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Aminothiazoles inhibit RANKL‐ and LPS‐mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells 下载免费PDF全文
Anna Kats Maria Norgård Zenebech Wondimu Catalin Koro Hernán Concha Quezada Göran Andersson Tülay Yucel‐Lindberg 《Journal of cellular and molecular medicine》2016,20(6):1128-1138
Periodontitis is characterized by chronic inflammation and osteoclast‐mediated bone loss regulated by the receptor activator of nuclear factor‐κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). The aim of this study was to investigate the effect of aminothiazoles targeting prostaglandin E synthase‐1 (mPGES‐1) on RANKL‐ and lipopolysaccharide (LPS)‐mediated osteoclastogenesis and prostaglandin E2 (PGE2) production in vitro using the osteoclast precursor RAW 264.7 cells. RAW 264.7 cells were treated with RANKL or LPS alone or in combination with the aminothiazoles 4‐([4‐(2‐naphthyl)‐1,3‐thiazol‐2‐yl]amino)phenol (TH‐848) or 4‐(3‐fluoro‐4‐methoxyphenyl)‐N‐(4‐phenoxyphenyl)‐1,3‐thiazol‐2‐amine (TH‐644). Aminothiazoles significantly decreased the number of multinucleated tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclast‐like cells in cultures of RANKL‐ and LPS‐stimulated RAW 264.7 cells, as well as reduced the production of PGE2 in culture supernatants. LPS‐treatment induced mPGES‐1 mRNA expression at 16 hrs and the subsequent PGE2 production at 72 hrs. Conversely, RANKL did not affect PGE2 secretion but markedly reduced mPGES‐1 at mRNA level. Furthermore, mRNA expression of TRAP and cathepsin K (CTSK) was reduced by aminothiazoles in RAW 264.7 cells activated by LPS, whereas RANK, OPG or tumour necrosis factor α mRNA expression was not significantly affected. In RANKL‐activated RAW 264.7 cells, TH‐848 and TH‐644 down‐regulated CTSK but not TRAP mRNA expression. Moreover, the inhibitory effect of aminothiazoles on PGE2 production was also confirmed in LPS‐stimulated human peripheral blood mononuclear cell cultures. In conclusion, the aminothiazoles reduced both LPS‐ and RANKL‐mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells, suggesting these compounds as potential inhibitors for treatment of chronic inflammatory bone resorption, such as periodontitis. 相似文献
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Megan J. Agajanian Matthew P. Walker Alison D. Axtman Roberta R. Ruela-de-Sousa D. Stephen Serafin Alex D. Rabinowitz David M. Graham Meagan B. Ryan Tigist Tamir Yuko Nakamichi Melissa V. Gammons James M. Bennett Rafael M. Couñago David H. Drewry Jonathan M. Elkins Carina Gileadi Opher Gileadi Paulo H. Godoi Michael B. Major 《Cell reports》2019,26(1):79-93.e8
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Zenebech Wondimu Gezahegn Gorfu Tomoyuki Kawataki Sergei Smirnov Peter Yurchenco Karl Tryggvason Manuel Patarroyo 《Matrix biology》2006,25(2):89-93
Laminins, a family of large heterotrimeric (alphabetagamma) proteins, are major components of basement membranes implicated in a variety of cellular functions. Different commercial laminin preparations isolated from human placenta have been widely used in functional studies but their molecular properties are poorly known. In the present study, we characterized several of these preparations by ELISA, silver staining and Western blotting, in comparison to mouse laminin 1 (alpha1beta1gamma1), and recombinant human laminins 2 (alpha2beta1gamma1), 8 (alpha4beta1gamma1) and 10 (alpha5beta1gamma1). The cell migration-promoting activity of different batches was also tested. The placenta laminin preparations differed from one another and consisted of highly fragmented proteins, a mixture of laminin isoforms, and/or contaminating fibronectin. Major functional differences between batches were also observed, reflecting molecular heterogeneity. Previous data obtained in functional studies using these preparations need to be interpreted with caution and may require revision, and future functional studies demand prior molecular characterization of the laminins, particularly their alpha-chain. 相似文献
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Noora Pet?j?niemi Matti Korhonen Jarkko Kortesmaa Karl Tryggvason Kiyotoshi Sekiguchi Hironobu Fujiwara Lydia Sorokin Lars-Eric Thornell Zenebech Wondimu Daniel Assefa Manuel Patarroyo Ismo Virtanen 《The journal of histochemistry and cytochemistry》2002,50(8):1113-1130
Recent studies suggest important functions for laminin-8 (Ln-8; alpha4beta1gamma1) in vascular and blood cell biology, but its distribution in human tissues has remained elusive. We have raised a monoclonal antibody (MAb) FC10, and by enzyme-linked immunoassay (EIA) and Western blotting techniques we show that it recognizes the human Ln alpha4-chain. Immunoreactivity for the Ln alpha4-chain was localized in tissues of mesodermal origin, such as basement membranes (BMs) of endothelia, adipocytes, and skeletal, smooth, and cardiac muscle cells. In addition, the Ln alpha4-chain was found in regions of some epithelial BMs, including epidermis, salivary glands, pancreas, esophageal and gastric glands, intestinal crypts, and some renal medullary tubules. Developmental differences in the distribution of Ln alpha4-chain were detected in skeletal muscle, walls of vessels, and intestinal crypts. Ln alpha4- and Ln alpha2-chains co-localized in BMs of fetal skeletal muscle cells and in some epithelial BMs, e.g., in gastric glands and acini of pancreas. Cultured human pulmonary artery endothelial (HPAE) cells produced Ln alpha4-chain as M(r) 180,000 and 200,000 doublet and rapidly deposited it to the growth substratum. In cell-free extracellular matrices of human kidney and lung, Ln alpha4-chain was found as M(r) 180,000 protein. 相似文献
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The voltage trace of neuronal activities can follow multiple timescale dynamics that arise from correlated membrane conductances. Such processes can result in power-law behavior in which the membrane voltage cannot be characterized with a single time constant. The emergent effect of these membrane correlations is a non-Markovian process that can be modeled with a fractional derivative. A fractional derivative is a non-local process in which the value of the variable is determined by integrating a temporal weighted voltage trace, also called the memory trace. Here we developed and analyzed a fractional leaky integrate-and-fire model in which the exponent of the fractional derivative can vary from 0 to 1, with 1 representing the normal derivative. As the exponent of the fractional derivative decreases, the weights of the voltage trace increase. Thus, the value of the voltage is increasingly correlated with the trajectory of the voltage in the past. By varying only the fractional exponent, our model can reproduce upward and downward spike adaptations found experimentally in neocortical pyramidal cells and tectal neurons in vitro. The model also produces spikes with longer first-spike latency and high inter-spike variability with power-law distribution. We further analyze spike adaptation and the responses to noisy and oscillatory input. The fractional model generates reliable spike patterns in response to noisy input. Overall, the spiking activity of the fractional leaky integrate-and-fire model deviates from the spiking activity of the Markovian model and reflects the temporal accumulated intrinsic membrane dynamics that affect the response of the neuron to external stimulation. 相似文献
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Gidey Yirga Wondimu Ersino Hans H. De Iongh Herwig Leirs Kindeya Gebrehiwot Jozef Deckers Hans Bauer 《Mammalian Biology》2013,78(3):193-197
We surveyed density and abundance of spotted hyena (Crocuta crocuta) in the highly degraded and prey depleted Wukro district, northern Ethiopia, with a human population density of 98 persons per square kilometer. A total of 117 spotted hyenas responded to callups, giving a hyena density of 52 hyenas per 100 km2 or a total population of 535 hyenas in the district. We quantified the economic impact of spotted hyena predation on livestock using semi structured interviews with randomly selected households. Respondents indicated a total loss of 203 domestic animals to hyena depredation over the past five years. Average annual depredation per household was 0.13 livestock worth US$ 6.1. The diet of spotted hyenas was assessed in three sub-districts by scat analysis and showed 99% prey items of domestic origin, only three of 211 scat contained hair of Ethiopian hare (Lepus fagani) and porcupine (Hystrix cristata). We conclude that hyenas in northern Ethiopia live at high density and eat almost exclusively anthropogenic food and are not dependent on conservation areas. 相似文献
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Michael Brad Strader Wayne A. Hicks Tigist Kassa Eileen Singleton Jayashree Soman John S. Olson Mitchell J. Weiss Todd L. Mollan Michael T. Wilson Abdu I. Alayash 《The Journal of biological chemistry》2014,289(32):22342-22357
A pathogenic V67M mutation occurs at the E11 helical position within the heme
pockets of variant human fetal and adult hemoglobins (Hb). Subsequent
post-translational modification of Met to Asp was reported in γ subunits
of human fetal Hb Toms River (γ67(E11)Val → Met) and β
subunits of adult Hb (HbA) Bristol-Alesha (β67(E11)Val → Met) that
were associated with hemolytic anemia. Using kinetic, proteomic, and crystal
structural analysis, we were able to show that the Met → Asp
transformation involves heme cycling through its oxoferryl state in the
recombinant versions of both proteins. The conversion to Met and Asp enhanced
the spontaneous autoxidation of the mutants relative to wild-type HbA and human
fetal Hb, and the levels of Asp were elevated with increasing levels of hydrogen
peroxide (H2O2). Using
H218O2, we verified incorporation of
18O into the Asp carboxyl side chain confirming the role of
H2O2 in the oxidation of the Met side chain. Under
similar experimental conditions, there was no conversion to Asp at the
αMet(E11) position in the corresponding HbA Evans (α62(E11)Val
→ Met). The crystal structures of the three recombinant Met(E11) mutants
revealed similar thioether side chain orientations. However, as in the solution
experiments, autoxidation of the Hb mutant crystals leads to electron density
maps indicative of Asp(E11) formation in β subunits but not in α
subunits. This novel post-translational modification highlights the
nonequivalence of human Hb α, β, and γ subunits with
respect to redox reactivity and may have direct implications to
α/β hemoglobinopathies and design of oxidatively stable Hb-based
oxygen therapeutics. 相似文献