Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Besides regulating leukocyte trafficking in normal and injured tissues, several chemokines may positively or negatively regulate angiogenesis. Here we report that CCL16 activates an angiogenic program in vascular endothelial cells by activating CCR1. CCL16 induces dose-dependent random and directional migration of endothelial cells isolated from large vessels and liver capillaries without inducing their proliferation. It also promotes endothelial differentiation into capillary-like structures in an in vitro assay and is angiogenic in the chick chorionallantoic membrane. These angiogenic activities are neutralized by a specific antibody against CCL16. The direct angiogenic activity of CCL16 is further amplified by its ability to prime endothelium to a mitogen signal induced by vascular endothelial growth factor A and to raise their basal production of CXCL8 and CCL2, 2 other angiogenic chemokines. BX471 (R-N-[5-chloro-2-[2-[4(4-fluorophenyl) methyl]-2-methyl-1-piperazinyl]-2-oxoethoxy]phenyl] urea hydrochloric acid salt), a CCR1 antagonist, inhibits angiogenic properties of CCL16, whereas blocking of CCR8 or desensitizing CCR2, which are both well known receptors for CCL16, did not abolish endothelial activation. CCL16 may be specifically cross-linked to CCR1 expressed on endothelial cells. The largely restricted CCL16 expression in the liver suggests that this chemokine may play a role in hepatic vascular formation during development and in angiogenesis associated to hepatic diseases.
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PMID:CCL16 activates an angiogenic program in vascular endothelial cells. 1295 70

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which accounts for the cAMP-modulated chloride conductance of airway epithelial cells. CFTR also regulates other membrane proteins like the negative regulation of the amiloride-sensitive epithelial sodium channel (ENaC). Mutations in the CFTR gene lead to hyperabsorption of sodium chloride and a reduction in the periciliary salt and water content which leads to impaired mucociliary clearance. It seems that a lack of functional CFTR leads to abnormal function of the NF-kappaB pathway in submucosal gland cells, causing an increased production of pro-inflammatory cytokines and the chemokine IL-8, and a pro-inflammatory environment. CFTR is also expressed in neutrophils and several neutrophil functions like cytokine production, migration, phagocytosis and apoptosis seem altered in CF. In this review we describe the role of airway epithelium and blood neutrophils in the viscious circle of inflammation and infection seen in CF.
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PMID:The role of airway epithelium and blood neutrophils in the inflammatory response in cystic fibrosis. 1596 36

Periodic arrays of nucleosomes were assembled on heterogeneous DNA using core histones, the histone chaperone NAP-1, and ATP-dependent chromatin assembly and remodeling factor (ACF). The mechanical properties of these complexes were interrogated by stretching them with optical tweezers. Abrupt events releasing approximately 55-95 base-pairs of DNA, attributable to the non-equilibrium unraveling of individual nucleosomes, were frequently observed. This finding is comparable with a previous observation of 72-80 bp unraveling events for nucleosomes assembled by salt dialysis on a repeating sea urchin 5 S RNA positioning element, but the unraveling force varied over a wider range ( approximately 5-65 pN, with the majority of events at lower force). Because ACF assembles nucleosomes uniformly on heterogeneous DNA sequences, as in native chromatin, we attribute this variation to a dependence of the unraveling force on the DNA sequence within individual nucleosomes. The mean force increased from 24 pN to 31 pN as NaCl was decreased from 100 mM to 5 mM. Spontaneous DNA re-wrapping events were occasionally observed in real time during force relaxation. The observed wide variations in the dynamic force needed to unravel individual nucleosomes and the occurrences of sudden DNA re-wrapping events may have an important regulatory influence on DNA-directed nuclear processes, such as the binding of transcription factors and the movement of polymerase complexes on chromatin.
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PMID:Forced unraveling of nucleosomes assembled on heterogeneous DNA using core histones, NAP-1, and ACF. 1600 89

Alkaline sphingomyelinase (alk-SMase) is a new member of the NPP (nucleotide pyrophosphatase/phosphodiesterase) family that hydrolyses SM (sphingomyelin) to generate ceramide in the intestinal tract. The enzyme may protect the intestinal mucosa from inflammation and tumorigenesis. PAF (platelet-activating factor) is a pro-inflammatory phospholipid involved in pathogenesis of inflammatory bowel diseases. We examined whether alk-SMase can hydrolyse and inactivate PAF. [3H]Octadecyl-labelled PAF was incubated with purified rat intestinal alk-SMase or recombinant human alk-SMase expressed in COS-7 cells. The hydrolytic products were assayed with TLC and MS. We found that alkSMase cleaved the phosphocholine head group from PAF and generated 1-O-alkyl-2-acetyl-sn-glycerol. Differing from the activity against SM, the activity against PAF was optimal at pH 7.5, inhibited by EDTA and stimulated by 0.1-0.25 mM Zn2+. The activity was abolished by site mutation of the predicted metal-binding sites that are conserved in all NPP members. Similar to the activity against SM, the activity against PAF was dependent on bile salt, particularly taurocholate and taurochenodeoxycholate. The V(max) for PAF hydrolysis was 374 mumol x h(-1) x (mg of protein)(-1). The hydrolysis of PAF and SM could be inhibited by the presence of SM and PAF respectively, the inhibition of PAF hydrolysis by SM being stronger. The PAF-induced MAPK (mitogen-activated protein kinase) activation and IL-8 (interleukin 8) release in HT-29 cells, and chemotaxis in leucocytes were abolished by alk-SMase treatment. In conclusion, alk-SMase hydrolyses and inactivates PAF by a phospholipase C activity. The finding reveals a novel function, by which alk-SMase may counteract the development of intestinal inflammation and colon cancer.
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PMID:Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity. 1625 17

The pharmacokinetics and metabolism of reparixin (formerly repertaxin), a potent and specific inhibitor of the chemokine CXCL8, were investigated in rats and dogs after intravenous administration of [14C]-reparixin L-lysine salt. Protein binding of reparixin was investigated in vitro in rat, dog, rabbit, cynomolgus monkey and human plasma. Plasma protein binding of reparixin was >99% in the laboratory animals and humans up to 50 microg ml-1, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, Vss was low (about 0.15 l kg-1) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t1/2 approximately 0.5 h) than in dogs (t1/2 approximately 10 h). Systemic exposure in dog was due primarily to parent drug, but metabolites played a more prominent role in rat. Oxidation of the isobutyl side-chain was the major metabolic pathway in rat, whereas hydrolysis of the amide bond predominated in dog. Urinary excretion, which accounted for 80-82% of the radioactive dose, was the major route of elimination in both species, and biotransformation of reparixin was complete before excretion.
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PMID:Species differences in the pharmacokinetics and metabolism of reparixin in rat and dog. 1685 80

Source apportionment study was performed, applying principal component analysis to the results of 221 chemical analyses of PM10 and PM2.5 samples collected daily from the industrial (but low traffic) Spanish town of Puertollano over a 14-month period during 2004-2005. Results reveal compositional variations attributable to different mixtures of natural and anthropogenic materials, mainly soil and rock dust (crustal), marine salt (only in PM10), petrochemical refinery emissions, and particles attributed to the combustion of local coal, which is unusually rich in Pb and Sb. During the study period there were 34 pollution episodes when PM10 exceeded 50 tg m(-3), mostly due to winter air temperature inversions, regional atmospheric stagnation, or African dust incursions (North African, NAF days: usually in summer). Whereas the crustal component during NAF episodes averaged 52% with a PM2.5/PM10 ratio of 0.54, this dropped to 29% and a PM2.5/PM10 of 0.67 during non-NAF days when anthropogenic materials predominated. Abnormally enhanced concentrations of pathfinder metallic trace elements provide additional evidence for source apportionment: thus aerosols with raised levels of Pb and Sb are associated with local coal combustion, Ni and V can be linked to petrochemical PM emissions, and Ti, Mn, Rb, and Ce are particularly characteristic of crustal dust incursions.
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PMID:PM source apportionment and trace metallic aerosol affinities during atmospheric pollution episodes: a case study from Puertollano, Spain. 1724 Sep 12

Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable/fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacter pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NFkappaB signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NFkappaB and TRAF6-MAP3K7-AP-1 signaling cascades in epithelial and immune cells through lipopolysaccharide recognition by TLR2 or TLR4. IL-1beta, IL-6, IL-8, TNFalpha and IFNgamma are elevated in gastric mucosa with Helicobacter pylori infection. IL-6 and TNFalpha induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF, RhoA, JNK, PKC, NFAT, and NLK signaling cascades. WNT-beta-catenin-TCF/LEF signaling induces upregulation of MYC, CCND1, WISP1, FGF20, JAG1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NFkappaB signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC, and NFAT signaling cascades. Helicobacter pylori infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch signaling, while DKK1 and SFRP1 inhibit WNT signaling. Stem cell signaling network, consisting of WNT, Notch, FGF, Hedgehog and BMP signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell signaling network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell signaling molecules could be utilized for the personalized medicine.
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PMID:Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. 1756 83

Part of the innate defense of bronchial epithelia against bacterial colonization is regulated secretion of salt, water, and mucus as well as defensins and cytokines involving MAP kinase activation and alterations in early gene expression. We tested two different types of immortalized human airway epithelial cells (S9, 16HBE14o-) for activation of Erk-type MAP kinases and for expression of c-Fos on treatment with Staphylococcus aureus culture supernatants from the stationary growth phase [optical density (OD)(540 nm) = 10] or with recombinant S. aureus hemolysins A and B (Hla, Hlb). OD10 supernatants activated Erk-type MAP kinases and c-Fos expression in a concentration-dependent manner. Hla induced Erk-type kinase phosphorylation in S9 but not in 16HBE14o- cells. Hlb induced Erk activation in either cell type. Basal and stimulated levels of Erk-type MAP kinase phosphorylation were sensitive to the Mek1 inhibitor PD-98059, indicating that the bacterial products activated the entire signaling cascade that coregulates IL-8 induction and secretion. While c-Fos expression was enhanced by OD10 supernatants, Hla, and Hlb in S9 cells, 16HBE14o- cells responded to OD10 supernatant and Hlb but not to Hla. In S9 cells, PD-98059 suppressed c-Fos upregulation by OD10 supernatant, Hla, or Hlb, indicating that c-Fos expression requires activation of Erk-type MAP kinases. In 16HBE14o- cells, however, c-Fos expression by OD10 supernatant was sensitive to PD-98059, while that induced by Hlb was not. This indicates that ingredients of OD10 supernatants other than Hla or Hlb are activating Erk-type MAP kinases in 16HBE14o- cells and that other intracellular signaling systems apart from Erk-type MAP kinases contribute to Hlb-mediated regulation of c-Fos. Thus interaction of bacterial factors with airway epithelial cells may be highly cell type specific.
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PMID:Virulence factors of Staphylococcus aureus induce Erk-MAP kinase activation and c-Fos expression in S9 and 16HBE14o- human airway epithelial cells. 1909 23

Although there is increasing clinical evidence that high salt intake contributes to cardiovascular events and deaths seemingly independent of hypertension, the molecular mechanism for increased atherogenesis remains unclear. Vessel wall inflammation secondary to proinflammatory cytokines is one mechanism for atherogenesis. The role of mitogen activated protein kinase (MAPK) p38 in cytokine production such as IL-1, TNF-alpha, and IL-8 are well established. The link between inflammation and salt intake likely includes p38 MAPK as hyperosmolar sodium chloride triggers phosphorylation of p38 MAPK and stimulates gene expression and synthesis of proinflammatory cytokines. Hence a possible link of high salt intake, inflammation, and atherogenesis may be one molecular mechanism for the association of high salt intake and cardiovascular events.
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PMID:Hyperosmolar sodium chloride, p38 mitogen activated protein and cytokine-mediated inflammation. 1957 5

The G protein-coupled P2Y(11) receptor is involved in immune system modulation. In-depth physiological evaluation is hampered, however, by a lack of selective and potent ligands. By screening a library of sulfonic and phosphonic acid derivatives at P2Y(11) receptors recombinantly expressed in human 1321N1 astrocytoma cells (calcium and cAMP assays), the selective non-nucleotide P2Y(11) agonist NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)carbonylimino))-bis(1,3-xylene-alpha,alpha'-diphosphonic acid) tetrasodium salt] was identified. NF546 had a pEC(50) of 6.27 and is relatively selective for P2Y(11) over P2Y(1), P2Y(2), P2Y(4), P2Y(6), P2Y(12), P2X(1), P2X(2), and P2X(2)-X(3). Adenosine-5'-O-(3-thio)triphosphate (ATPgammaS), a nonhydrolyzable analog of the physiological P2Y(11) agonist ATP, and NF546 use a common binding site as suggested by molecular modeling studies and their competitive behavior toward the nanomolar potency antagonist NF340 [4,4'-(carbonylbis(imino-3,1-(4-methyl-phenylene)carbonylimino))bis(naphthalene-2,6-disulfonic acid) tetrasodium salt] in Schild analysis. The pA(2) of NF340 was 8.02 against ATPgammaS and 8.04 against NF546 (calcium assays). NF546 was further tested for P2Y(11)-mediated effects in monocyte-derived dendritic cells. Similarly to ATPgammaS, NF546 led to thrombospondin-1 secretion and inhibition of lipopolysaccharide-stimulated interleukin-12 release, whereas NF340 inhibited these effects. Further, for the first time, it was shown that ATPgammaS or NF546 stimulation promotes interleukin 8 (IL-8) release from dendritic cells, which could be inhibited by NF340. In conclusion, we have described the first selective, non-nucleotide agonist NF546 for P2Y(11) receptors in both recombinant and physiological expression systems and could show a P2Y(11)-stimulated IL-8 release, further supporting the immunomodulatory role of P2Y(11) receptors.
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PMID:NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)-carbonylimino))-bis(1,3-xylene-alpha,alpha'-diphosphonic acid) tetrasodium salt] is a non-nucleotide P2Y11 agonist and stimulates release of interleukin-8 from human monocyte-derived dendritic cells. 1981 12


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