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991.
Lim CJ Kim N Lee EK Lee BH Oh KS Yoo SE Yi KY 《Bioorganic & medicinal chemistry letters》2011,21(8):2309-2312
Compounds containing 2-arybenzimidazole ring systems linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of structure-activity relationship studies led to the identification of compound 4c as a potent MCH-R1 antagonist (IC50 = 1 nM). This compound also has good metabolic stability, and favorable pharmacokinetic and brain penetration properties. However 4c was found to be potent inhibitor of the hERG potassium channel. 相似文献
992.
Mre11 plays an important role in repairing damaged DNA by cleaving broken ends and by providing a platform for other DNA repair proteins. Various Mre11 mutations have been identified in several types of cancer. We have determined the crystal structure of the human Mre11 core (hMre11), which contains the nuclease and capping domains. hMre11 dimerizes through the interfaces between loop β3-α3 from one Mre11 and loop β4-β5 from another Mre11, and between loop α2-β3 from one Mre11 and helices α2 and α3 from another Mre11, and assembles into a completely different dimeric architecture compared with bacterial or archaeal Mre11 homologs. Nbs1 binds to the region containing loop α2-β3 which participates in dimerization. The hMre11 structure in conjunction with biochemical analyses reveals that many tumorigenic mutations are primarily associated with Nbs1 binding and partly with nuclease activities, providing a framework for understanding how mutations inactivate Mre11. 相似文献
993.
Kam KY Yu SJ Jeong N Hong JH Jalin AM Lee S Choi YW Lee CK Kang SG 《Molecules and cells》2011,31(3):209-215
The therapeutic goal in treating cerebral ischemia is to reduce the extent of brain injury and thus minimize neurological
impairment. We examined the effects of p-hydroxybenzyl alcohol (HBA), an active component of Gastrodia elata Blume, on transient focal cerebral ischemia-induced brain injury with respect to the involvement of protein disulphide isomerase
(PDI), nuclear factor-E2-related factor 2 (Nrf2), and neurotrophic factors. All animals were ovariectomized 14 days before
ischemic injury. Ischemic injury was induced for 1 h by middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion.
Three days before MCAO, the vehicle-treated and the HBA-treated groups received intramuscular sesame oil and HBA (25 mg/kg
BW), respectively. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed decreased infarct volume in the ischemic lesion
of HBA-treated animals. HBA pretreatment also promoted functional recovery, as measured by the modified neurological severity
score (mNSS; p < 0.05). Moreover, expression of PDI, Nrf2, BDNF, GDNF, and MBP genes increased by HBA treatment. In vitro, H2O2-induced PC12 cell death was prevented by 24 h HBA treatment, but bacitracin, a PDI inhibitor, attenuated this cytoprotective
effect in a dose-dependent manner. HBA treatment for 2 h also induced nuclear translocation of Nrf2, possibly activating the
intracellular antioxidative system. These results suggest that HBA protects against brain damage by modulating cytoprotective
genes, such as Nrf2 and PDI, and neurotrophic factors. 相似文献
994.
In molecular testing using PCR, the target DNA is amplified via PCR and the sequence of interest is investigated via hybridization
with short oligonucleotide capture probes that are either in a solution or immobilized on solid supports such as beads or
glass slides. In this report, we report the discovery of assembly of DNA complex(es) between a capture probe and multiple
strands of the PCR product. The DNA complex most likely has branched structure. The assembly of branched DNA was facilitated
by the product of asymmetric PCR. The amount of branched DNA assembled was increased five fold when the asymmetric PCR product
was denatured and hybridized with a capture probe all in the same PCR reaction mixture. The major branched DNA species appeared
to contain three reverse strands (the strand complementary to the capture probe) and two forward strands. The DNA was sensitive
to S1 nuclease suggesting that it had single-stranded gaps. Branched DNA also appeared to be assembled with the capture probes
immobilized on the surface of solid support when the product of asymmetric PCR was hybridized. Assembly of the branched DNA
was also increased when hybridization was performed in complete PCR reaction mixture suggesting the requirement of DNA synthesis.
Integration of asymmetric PCR, heat denaturation and hybridization in the same PCR reaction mixture with the capture probes
immobilized on the surface of solid support achieved dramatic increase in the signal and sensitivity of detection of DNA.
Such a system should be advantageously applied for development of automated process for detection of DNA. 相似文献
995.
Lee GH Hwang JD Choi JY Park HJ Cho JY Kim KW Chae HJ Kim HR 《The international journal of biochemistry & cell biology》2011,43(9):1305-1317
BAX Inhibitor-1 (BI-1), a transmembrane protein on the endoplasmic reticulum, has been studied previously in various physio/pathological conditions, but not in bone cells. In this study, using the MG63 osteoblast cell line and osteoblasts differentiated from stem cells, the role of BI-1 was studied. First, expression of BI-1 was confirmed in osteoblasts, as well as osteoclasts, in mouse tibiae bone immunohistochemistry. For evaluation of a recently published property of BI-1, an acidic pH-dependent Ca2? channel-like effect in osteoblasts, acidic pH-associated cell death, and pro-inflammatory cytokine release were examined. In MG63 osteoblasts, acidic pH induced a pH-dependent increase in cell death and ER stress, as determined by elevated expression of GRP78, CHOP, phospho-eIF2α, IRE-1α, spliced XBP-1, and phospho-JNK. In osteoblasts, mitochondrial Ca2? also showed a strong pH-dependent increase. BI-1 knock-down using siRNA protected cells against acidic pH, regulating mitochondrial Ca2? accumulation, possibly via the acidic pH-dependent Ca2? channel-like effect of BI-1. BI-1 knock-down also resulted in inhibition of acidic pH-induced release of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. In addition, bone marrow stem cells were differentiated into human osteoblasts, which showed increased expression of BI-1 mRNA and protein. In differentiated primary human osteoblasts, acidic pH-associated cell death, mitochondrial Ca2? accumulation, and pro-inflammatory cytokine release were more significant than in non-differentiated stem cells. In summary, endogenous expression of BI-1 is associated with acidic pH-induced Ca2? release, cell death, and pro-inflammatory cytokine release in human osteoblasts. 相似文献
996.
Nicolas Bertheleme Pil Seok Chae Shweta Singh Danuta Mossakowska Michael M. Hann Kathrine J. Smith Julia A. Hubbard Simon J. Dowell Bernadette Byrne 《生物化学与生物物理学报:生物膜》2013
G-protein coupled receptors (GPCRs) are integral membrane cell surface receptors with key roles in mediating the cellular responses to a wide range of biologically relevant molecules including hormones, neurotransmitters and importantly the majority of currently available drugs. The first high-resolution, X-ray crystallographic structure of a GPCR, that of rhodopsin, was obtained in 2000. It took a further seven years for the next structure, that of the β2 adrenergic receptor. Remarkably, at the time of writing, there have been an astonishing 18 further independent high-resolution GPCR structures published in the last five years (overall total of 68 structures in different conformations or bound to different ligands). Of particular note is the recent structure of the β2 adrenergic receptor in complex with its cognate heterotrimeric G-protein revealing for the first time molecular details of the interaction between a GPCR and the complete G-protein. Together these structures have provided unprecedented detail into the mechanism of action of these incredibly important proteins. This review describes several key methodological advances that have made such extraordinarily fast progress possible. 相似文献
997.
Tracy Haldiman Chae Kim Yvonne Cohen Wei Chen Janis Blevins Liuting Qing Mark L. Cohen Jan Langeveld Glenn C. Telling Qingzhong Kong Jiri G. Safar 《The Journal of biological chemistry》2013,288(41):29846-29861
The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrPSc particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrPSc is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers. 相似文献
998.
Sung Yun Cho Byung Ho Lee Heejung Jung Chang Soo Yun Jae Du Ha Hyoung Rae Kim Chong Hak Chae Jeong Hyun Lee Ho Won Seo Kwang-Seok Oh 《Bioorganic & medicinal chemistry letters》2013,23(24):6711-6716
G-protein-coupled receptor kinase (GRK)-2 and -5 are emerging therapeutic targets for the treatment of cardiovascular disease. In our efforts to discover novel small molecules to inhibit GRK-2 and -5, a class of compound based on 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine was identified as a novel hit by high throughput screening campaign. Structural modification of parent benzoxazole scaffolds by introducing substituents on phenyl displayed potent inhibitory activities toward GRK-2 and -5. 相似文献
999.
Chi Hoon Park Hyeonjeong Choe In-Young Jang So Yeong Kwon Muhammad Latif Heung Kyoung Lee Hyeon Ji Lee Eun Hye Yang Jeong In Yun Chong Hak Chae Sung Yun Cho Sang Un Choi Jae Du Ha Heejung Jung Hyoung Rae Kim Pilho Kim Chong Ock Lee Chang-Soo Yun Kwangho Lee 《Bioorganic & medicinal chemistry letters》2013,23(22):6192-6196
The synthesis of bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines is described and their structure–activity-relationship to anaplastic lymphoma kinase (ALK) is presented. KRCA-0008 is selective and potent to ALK and Ack1, and displays drug-like properties without hERG liability. KRCA-0008 demonstrates in vivo efficacy comparable to Crizotinib in xenograft mice model. 相似文献
1000.
Eunhee Chae Yong-Je Shin Eun-Ju Ryu Mi Kyung Ji Nahm Ryune Cho Ki-Ho Lee Hyun Ji Jeong Soo-Jin Kim Yeonjung Choi Kyung Seok Oh Chun-Eung Park Young Soo Yoon 《Bioorganic & medicinal chemistry letters》2013,23(7):2134-2139
Development of SAR in a 5-aryl-3-acylpyridinyl-pyrazoles and 1-aryl-4-acylpyridinyl imidazoles series of mGlu5 receptor negative allosteric modulators (mGluR5 NAMs) using a functional cell-based assay is described in this Letter. Analysis of the Ligand-lipophilic efficiency (LipE) of compounds provided new insight for the design of potent mGluR5 negative allosteric modulators with anti-depressant activities. 相似文献