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131.
Chemical genetics employs diverse small-molecule compounds to elucidate biological processes in a manner analogous to the mutagenesis strategies at the core of classical genetics. Screening small-molecule libraries for compounds that induce a phenotype of interest represents the forward chemical genetic approach, whereas the reverse approach involves small molecules targeting a single protein. Here, we review key differences between the goals for small-molecule screening in industry versus academia, recent developments in high-throughput screening, and publicly available resources of compound collections, screening facilities, and databases. A particularly exciting outcome of a chemical genetic screen is the discovery of a previously unknown role for a protein in a pathway together with compounds that affect the function of that protein. In illustrative cases, such discoveries have led to progress toward therapeutic development and more commonly have increased the size of the small molecule "toolbox" available to the research community for the study of biological processes. 相似文献
132.
Tajima H Kawasumi M Chiba T Yamada M Yamashita K Nawa M Kita Y Kouyama K Aiso S Matsuoka M Niikura T Nishimoto I 《Journal of neuroscience research》2005,79(5):714-723
Humanin (HN) is a 24-amino acid peptide that protects neuronal cells from death caused by Alzheimer's disease (AD)-related genes and amyloid-beta (Abeta). Multiple studies have revealed its biochemical and neuroprotective characteristics in vitro; however, little has been known regarding whether HN is effective in vivo in AD model systems. We examined the effect of S14G-HN, a 1,000-fold more potent derivative of HN in vitro, on amnesia induced by Abeta25-35 in mice. The Y-maze test revealed that at least 50 pmol of S14G-HN by intracerebroventricular injection prevented Abeta-induced impairment of short-term/spatial working memory; however, 5 nmol of S14A-HN, a neuroprotection-defective mutant in vitro, did not prevent Abeta-induced amnesia. These results are in agreement with the structure-function correlation shown previously in vitro. In the water-finding task, S14G-HN prevented prolongation of finding latency (the time to find water) observed in Abeta-amnesic mice, indicating that S14G-HN also blocked Abeta-induced impairment of latent learning. In accordance with these observations, immunohistochemical analysis showed that S14G-HN sustained the number of cholinergic neurons in the basal forebrain and the striata nearly to the normal level. Furthermore, genistein, a specific inhibitor of tyrosine kinases, blocked recovery from scopolamine-induced amnesia by S14G-HN, suggesting that certain tyrosine kinase(s) are involved in the inhibitory function of S14G-HN in vivo. Taking these findings together, we conclude that S14G-HN has rescue activity against memory impairment caused by AD-related insults in vivo by activating the same intracellular neuroprotective machinery as elucidated previously in vitro. 相似文献
133.
Masaoki Harada Yuzo Kinoshita Masatoshi Moriyama Iichiro Kondo Mitsuru Nakahashi Harumi Kumagai Koichi Sasaki Masahiko Hosaka 《The Prostate》1994,25(3):147-155
Although the clinical effects of attempted nonsurgical treatment of benign prostatic hyperplasia have been well documented, detailed histological evaluation of the effects of treatment appears to be limited. The effect of long-term administration of an antiandrogen, chlormadinone acetate (CMA), on benign prostatic hyperplasia was evaluated with histological comparison of two biopsy specimens, one before treatment and one after treatment. Secretory epithelium showed obvious regressive changes with occasional basal cell prominence after CMA treatment. Stromal elements, however, did not show any marked changes, except for occasional edematous loosening. Scores of multiple epithelial parameters tended to be correlated with clinical improvement in urinary obstructive symptoms, especially in patients with predominant glandular hyperplasia. These results suggest that long-term administration of the potent antiandrogen CMA to inhibit dihydrotestosterone-receptor binding might be a useful therapeutic maneuver in patients with glandular hyperplasia, without any deterioration of the stromal component. © 1994 Wiley-Liss, Inc. 相似文献
134.
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136.
Takaaki Ohmori Susumu Sekigawa Masaoki Sunagawa Yoshimi Tatsumi Masato Ohshima Noboru Enoki Yoshiteru Kitahori Yoshio Hiasa Yoshio Murata 《Pathology international》1981,31(6):1097-1104
Histopathological study of the endstage kidney in a 50-year-old male who died after intermittent maintainance hemodialysis for 10 years was reported. At autopsy, both kidneys were contracted and characterized by grossly visible discrete multiple cysts. Histopathological study of consecutive sections of both kidneys revealed that these cysts were distributed throughout a completely disorganized parenchyma and were composed of dysplastic epithelial cells of different types and of structures, some of which revealed neoplastic transformation. 相似文献
137.
Shiga H Kobayashi Y Katsuyama H Yokoyama M Arakawa I 《Journal of prosthodontic research》2012,56(3):166-169
PurposeTo clarify whether there might be a gender difference in masticatory performance in dentate adults.MethodsThirty male subjects and thirty female subjects were asked to chew gummy jelly on their habitual chewing side for 10, 15 and 20 s and the amounts of glucose extraction were measured. The changes of both glucose extraction and standardized glucose extraction from 10 to 20 s were investigated differently for males and females. The amount of glucose extraction was compared between males and females for each chewing duration. In addition, in order to confirm a gender difference in occlusal force, the maximum occlusal force was compared between males and females.ResultsFor both males and females, the amount of glucose extraction was lowest for 10-s chewing and increased significantly for 15-s and 20-s chewing. The mean standardized glucose extraction values increased in proportion with the duration of chewing. The standard deviations of the standardized glucose extraction were very small (below 0.02) for all chewing durations in both males and females. With regard to comparison of the glucose extraction between males and females, the amount of glucose extraction was significantly larger for males than for females for all chewing durations. The maximum occlusal force was significantly larger for males.ConclusionIt was suggested that it might be important to take into consideration gender-related differences while analyzing masticatory performance in dentate adults. 相似文献
138.
Miyamoto M Miyamoto T Iwanami M Muramatsu S Asari S Nakano I Hirata K 《Sleep medicine》2012,13(1):102-106
Objectives
Transcranial sonography (TCS) has been shown to reveal hyperechogenicity of the substantia nigra (SN) in people with Parkinson’s disease and in approximately 10% of healthy subjects. It is hypothesized that SN hyperechogenicity in healthy subjects and patients with idiopathic rapid eye movement (REM) sleep behaviour disorder (iRBD) patients is a marker of vulnerability for Parkinson’s disease.Methods
TCS and positron emission tomography (PET) with 6-[18F] fluoro-meta-tyrosine (FMT), which can assess the level of the presynaptic dopaminergic nerve, were performed in 19 male patients with iRBD, mean age 66.4 (standard deviation [SD] 4.9) years, to assess nigrostriatal function.Results
Nine patients had pathological SN hyperechogenicity (mean age 66.8 [SD 3.9] years; 0.31 [SD 0.12] cm2) and 10 patients did not have SN hyperechogenicity (mean age 66.0 [SD 5.8] years; 0.11 [SD 0.06] cm2). FMT uptake at the putamen and caudate was significantly lower in iRBD patients with pathological SN hyperechogenicity compared with those without SN hyperechogenicity. However, no correlation was found between SN echogenicity and FMT uptake. This is in conflict with previous findings which showed that subjects with hyperechogenicity had lower FMT uptake in the striatum.Conclusion
Pathological hyperechogenic alterations in the SN in patients with iRBD may suggest the existence of preclinical SN dysfunction as determined by FMT-PET. 相似文献139.
140.
Izumi K Kanno H Umemoto S Hasumi H Osada Y Ota J Tsuchiya F Ogino I Harada M 《Hinyokika kiyo. Acta urologica Japonica》2007,53(5):315-318
A 66-year-old man visited our hospital complaining of a high prostate-specific antigen (PSA) (6.9 ng/ml) and dysuria. Prostatic needle biopsies revealed no malignancy in January 1998 and February 1999 (PSA 8.0 ng/ml). Transurethral resection of prostate (TURP) was performed in March 1999. Although none of the TURP specimen showed any malignancy, the PSA level remained high (3.7 ng/ml 1 year after the TURP), and gradually increased. About 3 years later, re-biopsy was done (PSA 13.2 ng/ml) and pathological finding was moderately differentiated adenocarcinoma (Gleason score 3 + 3 = 6). After 9-month MAB, radical prostatectomy (RP) was performed in January 2003 (PSA 4.2 ng/ml). Though the RP specimen showed moderately differentiated adenocarcinoma with negative capsule penetration and negative surgical margins, PSA decreased to 2.5 ng/ml and gradually increased. Computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy showed neither distant metastasis nor local recurrence. Review of the RP specimen revealed ductal carcinoma with positive capsular penetration and suspicion of positive surgical margins. Although the patient was treated with maximum androgen blockade, diethylstilbestrol diphosphate, and tegafururacil, PSA gradually increased and was kept at a high level (5-6 ng/ml). In December 2005, the patient complained of anal pain and MRI showed a 4.8 x 2.3 cm tumor in the prostatic bed. Needle biopsy of the tumor revealed ductal carcinoma (PSA 6.39 ng/ml). In January 2006 (PSA 11.9 ng/ml), we initiated a treatment with 66 Gy of intensity modulated radiation therapy. In November 2006, PSA decreased to 0.279 ng/ml, and the tumor reduced (3.8 x 1.0 cm) on MRI. 相似文献