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91.
Bianco F Ceruti S Colombo A Fumagalli M Ferrari D Pizzirani C Matteoli M Di Virgilio F Abbracchio MP Verderio C 《Journal of neurochemistry》2006,99(3):745-758
Microglia, glial cells with an immunocompetent role in the CNS, react to stimuli from the surrounding environment with alterations of their phenotypic response. Amongst other activating signals, the endotoxin lipopolysaccharide (LPS) is widely used as a tool to mimic bacterial infection in the CNS. LPS-activated microglia undergo dramatic changes in cell morphology/activity; in particular, they stop proliferating and differentiate from resting to effector cells. Activated microglia also show modifications of purinoreceptor signalling with a significant decrease in P2X(7) expression. In this study, we demonstrate that the down-regulation of the P2X(7) receptor in activated microglia may play an important role in the antiproliferative effect of LPS. Indeed, chronic blockade of the P2X(7) receptor by antagonists (oxidized ATP, KN62 and Brilliant Blue G), or treatment with the ATP-hydrolase apyrase, severely decreases microglial proliferation, down-regulation of P2X(7) receptor expression by small RNA interference (siRNA) decreases cell proliferation, and the proliferation of P2X(7)-deficient N9 clones and primary microglia, in which P2X(7) expression is down-regulated by siRNA, is unaffected by either LPS or P2X(7) antagonists. Furthermore, flow cytometric analysis indicates that exposure to oxidized ATP or treatment with LPS reversibly decreases cell cycle progression, without increasing the percentage of apoptotic cells. Overall, our data show that the P2X(7) receptor plays an important role in controlling microglial proliferation by supporting cell cycle progression. 相似文献
92.
The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor 总被引:15,自引:0,他引:15
Ciana P Fumagalli M Trincavelli ML Verderio C Rosa P Lecca D Ferrario S Parravicini C Capra V Gelosa P Guerrini U Belcredito S Cimino M Sironi L Tremoli E Rovati GE Martini C Abbracchio MP 《The EMBO journal》2006,25(19):4615-4627
Nucleotides and cysteinyl-leukotrienes (CysLTs) are unrelated signaling molecules inducing multiple effects through separate G-protein-coupled receptors: the P2Y and the CysLT receptors. Here we show that GPR17, a Gi-coupled orphan receptor at intermediate phylogenetic position between P2Y and CysLT receptors, is specifically activated by both families of endogenous ligands, leading to both adenylyl cyclase inhibition and intracellular calcium increases. Agonist-response profile, as determined by [(35)S]GTPgammaS binding, was different from that of already known CysLT and P2Y receptors, with EC(50) values in the nanomolar and micromolar range, for CysLTs and uracil nucleotides, respectively. Both rat and human receptors are highly expressed in the organs typically undergoing ischemic damage, that is, brain, heart and kidney. In vivo inhibition of GPR17 by either CysLT/P2Y receptor antagonists or antisense technology dramatically reduced ischemic damage in a rat focal ischemia model, suggesting GPR17 as the common molecular target mediating brain damage by nucleotides and CysLTs. In conclusion, the deorphanization of GPR17 revealed a dualistic receptor for two endogenous unrelated ligand families. These findings may lead to dualistic drugs of previously unexplored therapeutic potential. 相似文献
93.
A model of the carbohydrate recognition domain CRD, residues 111-245, of
hamster galectin-3 has been made using homology modeling and dynamics
minimization methods. The model is based on the known x-ray structures of
bovine galectin-1 and human galectin-2. The oligosaccharides
NeuNAc-alpha2,3-Gal-beta1,4-Glc and GalNAc-alpha1, 3-
[Fuc-alpha1,2]-Gal-beta1,4-Glc, known to be specific high-affinity ligands
for galectin-3, as well as lactose recognized by all galectins were docked
in the galectin-3 CRD model structure and a minimized binding conformation
found in each case. These studies indicate a putative extended
carbohydrate-binding subsite in the hamster galectin- 3 involving Arg139,
Glu230, and Ser232 for NeuNAc-alpha2,3-; Arg139 and Glu160 for
fucose-alpha1,2-; and Arg139 and Ile141 for GalNAc-alpha1,3- substituents
on the primary galactose. Each of these positions is variable within the
whole galectin family. Two of these residues, Arg139 and Ser232, were
selected for mutagenesis to probe their importance in this newly identified
putative subsite. Residue 139 adopts main-chain dihedral angles
characteristic of an isolated bridge structural feature, while residue 232
is the C-terminal residue of beta- strand-11, and is followed immediately
by an inverse gamma-turn. A systematic series of mutant proteins have been
prepared to represent the residue variation present in the aligned
sequences of galectins-1, - 2, and -3. Minimized docked models were
generated for each mutant in complex with NeuNAc-alpha2,3-Gal-beta1,4-Glc,
GalNAc-alpha1, 3-[Fuc- alpha1,2]-Gal-beta1,4- Glc, and Gal-beta1,4-Glc.
Correlation of the computed protein-carbohydrate interaction energies for
each lectin- oligosaccharide pair with the experimentally determined
binding affinities for fetuin and asialofetuin or the relative potencies of
lactose and sialyllactose in inhibiting binding to asiolofetuin is
consistent with the postulated key importance of Arg139 in recognition of
the extended sialylated ligand.
相似文献
94.
Nucleotide sequence analysis of the human salivary protein genes HIS1 and HIS2, and evolution of the STATH/HIS gene family 总被引:1,自引:0,他引:1
Human histatins are a family of low-M(r), neutral to very basic,
histidine-rich salivary polypeptides. They probably function as part of the
nonimmune host defense system in the oral cavity. A 39-kb region of DNA
containing the HIS1 and HIS2 genes was isolated from two human genomic
phage libraries as a series of overlapping clones. The nucleotide sequences
of the HIS1 gene and part of the HIS2(1) gene were determined. The
transcribed region of HIS1 spans 8.5 kb and contains six exons and five
introns. The HIS1 and HIS2(1) genes exhibit 89% overall sequence identity,
with exon sequences exhibiting 95% identity. The two loci probably arose by
a gene duplication event approximately 15-30 Mya. The HIS1 sequence data
were also compared with that of STATH. Human statherin is a low-M(r) acidic
phosphoprotein that acts as an inhibitor of precipitation of calcium
phosphate salts in the oral cavity. The HIS1 and STATH genes show nearly
identical overall gene structures. The HIS1 and STATH loci exhibit 77%-81%
sequence identity in intron DNA and 80%-88% sequence identity in noncoding
exons but only 38%-43% sequence identity in the protein-coding regions of
exons 4 and 5. These unusual data suggest that HIS1, HIS2, and STATH belong
to a single gene family exhibiting accelerated evolution between the HIS
and STATH coding sequences.
相似文献
95.
An exception to the generally conservative nature of plastid gene evolution
is the gene coding for the beta" subunit of RNA polymerase, rpoC2. Previous
work by others has shown that maize and rice have an insertion in the
coding region of rpoC2, relative to spinach and tobacco. To assess the
distribution of this extra coding sequence, we surveyed a broad
phylogenetic sample comprising 55 species from 17 angiosperm families by
using Southern hybridization. The extra coding sequence is restricted to
the grasses (Poaceae). DNA sequence analysis of 11 species from all five
subfamilies within the grass family demonstrates that the extra sequence in
the coding region of rpoC2 is a repetitive array that exhibits more than a
twofold increase in nucleotide substitution, as well as a large number of
insertion/deletion events, relative to the adjacent flanking sequences. The
structure of the array suggests that slipped-strand mispairing causes the
repeated motifs and adds to the mechanisms through which the coding
sequence of plastid genes are known to evolve. Phylogenetic analyses based
on the sequence data from grass species support several relationships
previously suggested by morphological work, but they are ambiguous about
broad relationships within the family.
相似文献
96.
Background
The Burkholderia cepacia complex (Bcc) is a collection of nine genotypically distinct but phenotypically similar species. They show wide ecological diversity and include species that are used for promoting plant growth and bio-control as well species that are opportunistic pathogens of vulnerable patients. Over recent years the Bcc have emerged as problematic pathogens of the CF lung. Pseudomonas aeruginosa is another important CF pathogen. It is able to synthesise hydrogen cyanide (HCN), a potent inhibitor of cellular respiration. We have recently shown that HCN production by P. aeruginosa may have a role in CF pathogenesis. This paper describes an investigation of the ability of bacteria of the Bcc to make HCN. 相似文献97.
98.
Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia 总被引:17,自引:0,他引:17
Bianco F Pravettoni E Colombo A Schenk U Möller T Matteoli M Verderio C 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(11):7268-7277
ATP has been indicated as a primary factor in microglial response to brain injury and inflammation. By acting on different purinergic receptors 2, ATP is known to induce chemotaxis and stimulate the release of several cytokines from these cells. The activation of purinergic receptors 2 in microglia can be triggered either by ATP deriving from dying cells, at sites of brain injury or by ATP released from astrocytes, in the absence of cell damage. By the use of a biochemical approach integrated with video microscopy experiments, we investigated the functional consequences triggered in microglia by ATP released from mechanically stimulated astrocytes, in mixed glial cocultures. Astrocyte-derived ATP induced in nearby microglia the formation and the shedding of membrane vesicles. Vesicle formation was inhibited by the ATP-degrading enzyme apyrase or by P2X(7)R antagonists. Isolation of shed vesicles, followed by IL-1beta evaluation by a specific ELISA revealed the presence of the cytokine inside the vesicular organelles and its subsequent efflux into the extracellular medium. IL-1beta efflux from shed vesicles was enhanced by ATP stimulation and inhibited by pretreatment with the P2X(7) antagonist oxidized ATP, thus indicating a crucial involvement of the pore-forming P2X(7)R in the release of the cytokine. Our data identify astrocyte-derived ATP as the endogenous factor responsible for microvesicle shedding in microglia and reveal the mechanisms by which astrocyte-derived ATP triggers IL-1beta release from these cells. 相似文献
99.
100.
Summary. A complex series of events involving inflammation, cell migration and proliferation, ECM stabilisation and remodelling, neovascularisation and apoptosis are crucial to the tissue response to injury. Wound healing involves the dynamic interactions of multiple cells types with components of the extracellular matrix (ECM) and growth factors. Impaired wound healing as a consequence of aging, injury or disease may lead to serious disabilities and poor quality of life. Abnormal wound healing may also lead to inflammatory and fibrotic conditions (such as renal and pulmonary fibrosis). Therefore identification of the molecular events underlying wound repair is essential to develop new effective treatments in support to patients and the wound care sector.Recent advances in the understating of the physiological functions of tissue transglutaminase a multi functional protein cross-linking enzyme which stabilises tissues have demonstrated that its biological activities interrelate with wound healing phases at multiple levels. This review describes our view of the function of tissue transglutaminase in wound repair under normal and pathological situations and highlights its potential as a strategic therapeutic target in the development of new treatments to improve wound healing and prevent scarring. 相似文献