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21.
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Lucas A Smolders Bj?rn P Meij David Onis Frank M Riemers Niklas Bergknut Richard Wubbolts Guy CM Grinwis Martin Houweling Marian JA Groot Koerkamp Dik van Leenen Frank CP Holstege Herman AW Hazewinkel Laura B Creemers Louis C Penning Marianna A Tryfonidou 《Arthritis research & therapy》2013,15(1):R23
Introduction
Early degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). The purpose of this study was to investigate the gene expression profiles involved in this process using NP tissue from non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occurring IVD degeneration.Methods
Dual channel DNA microarrays were used to compare 1) healthy NP tissue containing only NCs (NC-rich), 2) NP tissue with a mixed population of NCs and CLCs (Mixed), and 3) NP tissue containing solely CLCs (CLC-rich) in both non-chondrodystrophic and chondrodystrophic dogs. Based on previous reports and the findings of the microarray analyses, canonical Wnt signaling was further evaluated using qPCR of relevant Wnt target genes. We hypothesized that caveolin-1, a regulator of Wnt signaling that showed significant changes in gene expression in the microarray analyses, played a significant role in early IVD degeneration. Caveolin-1 expression was investigated in IVD tissue sections and in cultured NCs. To investigate the significance of Caveolin-1 in IVD health and degeneration, the NP of 3-month-old Caveolin-1 knock-out mice was histopathologically evaluated and compared with the NP of wild-type mice of the same age.Results
Early IVD degeneration involved significant changes in numerous pathways, including Wnt/β-catenin signaling. With regard to Wnt/β-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non-chondrodystrophic dogs. IVD degeneration involved significant down-regulation of axin2 gene expression. IVD degeneration involved significant down-regulation in Caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of wild-type mice was rich in viable NCs, whereas the NP of Caveolin-1 knock-out mice contained chondroid-like matrix with mainly apoptotic, small, rounded cells.Conclusions
Early IVD degeneration involves down-regulation of canonical Wnt signaling and Caveolin-1 expression, which appears to be essential to the physiology and preservation of NCs. Therefore, Caveolin-1 may be regarded an exciting target for developing strategies for IVD regeneration. 相似文献23.
24.
Philip Lijnzaad Dik van Leenen Marian JA Groot Koerkamp Patrick Kemmeren Frank CP Holstege 《The EMBO journal》2017,36(3):274-290
An important distinction is frequently made between constitutively expressed housekeeping genes versus regulated genes. Although generally characterized by different DNA elements, chromatin architecture and cofactors, it is not known to what degree promoter classes strictly follow regulatability rules and which molecular mechanisms dictate such differences. We show that SAGA‐dominated/TATA‐box promoters are more responsive to changes in the amount of activator, even compared to TFIID/TATA‐like promoters that depend on the same activator Hsf1. Regulatability is therefore an inherent property of promoter class. Further analyses show that SAGA/TATA‐box promoters are more dynamic because TATA‐binding protein recruitment through SAGA is susceptible to removal by Mot1. In addition, the nucleosome configuration upon activator depletion shifts on SAGA/TATA‐box promoters and seems less amenable to preinitiation complex formation. The results explain the fundamental difference between housekeeping and regulatable genes, revealing an additional facet of combinatorial control: an activator can elicit a different response dependent on core promoter class. 相似文献
25.
Background
The integrity of DNA molecules is fundamental for maintaining life. The DNA repair proteins protect organisms against genetic damage, by removal of DNA lesions or helping to tolerate them. DNA repair genes are best known from the gamma-proteobacterium Escherichia coli, which is the most understood bacterial model. However, genome sequencing raises questions regarding uniformity and ubiquity of these DNA repair genes and pathways, reinforcing the need for identifying genes and proteins, which may respond to DNA damage in other bacteria. 相似文献26.
Sebastian Anusha Baburajeev CP Chakrabhavi Dhananjaya Mohan Jessin Mathai Shobith Rangappa Surender Mohan Chandra Shardul Paricharak Lewis Mervin Julian E. Fuchs Mahedra M Andreas Bender Basappa Kanchugarakoppal S. Rangappa 《PloS one》2015,10(10)
In this work, we describe the ‘green’ synthesis of novel 6-(adamantan-1-yl)-2-substituted-imidazo[2,1-b][1,3,4]thiadiazoles (AITs) by ring formation reactions using 1-(adamantan-1-yl)-2-bromoethanone and 5-alkyl/aryl-2-amino1,3,4-thiadiazoles on a nano material base in ionic liquid media. Given the established activity of imidazothiadiazoles against M. tuberculosis, we next examined the anti-TB activity of AITs against the H37Rv strain using Alamar blue assay. Among the tested compounds 6-(adamantan-1-yl)-2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole (3f) showed potent inhibitory activity towards M. tuberculosis with an MIC value of 8.5 μM. The inhibitory effect of this molecule against M. tuberculosis was comparable to the standard drugs such as Pyrazinamide, Streptomycin, and Ciprofloxacin drugs. Mechanistically, an in silico analysis predicted sterol 14α-demethylase (CYP51) as the likely target and experimental activity of 3f in this system corroborated the in silico target prediction. In summary, we herein report the synthesis and biological evaluation of novel AITs against M. tuberculosis that likely target CYP51 to induce their antimycobacterial activity. 相似文献
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Reassortment is important for influenza virus evolution and the generation of novel viruses with pandemic potential; however, the factors influencing reassortment are still poorly understood. Here, using reverse genetics and a replicon assay, we demonstrated that a mixed polymerase complex containing a pandemic (H1N1) 2009 influenza virus PB2 on a seasonal H1N1 virus background has reduced polymerase activity, leading to impaired virus viability. Adaptation of viruses containing the mixed polymerase complex resulted in compensatory mutations in PB1. Taken together, our results identify the cooperation between PB2 and PB1 as an important restricting factor for reassortment of influenza viruses. 相似文献
29.
Studies on the binding site of the galactose-specific agglutinin PA-IL from Pseudomonas aeruginosa 总被引:1,自引:0,他引:1
The binding properties of Pseudomonas aeruginosa agglutinin-I (PA-IL) with
glycoproteins (gps) and polysaccharides were studied by both the
biotin/avidin-mediated microtiter plate lectin-binding assay and the
inhibition of agglutinin-glycan interaction with sugar ligands. Among 36
glycans tested for binding, PA-IL reacted best with two glycoproteins
containing Galalpha1-->4Gal determinants and a human blood group ABO
precursor equivalent gp, but this lectin reacted weakly or not at all with
A and H active gps or sialylated gps. Among the mammalian disaccharides
tested by the inhibition assay, the human blood group Pkactive
Galalpha1-->4Gal, was the best. It was 7.4-fold less active than
melibiose (Galalpha1-->6Glc). PA-IL has a preference for the
alpha-anomer in decreasing order as follows: Galalpha1-->6
>Galalpha1-->4 >Galalpha1-->3. Of the monosaccharides studied,
the phenylbeta derivatives of Gal were much better inhibitors than the
methylbeta derivative, while only an insignificant difference was found
between the Galalpha anomer of methyl- and p -NO2-phenyl derivatives. From
these results, it can be concluded that the combining size of the
agglutinin is as large as a disaccharide of the alpha-anomer of Gal at
nonreducing end and most complementary to Galalpha1-->6Glc. As for the
combining site of PA-IL toward the beta-anomer, the size is assumed to be
less than that of Gal; carbon-6 in the pyranose form is essential, and
hydrophobic interaction is important for binding.
相似文献
30.