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131.
Madsen-Duggan CB Debenham JS Walsh TF Toupence RB Huang SX Wang J Tong X Lao J Fong TM Schaeffer MT Xiao JC Huang CR Shen CP Stribling DS Shearman LP Strack AM MacIntyre DE Van der Ploeg LH Goulet MT 《Bioorganic & medicinal chemistry letters》2007,17(7):2031-2035
Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1. 相似文献
132.
Armstrong HE Galka A Lin LS Lanza TJ Jewell JP Shah SK Guthikonda R Truong Q Chang LL Quaker G Colandrea VJ Tong X Wang J Xu S Fong TM Shen CP Lao J Chen J Shearman LP Stribling DS Rosko K Strack A Ha S Van der Ploeg L Goulet MT Hagmann WK 《Bioorganic & medicinal chemistry letters》2007,17(8):2184-2187
Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia. 相似文献
133.
Yueqiong Lao Qian Li Nanshan Li Hong Liu Kuiliang Liu Guojun Jiang Nan Wei Canghai Wang Yadan Wang Jing Wu 《Biochemical and biophysical research communications》2019,508(2):339-347
DNA mismatch repair-proficient colon cancer is the most common type of colon cancer, but its initiation and progression are still unknown. Our previous study has revealed that a long noncoding RNA (lncRNA) ENST00000455974 was significantly associated with TNM stage and distant metastasis in patients with DNA mismatch repair-proficient (pMMR) colon cancer (CC). Here, firstly, we observed that ENST00000455974 was gradual increased across colon normal-adenoma-carcinoma-metastasis sequence by quantitative real-time PCR. Secondly, ENST00000455974 showed a better sensitivity and specificity than CEA and CA19-9 in the diagnosis of pMMR CC by drawing the receiver operating characteristic (ROC) curve. Thirdly, a higher level of ENST00000455974 was associated with a poorer patient survival. Furthermore, Knockdown of ENST00000455974 led to reduced proliferation and migration of colon cancer cells. Mechanistically, ENST00000455974 was mainly located in the nucleus of colon cancer cells and it promoted the growth and metastasis of pMMR CC cells through up-regulating JAG2. 相似文献
134.
Mingli Qin Shumei Li Yongzhi Zhao Cheng‐Yen Lao Zili Zhang Luan Liu Fei Fang Haoyang Wu Baorui Jia Zhiwei Liu Wei Wang Ye Liu Xuanhui Qu 《Liver Transplantation》2019,9(1)
Creating nanosized pores in 2D materials can increase the edge sites, improve the mass transfer, and contribute to different physical properties, which shows potential applications in many fields including filtration membranes, electronics and energy storage devices, and catalysts. An iconic member of this type of material is porous graphene. Herein, a unique 2D layered double hydroxide (LDH) nanomesh is designed and synthesized as a new class of 2D holey materials. It represents the first case of exfoliation method for preparing 2D holey materials among all published reports. As an oxygen evolution reaction electrocatalyst, the 2D CoCo‐LDH nanomesh has apparently lower onset overpotential (220 mV) than that of compact nanosheets without holes (270 mV) owing to the pores through the plane that offer more highly active edge sites with lower coordination number and promote the mass diffusion. This work opens up a new avenue for designing 2D porous materials for energy conversion and storage. 相似文献
135.
136.
Iulia Mihaila Benjamin L. Handen Bradley T. Christian Patrick J. Lao Karly A. Cody William E. Klunk Dana L. Tudorascu Annie D. Cohen Ozioma C. Okonkwo Sigan L. Hartley 《Developmental neurobiology》2019,79(7):738-749
The present study provided an investigation of associations between leisure activity and early Alzheimer’s disease neuropathology (i.e., brain β‐amyloid) and episodic memory in a sample of 65 adults with Down syndrome (aged 30–53 years), at baseline and follow‐up, approximately three years apart. Findings indicated that leisure activity at baseline was not associated with brain β‐amyloid at baseline or change in brain β‐amyloid from baseline to follow‐up. Greater cognitively stimulating leisure activity at baseline was associated with better episodic memory at baseline, and greater social leisure activity at baseline was associated with less decline in episodic memory from baseline to follow‐up. High (as opposed to low) levels of social and overall leisure activity at baseline moderated the association between increase in brain β‐amyloid and decline in episodic memory, from baseline to follow‐up. Findings suggest that cognitively stimulating and social leisure activity could protect against the effect of Alzheimer’s disease neuropathology on episodic memory in adults with Down syndrome. 相似文献
137.
138.
Thomas J. Cahill Vincenzo Leo Matthew Kelly Alexander Stockenhuber Nolan W. Kennedy Leyuan Bao Grazia Cereghetti Andrew R. Harper Gabor Czibik Chunyan Lao Mohamed Bellahcene Violetta Steeples Safar Ghaffari Arash Yavari Alice Mayer Joanna Poulton David J. P. Ferguson Luca Scorrano Nishani T. Hettiarachchi Chris Peers John Boyle R. Blake Hill Alison Simmons Hugh Watkins T. Neil Dear Houman Ashrafian 《The Journal of biological chemistry》2015,290(43):25907-25919
We have reported previously that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy. The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and to define the cellular sequelae leading to heart failure in the Python monogenic dilated cardiomyopathy model. We found that the C452F mutation increased Drp1 GTPase activity. The mutation also conferred resistance to oligomer disassembly by guanine nucleotides and high ionic strength solutions. In a mouse embryonic fibroblast model, Drp1 C452F cells exhibited abnormal mitochondrial morphology and defective mitophagy. Mitochondria in C452F mouse embryonic fibroblasts were depolarized and had reduced calcium uptake with impaired ATP production by oxidative phosphorylation. In the Python heart, we found a corresponding progressive decline in oxidative phosphorylation with age and activation of sterile inflammation. As a corollary, enhancing autophagy by exposure to a prolonged low-protein diet improved cardiac function in Python mice. In conclusion, failure of Drp1 disassembly impairs mitophagy, leading to a downstream cascade of mitochondrial depolarization, aberrant calcium handling, impaired ATP synthesis, and activation of sterile myocardial inflammation, resulting in heart failure. 相似文献
139.
Kang Xiao Yinyin Wang Zhijie Chang Yuanzhi Lao Donald C. Chang 《Biochemical and biophysical research communications》2014
Mcl-1 is a major anti-apoptotic Bcl-2 family protein. It is well known that Mcl-1 can interact with certain pro-apoptotic Bcl-2 family proteins in normal cells to neutralize their pro-apoptotic functions, thus prevent apoptosis. In addition, it was recently found that Mcl-1 can also inhibit mitochondrial calcium uptake. The detailed mechanism, however, is still not clear. Based on Yeast Two-Hybrid screening and co-immunoprecipitation, we identified a mitochondrial protein p32 (C1qbp) as a novel binding partner of Mcl-1. We found that p32 had a number of interesting properties: (1) p32 can positively regulate UV-induced apoptosis in HeLa cells. (2) Over-expressing p32 could significantly promote mitochondrial calcium uptake, while silencing p32 by siRNA suppressed it. (3) In p32 knockdown cells, Ruthenium Red treatment (an inhibitor of mitochondrial calcium uniporter) showed no further suppressive effect on mitochondrial calcium uptake. In addition, in Ruthenium Red treated cells, Mcl-1 also failed to suppress mitochondrial calcium uptake. Taken together, our findings suggest that p32 is part of the putative mitochondrial uniporter that facilitates mitochondrial calcium uptake. By binding to p32, Mcl-1 can interfere with the uniporter function, thus inhibit the mitochondrial Ca2+ uploading. This may provide a novel mechanism to explain the anti-apoptotic function of Mcl-1. 相似文献
140.
Mosaic mutant analysis, the study of cellular defects in scattered mutant cells in a wild-type environment, is a powerful approach for identifying critical functions of genes and has been applied extensively to invertebrate model organisms. A highly versatile technique has been developed in mouse: MASTR (mosaic mutant analysis with spatial and temporal control of recombination), which utilizes the increasing number of floxed alleles and simultaneously combines conditional gene mutagenesis and cell marking for fate analysis. A targeted allele (R26(MASTR)) was engineered; the allele expresses a GFPcre fusion protein following FLP-mediated recombination, which serves the dual function of deleting floxed alleles and marking mutant cells with GFP. Within 24 hr of tamoxifen administration to R26(MASTR) mice carrying an inducible FlpoER transgene and a floxed allele, nearly all GFP-expressing cells have a mutant allele. The fate of single cells lacking FGF8 or SHH signaling in the developing hindbrain was analyzed using MASTR, and it was revealed that there is only a short time window when neural progenitors require FGFR1 for viability and that granule cell precursors differentiate rapidly when SMO is lost. MASTR is a powerful tool that provides cell-type-specific (spatial) and temporal marking of mosaic mutant cells and is broadly applicable to developmental, cancer, and adult stem cell studies. 相似文献