLI allowed for the detection of abnormalities in 150 (91%) and 132 (80%) hands, respectively. Measurements of all NCSs parameters were abnormal in obese than in non-obese patients when compared to the BMI. The newer nerve conduction techniques and combining different NCSs tests are more sensitive than single conventional NCS test for the diagnosis of suspected CTS. Meanwhile, CTS is associated with increasing BMI. 相似文献
95.
Ando R Amano Y Nakamura H Arai N Kuwajima I 《Bioorganic & medicinal chemistry letters》2006,16(12):3315-3318
Novel kazusamycin A derivatives were designed in the viewpoint of decrease of reactivity at the alpha,beta-unsaturated delta-lactone moiety against Michael-type addition. Although 25-30 steps were required for the synthesis of each compound, their syntheses were achieved. Cytotoxicity against HPAC cell line was evaluated, and two of them exhibited comparable potency to kazusamycin A. Hepatic toxicity of these designed compounds was much lower than that of kazusamycin A. 相似文献
96.
97.
De Jonghe BC Hayes MR Banno R Skibicka KP Zimmer DJ Bowen KA Leichner TM Alhadeff AL Kanoski SE Cyr NE Nillni EA Grill HJ Bence KK 《American journal of physiology. Endocrinology and metabolism》2011,300(6):E1002-E1011
The adipose tissue-derived hormone leptin regulates energy balance through catabolic effects on central circuits, including proopiomelanocortin (POMC) neurons. Leptin activation of POMC neurons increases thermogenesis and locomotor activity. Protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of leptin signaling. POMC neuron-specific deletion of PTP1B in mice results in reduced high-fat diet-induced body weight and adiposity gain due to increased energy expenditure and greater leptin sensitivity. Mice lacking the leptin gene (ob/ob mice) are hypothermic and cold intolerant, whereas leptin delivery to ob/ob mice induces thermogenesis via increased sympathetic activity to brown adipose tissue (BAT). Here, we examined whether POMC PTP1B mediates the thermoregulatory response of CNS leptin signaling by evaluating food intake, body weight, core temperature (T(C)), and spontaneous physical activity (SPA) in response to either exogenous leptin or 4-day cold exposure (4°C) in male POMC-Ptp1b-deficient mice compared with wild-type controls. POMC-Ptp1b(-/-) mice were hypersensitive to leptin-induced food intake and body weight suppression compared with wild types, yet they displayed similar leptin-induced increases in T(C). Interestingly, POMC-Ptp1b(-/-) mice had increased BAT weight and elevated plasma triiodothyronine (T(3)) levels in response to a 4-day cold challenge, as well as reduced SPA 24 h after cold exposure, relative to controls. These data show that PTP1B in POMC neurons plays a role in short-term cold-induced reduction of SPA and may influence cold-induced thermogenesis via enhanced activation of the thyroid axis. 相似文献
98.
Kamada Y Kiso S Yoshida Y Chatani N Kizu T Hamano M Tsubakio M Takemura T Ezaki H Hayashi N Takehara T 《American journal of physiology. Gastrointestinal and liver physiology》2011,301(6):G1031-G1043
Recent studies indicate an accelerated progression of nonalcoholic steatohepatitis (NASH) in postmenopausal women. Hypercholesterolemia, an important risk factor for NASH progression, is often observed after menopause. This study examined the effects of estrogen on NASH in ovariectomized (OVX) mice fed a high-fat and high-cholesterol (HFHC) diet. To investigate the effects of estrogen deficiency, OVX mice and sham-operated (SO) mice were fed normal chow or HFHC diet for 6 wk. Next, to investigate the effects of exogenous estrogen replenishment, OVX mice fed with HFHC diet were treated with implanted hormone release pellets (containing 17β-estradiol or placebo vehicle) for 6 wk. OVX mice on the HFHC diet showed enhanced liver injury with increased liver macrophage infiltration and elevated serum cholesterol levels compared with SO-HFHC mice. Hepatocyte monocyte chemoattractant protein-1 (MCP1) protein expression in OVX-HFHC mice was also enhanced compared with SO-HFHC mice. In addition, hepatic inflammatory gene expressions, including monocytes chemokine (C-C motif) receptor 2 (CCR2), were significantly elevated in OVX-HFHC mice. Estrogen treatment improved serum cholesterol levels, liver injury, macrophage infiltration, and inflammatory gene expressions in OVX-HFHC mice. Moreover, the elevated expression of liver CCR2 and MCP1 were decreased by estrogen treatment in OVX-HFHC mice, whereas low-density lipoprotein dose dependently enhanced CCR2 expression in THP1 monocytes. Our study demonstrated that estrogen deficiency accelerated NASH progression in OVX mice fed HFHC diet and that this effect was improved by estrogen therapy. Hypercholesterolemia in postmenopausal women would be a potential risk factor for NASH progression. 相似文献
99.
Ogawa M Yamaji R Higashimura Y Harada N Ashida H Nakano Y Inui H 《The Journal of biological chemistry》2011,286(48):41455-41465
Skeletal muscles express estrogen receptor (ER) α and ERβ. However, the roles of estrogens acting through the ERs in skeletal muscles remain unclear. The effects of 17β-estradiol (E2) on myogenesis were studied in C2C12 myoblasts. E2 and an ERα-selective agonist propylpyrazole-triol depressed myosin heavy chain (MHC), tropomyosin, and myogenin levels and repressed the fusion of myoblasts into myotubes. ER antagonist ICI 182,780 cancelled E2-repressed myogenesis. E2 induced ubiquitin-specific peptidase 19 (USP19) expression during myogenesis. E2 replacement increased USP19 expression in the gastrocnemius and soleus muscles of ovariectomized mice. Knockdown of USP19 inhibited E2-repressed myogenesis. Mutant forms of USP19 lacking deubiquitinating activity increased MHC and tropomyosin levels. E2 decreased ubiquitinated proteins during myogenesis, and the E2-decreased ubiquitinated proteins were increased by knockdown of USP19. Propylpyrazole-triol increased USP19 expression, and ICI 182,780 inhibited E2-increased USP19 expression. Overexpression of ERα or knockdown of ERβ enhanced the effects of E2 on the levels of USP19, MHC, and tropomyosin, whereas knockdown of ERα, overexpression of ERβ, or an ERβ-selective agonist diarylpropionitrile abolished their effects. A mutant form of ERα that is constitutively localized in the nucleus increased USP19 expression and decreased MHC and tropomyosin expression in the presence of E2. Furthermore, in skeletal muscle satellite cells, E2 inhibited myogenesis and increased USP19 expression, and diarylpropionitrile repressed E2-increased USP19 expression. These results demonstrate that (i) E2 induces USP19 expression through nuclear ERα, (ii) increased USP19-mediated deubiquitinating activity represses myogenesis, and (iii) ERβ inhibits ERα-activated USP19 expression. 相似文献