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101.
Hideo Kohno Yu Chen Brian M. Kevany Eric Pearlman Masaru Miyagi Tadao Maeda Krzysztof Palczewski Akiko Maeda 《The Journal of biological chemistry》2013,288(21):15326-15341
Although several genetic and biochemical factors are associated with the pathogenesis of retinal degeneration, it has yet to be determined how these different impairments can cause similar degenerative phenotypes. Here, we report microglial/macrophage activation in both a Stargardt disease and age-related macular degeneration mouse model caused by delayed clearance of all-trans-retinal from the retina, and in a retinitis pigmentosa mouse model with impaired retinal pigment epithelium (RPE) phagocytosis. Mouse microglia displayed RPE cytotoxicity and increased production of inflammatory chemokines/cytokines, Ccl2, Il1b, and Tnf, after coincubation with ligands that activate innate immunity. Notably, phagocytosis of photoreceptor proteins increased the activation of microglia/macrophages and RPE cells isolated from model mice as well as wild-type mice. The mRNA levels of Tlr2 and Tlr4, which can recognize proteins as their ligands, were elevated in mice with retinal degeneration. Bone marrow-derived macrophages from Tlr4-deficient mice did not increase Ccl2 after coincubation with photoreceptor proteins. Tlr4−/−Abca4−/−Rdh8−/− mice displayed milder retinal degenerative phenotypes than Abca4−/−Rdh8−/− mice. Additionally, inactivation of microglia/macrophages by pharmacological approaches attenuated mouse retinal degeneration. This study demonstrates an important contribution of TLR4-mediated microglial activation by endogenous photoreceptor proteins in retinal inflammation that aggravates retinal cell death. This pathway is likely to represent an underlying common pathology in degenerative retinal disorders. 相似文献
102.
Divyendu Singh Rongsu Qi Jarrat L. Jordan Lani San Mateo C. Cheng Kao 《The Journal of biological chemistry》2013,288(12):8258-8268
LL-37 is an antimicrobial peptide produced by human cells that can down-regulate the lipopolysaccharide-induced innate immune responses and up-regulate double-stranded (ds) RNA-induced innate responses through Toll-like receptor 3 (TLR3). The murine LL-37 ortholog, mCRAMP, also inhibited lipopolysaccharide-induced responses, but unlike LL-37, it inhibited viral-induced responses in mouse cells. A fluorescence polarization assay showed that LL-37 was able to bind dsRNA better than mCRAMP. In the human lung epithelial cell line BEAS-2B, LL-37, but not mCRAMP, colocalized with TLR3, and the colocalization was increased in the presence of dsRNA. The presence of poly(I:C) increased the accumulation of LL-37 in Rab5 endosomes. Signaling by cells induced with both LL-37 and poly(I:C) was sensitive to inhibitors that affect clathrin-independent trafficking, whereas signaling by poly(I:C) alone was not, suggesting that the LL-37-poly(I:C) complex trafficked to signaling endosomes by a different mechanism than poly(I:C) alone. siRNA knockdown of known LL-37 receptors identified that FPRL1 was responsible for TLR3 signaling induced by LL-37-poly(I:C). These results show that LL-37 and mCRAMP have different activities in TLR3 signaling and that LL-37 can redirect trafficking of poly(I:C) to effect signaling by TLR3 in early endosomes in a mechanism that involves FPRL1. 相似文献
103.
Storrs L. Olson Paul J. Hearty 《Biological journal of the Linnean Society. Linnean Society of London》2013,110(1):235-243
Hermit‐crab transported shells of the West Indian top shell Cittarium pica occur in numerous terrestrial fossil deposits on Bermuda, which is the most remote outpost of this Caribbean species. Cittarium is so far known only from deposits of interglacial ages corresponding to marine isotope stages (MIS) 11, 9, 5e, and 1 (Holocene). In at least the cases of MIS 11 and 5e, Cittarium appears at the very beginning of the interglacial. The species is definitely absent from well‐stratified cave deposits of the last glacial (MIS 4–2). It is hypothesized that colder sea‐surface temperatures (SSTs) during glacial periods caused Cittarium to be extirpated on Bermuda, and that it has made at least four independent colonizations of the island in the past 400 000 years. Because of the limited larval life of Cittarium, the window for colonization may be a very narrow period at the onset of interglacials when the SST has risen sufficiently to make Bermuda habitable but the velocity of the Gulf Stream is still sufficiently rapid to transport viable larvae from the Bahamas. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2013, 110 , 235–243. 相似文献
104.
D.I. Kosik-Bogacka A. Wojtkowiak-Giera A. Kolasa D. Czernomysy-Furowicz N. Lanocha E. Wandurska-Nowak R. Salamatin P.P. Jagodzinski 《Experimental parasitology》2013
Toll-like receptors in the gastrointestinal tract can influence intestinal homeostasis and play a role in the repair and restitution of intestinal epithelium following tissue damage. In our previous study a statistically significant increase in the level of TLR4 and TLR2 gene expression was observed in rats in early stages of hymenolepidosis. Moreover, the immunopositive cell number and the intensity of immunohistochemical staining (indicating the presence of TLRs within intestinal epithelial cells) increased over the infection period. 相似文献
105.
Burcu Kaplan-Türköz Thomas Koelblen Christine Felix Marie-Pierre Candusso David O’Callaghan Annette C. Vergunst Laurent Terradot 《FEBS letters》2013
BtpA/Btp1/TcpB is a virulence factor produced by Brucella species that possesses a Toll interleukin-1 receptor (TIR) domain. Once delivered into the host cell, BtpA interacts with MyD88 to interfere with TLR signalling and modulates microtubule dynamics. Here the crystal structure of the BtpA TIR domain at 3.15 Å is presented. The structure shows a dimeric arrangement of a canonical TIR domain, similar to the Paracoccus denitrificans Tir protein but secured by a unique long N-terminal α-tail that packs against the TIR:TIR dimer. Structure-based mutations and multi-angle light scattering experiments characterized the BtpA dimer conformation in solution. The structure of BtpA will help with studies to understand the mechanisms involved in its interactions with MyD88 and with microtubules. 相似文献
106.
Kerem Teralı Rebecca L. Beavil Richard W. Pickersgill Mark van der Giezen 《Biochemical and biophysical research communications》2013
Small inorganic assemblies of alternating ferrous/ferric iron and sulphide ions, so-called iron–sulphur (Fe–S) clusters, are possibly nature’s most ancient prosthetic groups. One of the early actors in Fe–S cluster biosynthesis is a protein complex composed of a cysteine desulphurase, Nfs1, and its functional binding partner, Isd11. Although the essential function of Nfs1·Isd11 in the liberation of elemental sulphur from free cysteine is well established, little is known about its structure. Here, we provide evidence that shows Isd11 has a profound effect on the oligomeric state of Nfs1. 相似文献
107.
Pingping He Xinping Ouyang Shouhong Zhou Weidong Yin Chaoke Tang Moshe Laudon Shaowen Tian 《Hormones and behavior》2013
Previous studies have shown that melatonin is implicated in modulating learning and memory processing. Melatonin also exerts neuroprotective activities against Aβ-induced injury in vitro and in vivo. Neu-P11 (piromelatine, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide) is a novel melatonin (MT1/MT2) receptor agonist and a serotonin 5-HT1A/1D receptor agonist recently developed for the treatment of insomnia. In the present study we firstly investigated whether Neu-P11 and melatonin enhance memory performance in the novel object recognition (NOR) task in rats, and then assessed whether Neu-P11 and melatonin improve neuronal and cognitive impairment in a rat model of Alzheimer' disease (AD) induced by intrahippocampal Aβ(1–42) injection. The results showed that a single morning or afternoon administration of Neu-P11 enhanced object recognition memory measured at 4 or 24 h after training. Melatonin was effective in the memory facilitating effects only when administered in the afternoon. Further results showed that intrahippocampal Aβ(1–42) injection resulted in hippocampal cellular loss, as well as decreased learning ability and memory in the Y maze and NOR tasks in rats. Neu-P11 but not melatonin attenuated cellular loss and cognitive impairment in the rat AD model. The current data suggest that Neu-P11 may serve as a novel agent for the treatment of AD. 相似文献
108.
David R. Bauman Alan Whitehead Lisa C. Contino Jisong Cui Margarita Garcia-Calvo Xin Gu Nancy Kevin Xiuying Ma Lee-yuh Pai Kashmira Shah Xiaolan Shen Sloan Stribling Hratch J. Zokian Joe Metzger Diane E. Shevell Sherman T. Waddell 《Bioorganic & medicinal chemistry letters》2013,23(12):3650-3653
In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11β-HSD1 inhibitors, we examined a set of 11β-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11β-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11β-HSD1 independent pathway. 相似文献
109.
Changning Wang Christian K. Moseley Stephen M. Carlin Colin M. Wilson Ramesh Neelamegam Jacob M. Hooker 《Bioorganic & medicinal chemistry letters》2013,23(11):3389-3392
EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [3H]-EMPA suggest that it may be used as an imaging agent for OX2 receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [11C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([11C]EMPA), and evaluation as a potential PET tracer for OX2 receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [11C]CH3I in the presence of cesium carbonate in DMSO at room temp afforded [11C]EMPA in 1.5–2.5% yield (non-decay corrected relative to trapped [11C]CH3I at EOS) with ?95% chemical and radiochemical purities. The total synthesis time was 34–36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [11C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging. 相似文献
110.
Patterns of nuclear and organelle inheritance among artificial hybrids of the seaweeds Fucus serratus and F. evanescens were detected using single-strand conformation polymorphism (SSCP). Three alleles were identified in the 231?bp rDNA-ITS1 gene (nuclear): two in F. serratus and one in F. evanescens. Alleles differed by 1–2?bp and all hybrids possessed one allele from each parent. Two haplotypes were present in the 288?bp Rubisco spacer (chloroplast), differentiated by a 33?bp indel. Two haplotypes differing by a single nucleotide were found in a 135?bp region of nad11 gene (mitochondrion). Both organelles are maternally inherited, as all hybrids contained the haplotypes of the parent contributing the egg. Although laboratory hybrids among Fucus spp. have been produced previously, this is the first time that both nuclear and cytoplasmic genetic markers have been used to document inheritance patterns. SSCPs analysed on an automated sequencer offer a rapid and powerful approach for identifying suspected hybrids from field samples, as well as a screen for intraspecific and intra-individual variation in DNA regions prior to confirmation of variations by sequencing. 相似文献