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71.
Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin 总被引:1,自引:0,他引:1 下载免费PDF全文
72.
Asma Tlili Alexander Hoischen Clémentine Ripoll Eva Benabou Anne Badel Anne Ronan Renaud Touraine Yann Grattau Samantha Stora Bregje van Bon Bert de Vries Bj?rn Menten Nele Bockaert Joseph Gecz Stylianos E. Antonarakis Dominique Campion Marie-Claude Potier Henri Bléhaut Jean-Maurice Delabar Nathalie Janel 《Molecular neurobiology》2012,46(2):297-303
Down syndrome or trisomy 21 is the most common genetic disorder leading to mental retardation. One feature is impaired short- and long-term spatial memory, which has been linked to altered brain-derived neurotrophic factor (BDNF) levels. Mouse models of Down syndrome have been used to assess neurotrophin levels, and reduced BDNF has been demonstrated in brains of adult transgenic mice overexpressing Dyrk1a, a candidate gene for Down syndrome phenotypes. Given the link between DYRK1A overexpression and BDNF reduction in mice, we sought to assess a similar association in humans with Down syndrome. To determine the effect of DYRK1A overexpression on BDNF in the genomic context of both complete trisomy 21 and partial trisomy 21, we used lymphoblastoid cell lines from patients with complete aneuploidy of human chromosome 21 (three copies of DYRK1A) and from patients with partial aneuploidy having either two or three copies of DYRK1A. Decreased BDNF levels were found in lymphoblastoid cell lines from individuals with complete aneuploidy as well as those with partial aneuploidies conferring three DYRK1A alleles. In contrast, lymphoblastoid cell lines from individuals with partial trisomy 21 having only two DYRK1A copies displayed increased BDNF levels. A negative correlation was also detected between BDNF and DYRK1A levels in lymphoblastoid cell lines with complete aneuploidy of human chromosome 21. This finding indicates an upward regulatory role of DYRK1A expression on BDNF levels in lymphoblastoid cell lines and emphasizes the role of genetic variants associated with psychiatric disorders. 相似文献
73.
Campos-Junior PH Costa GM Lacerda SM Rezende-Neto JV de Paula AM Hofmann MC de França LR 《Biology of reproduction》2012,86(5):155, 1-155,10
In the seminiferous epithelium, spermatogonial stem cells (SSCs) are located in a particular environment called the "niche" that is controlled by the basement membrane, key testis somatic cells, and factors originating from the vascular network. However, the role of Leydig cells (LCs) as a niche component is not yet clearly elucidated. Recent studies showed that peccaries (Tayassu tajacu) present a peculiar LC cytoarchitecture in which these cells are located around the seminiferous tubule lobes, making the peccary a unique model for investigating the SSC niche. This peculiarity allowed us to subdivide the seminiferous tubule cross-sections in three different testis parenchyma regions (tubule-tubule, tubule-interstitium, and tubule-LC contact). Our aims were to characterize the different spermatogonial cell types and to determine the location and/or distribution of the SSCs along the seminiferous tubules. Compared to differentiating spermatogonia, undifferentiated spermatogonia (A(und)) presented a noticeably higher nuclear volume (P < 0.05), allowing an accurate evaluation of their distribution. Immunostaining analysis demonstrated that approximately 93% of A(und) were GDNF receptor alpha 1 positive (GFRA1(+)), and these cells were preferentially located adjacent to the interstitial compartment without LCs (P < 0.05). The expression of colony-stimulating factor 1 was observed in LCs and peritubular myoid cells (PMCs), whereas its receptor was present in LCs and in GFRA1(+) A(und). Taken together, our findings strongly suggest that LCs, different from PMCs, might play a minor role in the SSC niche and physiology and that these steroidogenic cells are probably involved in the differentiation of A(und) toward type A(1) spermatogonia. 相似文献
74.
Poras H Duquesnoy S Dange E Pinon A Vialette M Fournié-Zaluski MC Ouimet T 《The Journal of biological chemistry》2012,287(24):20221-20230
Legionella pneumophila has been shown to secrete a protease termed major secretory protein (Msp). This protease belongs to the M4 family of metalloproteases and shares 62.9% sequence similarity with pseudolysin (EC 3.4.24.26). With the aim of developing a specific enzymatic assay for the detection and quantification of Msp, the Fluofast substrate library was screened using both enzymes in parallel. Moreover, based on the crystal structure of pseudolysin, a model of the Msp structure was built. Screening of the peptide library identified a lead substrate specifically cleaved by Msp that was subsequently optimized by rational design. The proposed model for Msp is consistent with the enzymatic characteristics of the studied peptide substrates and provides new structural information useful for the characterization of the protease. This study leads to the identification of the first selective and high affinity substrate for Msp that is able to detect picomolar concentrations of the purified enzyme. The identified substrate could be useful for the development of a novel method for the rapid detection of Legionella. 相似文献
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77.
Bourgeois-Daigneault MC Thibodeau J 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(10):4959-4970
Some members of the membrane-associated RING-CH family of E3 ubiquitin ligases (MARCHs) are membrane-bound and target major players of the immune response. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs. It is induced by IL-10 and despite a strong increase in mRNA expression in human primary monocytes, the protein remains hardly detectable. To gain insights into the posttranslational regulation of MARCH1, we investigated whether its expression is itself regulated by ubiquitination. Our results demonstrate that MARCH1 is ubiquitinated in transfected human cell lines. Polyubiquitin chain-specific Abs revealed the presence of K48-linked polyubiquitin chains. A mutant devoid of lysine residues in the N- and C-terminal regions was less ubiquitinated and had a prolonged half-life. Reduced ubiquitination was also observed for an inactive mutated form of the molecule (M1WI), suggesting that MARCH1 is capable of autoubiquitination. Immunoprecipitation and energy transfer experiments demonstrated that MARCH1 homodimerizes and also forms heterodimers with others family members. Coexpression of MARCH1 decreased the protein levels of the inactive M1WI, suggesting a transubiquitination process. Taken together, our results suggest that MARCH1 may regulate its own expression through dimerization and autoubiquitination. 相似文献
78.
Vendeville S Lin TI Hu L Tahri A McGowan D Cummings MD Amssoms K Canard M Last S Van den Steen I Devogelaere B Rouan MC Vijgen L Berke JM Dehertogh P Fransen E Cleiren E van der Helm L Fanning G Van Emelen K Nyanguile O Simmen K Raboisson P 《Bioorganic & medicinal chemistry letters》2012,22(13):4437-4443
Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC(50) of 82 nM) with minimal associated cell toxicity (CC(50)>20 μM) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic. 相似文献
79.
BackgroundPolycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenemia, from ovarian and adrenal origin, and is characterized by insulin resistance (IR). Studies found that raising in vivo non-esterified fatty acid (NEFA) levels, which induces lipotoxicity, increases androgen levels and IR. The aim of this study was therefore to determine the effects of in vitro over-exposure to NEFA on androgen synthesis in a bovine adrenocortical cell model.MethodsBovine fasciculata/reticularis cells were cultured for 2 days in the absence or presence of ACTH (10 nmol/L) or Forskolin (fsk, 10 μmol/L), alone or in combination with the saturated fatty acid (FA) palmitate (100 μmol/L). Steroid production was measured in medium and corrected for initial cell seeding count. CYP17 protein expression and ERK1/2 phosphorylation were assessed by Western blotting.ResultsUnder unstimulated conditions, dehydroepiandrosterone (DHEA) levels were barely detected and no difference was observed after palmitate exposure, which was also the case for CYP17 expression and ERK1/2 phosphorylation. Under stimulation, palmitate exposure increased DHEA production by 38% and 69%, for ACTH and fsk, respectively, as compared to untreated conditions (Ps ? 0.05). In palmitate-treated vs untreated cells, fsk-stimulated ERK1/2 phosphorylation was reduced by 46% (P = 0.0047), but stimulated CYP17 expression was not significantly affected.ConclusionIn a model of androgen-producing cells, under stimulated conditions, overexposure to saturated FAs significantly increases androgen production and reduces MEK/ERK activation. Therefore, this study is the first to demonstrate that lipotoxicity can directly trigger androgen overproduction in vitro, in addition to its well-described impact on IR, which strongly supports a central role of lipotoxicity in PCOS pathophysiology. 相似文献
80.
G De Serres MC Gariépy B Coleman I Rouleau S McNeil M Benoît A McGeer A Ambrose J Needham C Bergeron C Grenier K Sleigh A Kallos M Ouakki N Ouhoummane G Stiver L Valiquette A McCarthy J Bettinger;PHAC-CIHR influenza Research Network 《PloS one》2012,7(7):e38563