Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulating evidence suggests that C-reactive protein (CRP), at concentrations known to predict diverse vascular insults, directly promotes endothelial cell activation, uncovering a proatherosclerotic and proinflammatory phenotype. In the present study, we hypothesized that (a). hyperglycemia would serve to exaggerate the proatherogenic effects of CRP and (b). the PPARgamma agonist, rosiglitazone would attenuate this effect. Human saphenous vein endothelial cells were studied under the following conditions (n= 10 per group): control, human recombinant CRP (25 microg/ml, 24 h), hyperglycemia (25 mM, 24 h) and hyperglycemia + CRP. In each case, the effects of co-incubation with rosiglitazone (1 microM) were evaluated. Nitric oxide and endothelin-1 release from endothelial cells was quantified, in addition to the expression of adhesion molecules and monocyte chemoattractant chemokine (MCP-1). Incubation of endothelial cells with CRP increased endothelin-1 production, and upregulated adhesion molecule and MCP-1 expression. These proatherogenic effects of CRP were potentiated in the presence of hyperglycemia. CRP also decreased endothelial nitric oxide release, and this effect remained unchanged by hyperglycemia. Importantly, the PPARgamma agonist, rosiglitazone, attenuated the proatherogenic effects of CRP under both basal and hyperglycemic conditions. The direct proatherogenic actions of CRP are exaggerated in the hyperglycemic milieu, and attenuated by rosiglitazone. Elevated CRP levels in patients with diabetes may serve to uncover a severe proatherogenic phenotype.
J Mol Cell Cardiol 2003 Apr
PMID:Hyperglycemia potentiates the proatherogenic effects of C-reactive protein: reversal with rosiglitazone. 1268 21

C-reactive protein (CRP) is an acute phase protein in humans and rabbits that has the ability to bind a number of biologically important ligands including phosphocholine (PCh), histones, and polycations. In addition to this recognition function, ligand-complexed or aggregated CRP is capable of activating the classical complement pathway. We have generated two strains of transgenic mice in order to study CRP-binding to PCh and consequent complement activation. Based on crystallographic and mutagenesis studies in human CRP (huCRP), we mutated Phe66 and Glu81 in the rabbit CRP (rbCRP) gene and generated a strain of transgenic mice (F66Y/E81K), which expressed this variant form of rbCRP. We also mutated Tyr175 in rbCRP to generate transgenic mice which expressed a variant form of rbCRP (Y175A). In vitro, F66Y/E81K rbCRP purified from serum had dramatically reduced binding to PCh. Additionally F66Y/E81K rbCRP not only maintained its ability to bind polycations and histones, but also bound more avidly to specific histones and lysine polymers than wild type (wt) rbCRP. Y175A rbCRP was not able to activate complement when bound to pneumococcal C-polysaccharide (PnC), but was, along with F66Y/E81K and wild type rbCRP, able to activate complement when bound to a small lysine polymer or when directly adsorbed to a solid phase. This complement activation presumably occurs through the classical complement pathway as the three rbCRPs, adsorbed to a solid phase, bound C1q. Taken together, our results demonstrate that the PCh-binding and the polycation-binding sites on rbCRP are distinct but possibly overlapping. The conformational changes in the C1q-binding site of CRP to activate complement depend on the nature of the ligand and on the location of the ligand-binding site.
Mol Immunol 2003 Jun
PMID:The phosphocholine and the polycation-binding sites on rabbit C-reactive protein are structurally and functionally distinct. 1274 11

The aim of our study was to evaluate whether a single dose of cerivastatin at the time of admission of patients with unstable angina pectoris (UAP) or non-Q-wave myocardial infarction (NQMI) can influence the serum level of C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-8 (IL-8) 24 h later. Forty-four patients with rest chest pain and subendocardial ischemia on ECG were randomized to receive cerivastatin 0.3 mg at the time of admission (group C+) to standard therapy or to remain just on standard therapy (group C-). Blood samples for determination of troponin I (TI), CRP, IL-6 and IL-8 were collected at admission (entry level) and 24 h later (final level). Patients with non-physiological baseline levels of TI, as well as patients with progression to Q wave MI were excluded. All baseline, clinical and demographic data and final values of TI were comparable in the two groups. In patients treated with cerivastatin (group C+, n = 13) we observed decrease in the CRP level (-6.73 +/- 3.93 mg/L); on the other hand, in group C- (n = 17) the CRP level increased (+7.92 +/- 2.77 mg/L, p = 0.004). Similar differences were observed also in IL-6: in group C+ the level was significantly reduced as compared with the increase in group C- (-0.76 +/- 0.52 vs. 4.58 +/- 1.49 ng/L, p = 0.005). The level of IL-8 was not affected. Our results suggest that early treatment with cerivastatin can decrease the serum level of CRP and IL-6 in patients with UAP/NQMI; this might positively influence their prognosis. Nevertheless, further studies are needed to support this hypothesis.
Mol Cell Biochem 2003 Apr
PMID:The effect of early treatment by cerivastatin on the serum level of C-reactive protein, interleukin-6, and interleukin-8 in the patients with unstable angina and non-Q-wave myocardial infarction. 1284 42

In Crohn's disease (CD) CD4(+) T-cells producing tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are important for disease progression. T-cell vaccination with such attenuated (gamma-irradiated) CD4(+) T cells may ameliorate the auto-reactive actions of Type-1 T cells through stimulation of interleukin-10 (IL-10)-producing regulatory T cells. This study aimed to propagate and use gut-derived type-1 CD4(+) T-cells for vaccination in CD. In a case study, two patients with CD-activity index (CDAI) >150 for >1 year were vaccinated with 800 x 10(6) attenuated autologous gut-derived CD4(+) T cells producing Type-1 cytokine -- grown in the presence of high concentrations of only IL-2 and IL-4. The T-cell vaccination was safe, causing only minor redness and tenderness at the injection sites. In Case 2, the treatment brought 3-years with active steroid-resistant CD into remission. CDAI dropped from 171 to 76, CD-endoscopic index of severity fell from 20 to eight and C-reactive protein reduced from 165 to 70 nmol/L. Case 1 received rescue infliximab (there was disease progression before sufficient quantities of cells were ready for the second vaccination). We concluded that it is possible to propagate T cells for autologous vaccination for CD and that treatment was safe. One patient, vaccinated according to the protocol, improved with sustained result for >1 year.
Cytokines Cell Mol Ther 2002
PMID:T-cell vaccination in Crohn's disease: principles and presentation of the first two cases. 1285 Aug 11

This study assessed in a wide population of advanced cancer patients the biological parameters relevant to cancer cachexia, such as serum levels of proinflammatory cytokines (IL-1beta, IL-6, TNFalpha), IL-2, acute-phase proteins (C-reactive protein and fibrinogen), leptin, and relevant to oxidative stress (OS), such as ROS, body antioxidant enzymes GPx and SOD. We also studied the ability of effective antioxidant agents alpha-lipoic acid (ALA), N-acetyl cysteine (NAC), and amifostine (AMI) added into culture to induce lymphocyte progression through the cell cycle, namely to enter into S phase. Additionally, we assessed the most significant clinical indexes of nutritional status such as body mass index and disease progression such as stage and ECOG-PS in the same cancer patient population. Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs isolated from 120 cancer patients and 60 controls, with or without ALA, NAC, or AMI, was studied. The biological parameters relevant to cancer cachexia and OS were also studied. The addition of antioxidants ALA, NAC and AMI, enhanced significantly the progression through the cell cycle, namely from G0/G1 to S phase, of PBMCs isolated from cancer patients (+132%, +150% and +141%, respectively). The percentage of PHA-stimulated PBMCs of cancer patients entering S phase, which was significantly lower than that of controls, increased significantly to more than physiological level after coculture with antioxidants. ROS levels were significantly higher and GPx and SOD activities significantly lower in cancer patients than controls. Serum levels of IL-1 beta, IL-6, and TNFalpha were significantly higher and serum levels of IL-2 and leptin significantly lower in cancer patients than controls. Serum levels of C-reactive protein and fibrinogen were significantly higher in cancer patients than controls. A significant correlation was found in laboratory parameters only between serum levels of leptin and body mass index. Patients with advanced cancer thus exhibit both a high-grade OS and a chronic inflammatory condition. Antioxidant agents ALA, NAC, and AMI enhanced significantly the PBMCs progression through the cell cycle, thus providing evidence of their potential role in the functional restoration of the immune system in advanced cancer patients. Our data warrant further investigation with adequate clinical trials.
J Mol Med (Berl) 2003 Oct
PMID:Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. 1292 88

We have examined a possibility whether or not severity and extent of coronary atherosclerosis may associate with degree of local inflammation in relation to endothelial dysfunction as is indicated by reduced NO formation. Blood samples were obtained from aortic root (Ao) and coronary sinus (CS) of 39 patients who underwent coronary angiography. Plasma NOx levels (nitrite + nitrate, stable NO end-products) were evaluated by HPLC-Griess system, and markers of inflammation, C-reactive protein (CRP) and serum amyloid A protein (SAA), were measured by Latex Turbidimetric Immunoassay. To evaluate the changes of these substances through coronary circulation, the percentage changes of respective markers [(CS - Ao) x 100/Ao] were calculated. The extent and severity of atherosclerosis of left coronary arteries were evaluated with Gensini Score (GS). The GS correlated with the percentage changes of NOx (r = -0.35, p < 0.05) and that of SAA (r = 0.43, p < 0.05) across coronary circulation, but not with changes in CRP. Moreover, the percentage changes of NOx correlated with that of SAA (r = -0.36, p < 0.05). These results indicated that severity and extent of coronary atherosclerosis related to degree of local inflammation which has a possible association with coronary endothelial dysfunction.
Mol Cell Biochem 2003 Jul
PMID:Association between coronary endothelial dysfunction and local inflammation of atherosclerotic coronary arteries. 1295

Induction of C-reactive protein (CRP) synthesis in hepatocytes by cytokines occurs at the transcriptional level. In Hep3B cells, the transcription factors C/EBPbeta, STAT3, and Rel p50 have been shown to participate in this process. A C/EBP binding site centered at -53 and an overlapping nonconsensus kappaB site on the promoter are critical for CRP expression. We have previously found that an oligonucleotide containing a kappaB site diminished binding of C/EBPbeta to the C/EBP site, suggesting that unidentified Rel proteins present in Hep3B nuclei facilitate the formation of C/EBPbeta-complexes. The current studies were undertaken to determine which of the five Rel proteins, p50/p65/p52/c-Rel/RelB, play such a role. Mutation of the nonconsensus kappaB site did not abolish binding of C/EBPbeta to its binding site, indicating that this site was not necessary for the formation of C/EBPbeta-complexes. Depletion of Rel proteins from Hep3B nuclei led to decreased formation of C/EBPbeta-complexes on a CRP promoter-derived oligonucleotide that contained only the intact C/EBP binding site but not the nonconsensus kappaB site. This finding indicates that Rel proteins are involved in the binding of C/EBPbeta to its binding site by a kappaB site-independent mechanism. Electrophoretic mobility shift assays (EMSAs) revealed that it was c-Rel that facilitated formation of C/EBPbeta-complexes and that c-Rel bound directly to C/EBPbeta-complexes formed on the C/EBP site. Cotransfection of c-Rel enhanced the induction of CRP promoter-driven luciferase activity and enhanced endogenous CRP expression in cells transfected with C/EBPbeta. We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter.
Mol Immunol 2003 Oct
PMID:Transcription factor c-Rel enhances C-reactive protein expression by facilitating the binding of C/EBPbeta to the promoter. 1452 18

Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.2 within an interval linked with SLE. We have investigated the candidate genes CRP and APCS in two cohorts totalling 586 UK simplex SLE families. The inheritance of an intronic dinucleotide repeat and seven single nucleotide polymorphisms in the CRP and APCS genes was examined by application of family-based tests of association and linkage. Basal levels of CRP were influenced independently by two polymorphisms at the CRP locus, CRP 2 and CRP 4. Furthermore, the latter polymorphism was linked/associated with SLE and antinuclear autoantibody production. Thus, the polymorphism associated with reduced basal CRP was also associated with the development of SLE. These data support the hypothesis that defective disposal of potentially immunogenic material is a contributory factor in lupus pathogenesis. The identification of polymorphisms that determine basal CRP levels has implications in ischaemic heart disease, where CRP level is an important predictor of risk.
Hum Mol Genet 2004 Jan 01
PMID:Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. 1464 6

Macrophage scavenger receptors (MSR) promote atherosclerotic lesion formation, and modulation of MSR activity has been shown to influence atherosclerosis. Soluble receptors are effective in inhibiting receptor-mediated functions in various diseases. We have generated a secreted macrophage scavenger receptor (sMSR) that consists of the bovine growth hormone signal sequence and the human MSR A I extracellular domains. sMSR reduces degradation of atherogenic modified low-density lipoproteins and monocyte/macrophage adhesion on endothelial cells in vitro. To test long-term effects of sMSR, atherosclerosis-susceptible LDLR knockout mice were transduced via the tail vein with an adeno-associated virus (AAV) expressing sMSR or control enhanced green fluorescent protein (EGFP), and a Western-type diet was started. Gene transfer caused a temporary elevation in alkaline phosphatase and aspartate amino transferase values without a change in C-reactive protein. sMSR protein was detected in the plasma of the transduced mice by a specific ELISA 6 months after the gene transfer. AAV-mediated sMSR gene transfer reduced atherosclerotic lesion area in the aorta by 21% (P < 0.05) compared to EGFP-transduced control mice. Even though eradication of established disease was not possible, atherosclerotic lesion formation could be modified using AAV-mediated gene transfer of the decoy sMSR.
Mol Ther 2003 Dec
PMID:Adeno-associated virus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor reduces atherosclerotic lesion formation in LDL receptor knockout mice. 1466 92

The molecular mass and sedimentation coefficient of native C-reactive protein in solution were determined by analytical ultracentrifugation in the presence and absence of calcium ions. Pentameric C-reactive protein was shown to be the major macroscopic form of this protein in solution. The removal of calcium ions from solution caused decompaction of the protein accompanied by changes in its hydrodynamic parameters. The sedimentation coefficient s20(0), w of pentameric C-reactive protein in solution containing 2 mM--Ca2+ (6.6S) exceeded that for C-reactive protein in solution containing 2 mM EDTA (6.4S). Analysis of average molecular masses Mw and Mz obtained from sedimentation data demonstrated that the solution of highly purified protein was not homogeneous. As shown by intermolecular crosslinking, the solution also contained the 241-kDa decamer of C-reactive protein (9.5S) as a separate macroscopic form, whose share hardly reached 10% in the presence of 2 mM Ca2+ and increased after removal of calcium ions. The decamers were shown to result from intermolecular association of the pentamers.
Mol Biol (Mosk)
PMID:[Effect of Ca2+ ions on hydrodynamic properties of pentamer and decamer of C-reactive protein in solution]. 1471 3


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