UMLS:C0021311 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0021311 (Infection)
38,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Helicobacter pylori, one of the most common bacterial pathogens, colonizes the human stomach and causes a variety of gastric diseases. This pathogen elicits a range of phenotypic responses in infected cultured AGS gastric epithelial cells, including expression of proinflammatory genes and changes in the actin cytoskeleton. Some of these responses are mediated by the type IV secretion system (T4SS) encoded by the cag pathogenicity island. We have used two global approaches, namely 2-DE combined with PMF and cDNA expression array analyses, to study in both a comprehensive and quantitative manner the protein profile and the temporal patterns of mRNA accumulation in AGS cells upon infection with H. pylori and isogenic T4SS mutants. We identified 140 transcripts and detected 190 protein species that were differentially regulated upon infection. Infection with wild-type H. pylori induced expression of a variety of host genes and changes in protein pattern involved in transcriptional responses, cell shape regulation and signal transduction. Among them, some were differentially regulated in a cag PAI-dependent manner, as shown by both the proteomic and cDNA expression array approaches. While 2-DE and PMF allowed us to examine the protein profiles in the infected host, array analysis enabled us to demonstrate dynamic temporal changes in host gene expression profile. In conclusion, our combined application of the two global approaches provides further molecular details on how the host cell responds to infection by H. pylori and its isogenic T4SS mutants on both transcriptional and protein levels. The findings pinpoint host proteins such as serine/threonine and tyrosine kinases, transcription factors, cell cycle related components and actin cytoskeletal signaling molecules as potential targets of individual H. pylori virulence determinants. This study serves as a basis for future work on transcription and proteome analyses of the H. pylori infection model.
...
PMID:Gene expression and protein profiling of AGS gastric epithelial cells upon infection with Helicobacter pylori. 1614 11

For fluoroquinolones AUC/MIC ratios are known to correlate with clinical outcomes for patients suffering from respiratory tract infections (RTI) and complicated skin and skin structure infections (cSSSI). This paper describes the results of a population PK/PD analysis followed by Monte Carlo simulations to estimate clinical outcome and the microbiological breakpoints for a 400 mg once-daily moxifloxacin (MFX) treatment schedule. Based on PK data from 416 subjects, a non-compartmental population PK model was developed first to describe the expected exposure (AUC) distribution in humans. Height and gender were the main population covariates with moderate influence on PK variability. Albumin, bilirubin, and creatinine clearance (as derived from serum creatinine according to Cockroft and Gault) had a mild effect on AUC. Residual unexplained variability of AUC was low (13.1%). To describe the PD function the MIC distribution pattern of more than 3,000 isolates of S. pneumoniae as the representative pathogen for RTI (MIC90, range: 0.125; 0.006-4 mg/l) was built into the population PK/PD model for RTI, while 126 isolates of methicillin-susceptible Staphylococcus aureus strains (MIC90, range: 0.125; 0.03-4 mg/l) were the basis for the PD function in cSSSI. Simulations for 20,000 (RTI) and 4,000 (cSSSI) subjects were performed to evaluate the AUC/MIC characteristics for moxifloxacin for these two diseases. Overall, a target hit rate was THR = 99% for RTI, while it amounted to THR = 97.5% for cSSSI when applying a threshold of AUIC > 30 [h] as the PK/PD surrogate parameter which is predictive for a positive clinical outcome. A target hit rate of THR = 93.6 % (RTI) and 97.3% (cSSSI), respectively, was predicted when assuming that an AUIC of > 125 [h] is indicative of clinical success (as shown for ciprofloxacin and severe RTIs due to gram-negative infections). In clinical trials with patients receiving 400 mg moxifloxacin once daily for the treatment of community-acquired pneumonia (CAP) success rate was approximately 93.5%. From the simulations performed for RTI an analysis of the overall likelihood of therapeutic failure broken down according to MICs suggests that the risk of a negative clinical outcome at a MIC = 1 mg/l is approximately 0.25% (for MIC = 2 mg/l: predicted likelihood approximately 0.5%) assuming that a cutoff of AUIC = 30 [h] is applicable. Likewise, for cSSSI the probability to fail is predicted as 1.6% at a MIC = 2 mg/l (no strains with MICs between 0.5 and 1 mg/l available from the clinical isolates). These findings are in line with the breakpoint definition of the former National Committee for Clinical Laboratory Standards (NCCLS) for MFX (=1 mg/L to differentiate between susceptible and intermediately susceptible microorganisms; = 2 mg/l to separate intermediate from resistant pathogens). The results of the investigation indicate that the noncompartmental PK/PD model for MFX is suitable to predict clinical outcomes in CAP and cSSSI caused by gram-positive aerobe pathogens. They confirmed that a 400 mg once-daily dosing regimen is suitable to treat these diseases successfully. They are in agreement with the microbiological breakpoints determined by independent methods by the Clinical and Laboratory Standards Institute (CLSI) (former NCCLS).
Infection 2005 Dec
PMID:The integrated use of pharmacokinetic and pharmacodynamic models for the definition of breakpoints. 1651 9

Enterohaemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) both utilize type III secretion systems that translocate the effector protein Tir into the plasma membrane of mammalian cells in order to stimulate localized actin assembly into 'pedestals'. The Tir molecule that EPEC delivers is phosphorylated within its C-terminus on tyrosine-474, and a clustered 12-residue phosphopeptide encompassing this residue initiates an efficient signalling cascade that triggers actin polymerization. In addition to Y474, tyrosine-454 of EPEC Tir is phosphorylated, although inefficiently, and promotes actin polymerization at low levels. In contrast to EPEC Tir, EHEC Tir lacks Y474 and triggers pedestal formation in a phosphotyrosine-independent manner by interacting with an additional effector protein, EspF(U). To identify EHEC Tir sequences that regulate localized actin assembly, we circumvented the strict requirements for type III translocation and directly expressed Tir derivatives in mammalian cells by transfection. Infection of Tir-expressing cells with a Tir-deficient EHEC strain demonstrated that ectopically expressed Tir localizes to the plasma membrane, is modified by mammalian serine-threonine kinases and is fully functional for actin pedestal formation. Removal of portions of the cytoplasmic N-terminus of Tir resulted in the generation of abnormally long pedestals, indicating that this region of EHEC Tir influences pedestal length. In the presence of the entire N-terminal domain, a 12-residue peptide from the C-terminus of EHEC Tir is both necessary and sufficient to recruit EspF(U) and initiate actin pedestal formation. This peptide encompasses the portion of EHEC Tir analogous to the EPEC Tir-Y454 region and is present within the Tir molecules of all pedestal-forming bacteria, suggesting that this sequence harbours a conserved signalling function.
...
PMID:Enterohaemorrhagic Escherichia coli Tir requires a C-terminal 12-residue peptide to initiate EspF-mediated actin assembly and harbours N-terminal sequences that influence pedestal length. 1692 67

AMP-activated protein kinase (AMPK) is a major metabolic regulator in the cardiac myocyte. Recently, LKB1 was identified as a kinase that regulates AMPK. Using immunoblot analysis, we confirmed high expression of LKB1 in isolated rat cardiac myocytes but show that, under basal conditions, LKB1 is primarily localized to the nucleus, where it is inactive. We examined the role of LKB1 in cardiac myocytes, using adenoviruses that express LKB1, and its binding partners Ste20-related adaptor protein (STRADalpha) and MO25alpha. Infection of neonatal rat cardiac myocytes with all three adenoviruses substantially increased LKB1/STRADalpha/MO25alpha expression, LKB1 activity, and AMPKalpha phosphorylation at its activating phosphorylation site (threonine-172). Since activation of AMPK can inhibit hypertrophic growth and since LKB1 is upstream of AMPK, we hypothesized that expression of an active LKB1 complex would also inhibit protein synthesis associated with hypertrophic growth. Expression of the LKB1/STRADalpha/MO25alpha complex in neonatal rat cardiac myocytes inhibited the increase in protein synthesis observed in cells treated with phenylephrine (measured via [(3)H]phenylalanine incorporation). This was associated with a decreased phosphorylation of p70S6 kinase and its substrate S6 ribosomal protein, key regulators of protein synthesis. In addition, we show that the pathological cardiac hypertrophy in transgenic mice with cardiac-specific expression of activated calcineurin is associated with a significant decrease in LKB1 expression. Together, our data show that increased LKB1 activity in the cardiac myocyte can decrease hypertrophy-induced protein synthesis and suggest that LKB1 activation may be a method for the prevention of pathological cardiac hypertrophy.
...
PMID:Expression of an active LKB1 complex in cardiac myocytes results in decreased protein synthesis associated with phenylephrine-induced hypertrophy. 1709 23

Infection of domestic cats with feline immunodeficiency virus (FIV) is an important model system for studying human immunodeficiency virus type 1 (HIV-1) infection due to numerous similarities in pathogenesis induced by these two lentiviruses. However, many molecular aspects of FIV replication remain poorly understood. It is well established that retroviruses use short peptide motifs in Gag, known as late domains, to usurp cellular endosomal sorting machinery and promote virus release from infected cells. For example, the Pro-Thr/Ser-Ala-Pro [P(T/S)AP] motif of HIV-1 Gag interacts directly with Tsg101, a component of the endosomal sorting complex required for transport I (ESCRT-I). A Tyr-Pro-Asp-Leu (YPDL) motif in equine infectious anemia virus (EIAV), and a related sequence in HIV-1, bind the endosomal sorting factor Alix. In this study we sought to identify and characterize FIV late domain(s) and elucidate cellular machinery involved in FIV release. We determined that mutagenesis of a PSAP motif in FIV Gag, small interfering RNA-mediated knockdown of Tsg101 expression, and overexpression of a P(T/S)AP-binding fragment of Tsg101 (TSG-5') each inhibited FIV release. We also observed direct binding of FIV Gag peptides to Tsg101. In contrast, mutagenesis of a potential Alix-binding motif in FIV Gag did not affect FIV release. Similarly, expression of the HIV-1/EIAV Gag-binding domain of Alix (Alix-V) did not disrupt FIV budding, and FIV Gag peptides showed no affinity for Alix-V. Our data demonstrate that FIV relies predominantly on a Tsg101-binding PSAP motif in the C terminus of Gag to promote virus release in HeLa cells, and this budding mechanism is highly conserved in feline cells.
...
PMID:Molecular characterization of feline immunodeficiency virus budding. 1809 66

The human pathogen Helicobacter pylori influences cell adhesion, proliferation, and apoptosis and is involved in gastric adenocarcinoma formation. In our study we analyzed the impact of H. pylori infection on the regulation of beta-catenin, which plays a central role in both cell adhesion and tumorigenesis. Infection of Madin-Darby canine kidney cells with H. pylori led to suppression of Ser/Thr phosphorylation and ubiquitin-dependent degradation of beta-catenin and to up-regulation of lymphoid enhancer-binding factor/T cell factor (LEF/TCF)-dependent transcription. The impaired Ser/Thr phosphorylation of beta-catenin was accompanied by an increase of glycogen synthase kinase 3beta phosphorylation. Inhibition of Akt kinase, an up-stream regulator of glycogen synthase kinase 3, by a specific inhibitor Akti-1/2 or depletion of Akt with siRNA restored Ser/Thr phosphorylation of beta-catenin. We conclude that glycogen synthase kinase 3beta activity exerts an important role in beta-catenin regulation and LEF/TCF transactivation in H. pylori-infected Madin-Darby canine kidney cells.
...
PMID:Helicobacter pylori suppresses glycogen synthase kinase 3beta to promote beta-catenin activity. 1877 41

Infection with feline infectious peritonitis virus (FIPV), a feline coronavirus, frequently leads to death in spite of a strong humoral immune response. In previous work, we reported that infected monocytes, the in vivo target cells of FIPV, express viral proteins in their plasma membranes. These proteins are quickly internalized upon binding of antibodies. As the cell surface is cleared from viral proteins, internalization might offer protection against antibody-dependent cell lysis. Here, the internalization and subsequent trafficking of the antigen-antibody complexes were characterized using biochemical, cell biological and genetic approaches. Internalization occurred through a clathrin- and caveolae-independent pathway that did not require dynamin, rafts, actin or rho-GTPases. These findings indicate that the viral antigen-antibody complexes were not internalized through any of the previously described pathways. Further characterization showed that this internalization process was independent from phosphatases and tyrosine kinases but did depend on serine/threonine kinases. After internalization, the viral antigen-antibody complexes passed through the early endosomes, where they resided only briefly, and accumulated in the late endosomes. Between 30 and 60 min after antibody addition, the complexes left the late endosomes but were not degraded in the lysosomes. This study reveals what is probably a new internalization pathway into primary monocytes, confirming once more the complexity of endocytic processes.
...
PMID:Surface-expressed viral proteins in feline infectious peritonitis virus-infected monocytes are internalized through a clathrin- and caveolae-independent pathway. 1893 Oct 69

Capsicum plants harboring the Hk gene (Hk) show resistance to Paprika mild mottle virus (PaMMV) at 32 degrees C but not 24 degrees C. To identify the viral elicitor that activates the Hk-mediated resistance, several chimeric viral genomes were constructed between PaMMV and Tobacco mosaic virus-L. Infection patterns of these chimeric viruses in Hk-harboring plants revealed responsibility of PaMMV replicase genes for activation of the Hk-mediated resistance. The comparison of nucleotide sequence of replicase genes between PaMMV and PaHk1, an Hk-resistance-breaking strain of PaMMV, revealed that the adenine-to-uracil substitution at the nucleotide position 721 causes an amino acid change from threonine to serine at the 241st residue in the methyltransferase domain. Introduction of the A721U mutation into the replicase genes of parental PaMMV overcame the Hk resistance at 32 degrees C. The results indicate that Hk-mediated resistance is induced by PaMMV replicase proteins and that methyltransferase domain has a role in this elicitation.
...
PMID:Single amino acid substitution in the methyltransferase domain of Paprika mild mottle virus replicase proteins confers the ability to overcome the high temperature-dependent Hk gene-mediated resistance in Capsicum plants. 1910 Jul 93

The forkhead box transcription factor FOXO1 is highly expressed in granulosa cells of growing follicles but is down-regulated by FSH in culture or by LH-induced luteinization in vivo. To analyze the function of FOXO1, we infected rat and mouse granulosa cells with adenoviral vectors expressing two FOXO1 mutants: a gain-of-function mutant FOXOA3 that has two serine residues and one threonine residue mutated to alanines rendering this protein constitutively active and nuclear and FOXOA3-mutant DNA-binding domain (mDBD) in which the DBD is mutated. The infected cells were then treated with vehicle or FSH for specific time intervals. Infection of the granulosa cells was highly efficient, caused only minimal apoptosis, and maintained FOXO1 protein at levels of the endogenous protein observed in cells before exposure to FSH. RNA was prepared from control and adenoviral infected cells exposed to vehicle or FSH for 12 and 24 h. Affymetrix microarray and database analyses identified, and real time RT-PCR verified, that genes within the lipid, sterol, and steroidogenic biosynthetic pathways (Hmgcs1, Hmgcr, Mvk, Sqle, Lss, Cyp51, Tm7sf2, Dhcr24 and Star, Cyp11a1, and Cyp19), including two key transcriptional regulators Srebf1 and Srebf2 of cholesterol biosynthesis and steroidogenesis (Nr5a1, Nr5a2), were major targets induced by FSH and suppressed by FOXOA3 and FOXOA3-mDBD in the cultured granulosa cells. By contrast, FOXOA3 and FOXOA3-mDBD induced expression of Cyp27a1 mRNA that encodes an enzyme involved in cholesterol catabolism to oxysterols. The genes up-regulated by FSH in cultured granulosa cells were also induced in granulosa cells of preovulatory follicles and corpora lutea collected from immature mice primed with FSH (equine choriogonadotropin) and LH (human choriogonadotropin), respectively. Conversely, Foxo1 and Cyp27a1 mRNAs were reduced by these same treatments. Collectively, these data provide novel evidence that FOXO1 may play a key role in granulosa cells to modulate lipid and sterol biosynthesis, thereby preventing elevated steroidogenesis during early stages of follicle development.
...
PMID:FSH and FOXO1 regulate genes in the sterol/steroid and lipid biosynthetic pathways in granulosa cells. 1919 34

Helicobacter pylori is a major etiological agent in the development of chronic gastritis, duodenal ulcer and gastric carcinoma in humans. Virulent H. pylori strains harbor a type IV secretion system (T4SS) encoded by the cag pathogenicity island. This T4SS injects the CagA protein into gastric epithelial cells leading to actin-cytoskeletal rearrangements followed by cell elongation and scattering. Here we report that PMA (4beta-phorbol-12-myristate-13-acetate), a well-known cell-permeable activator of protein kinase C (PKC), induces a remarkably similar cellular phenotype as compared to infection with H. pylori. PKCs comprise a large family of serine/threonine kinases which are important for multiple physiological processes of host cells. We therefore investigated the role of individual PKC members and the signalling pathways involved in phenotypical outcome. Using isoform-specific silencing RNAs and pharmacological inhibitors we found that two isoforms, PKC-alpha and PKC-delta, were essential for both PMA- and H. pylori-induced elongation phenotype. Furthermore, we provide evidence that PKC-delta activity is profoundly stimulated during the course of infection using activation-specific antibodies against PKC phosphorylated at threonine residue 505 or serine residue 660. Infection with H. pylori wild-type and mutants showed that at least two bacterial factors activate PKC-delta in a time-dependent manner, one of which is CagA. Immunofluorescence microscopy studies further demonstrated that phosphorylated PKC-delta is accumulated and recruited to dynamic actin-structures at the cell membrane. Finally, we show that PKC-delta specifically targets Raf kinase to stimulate the Erk1/2 kinase pathway, which is also crucial for phenotypical outcome. Thus, PKC-delta is another important mediator of H. pylori-induced pathogenesis.
...
PMID:Helicobacter pylori activates protein kinase C delta to control Raf in MAP kinase signalling: role in AGS epithelial cell scattering and elongation. 1943 14

<< Previous 1 2 3 4 5 6 Next >>