Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A Limulus intracellular coagulation inhibitor, designated LICI, was isolated from hemocytes of the Japanese horseshoe crab (Tachypleus tridentatus), using three steps of chromatography, including dextran sulfate-Sepharose CL-6B, Sephacryl S-200, and Mono S. LICI is a single-chain glycoprotein with an apparent M(r) = 48,000 estimated by SDS-polyacrylamide gel electrophoresis. It blocks the amidolytic activities of Limulus lipopolysaccharide-sensitive serine protease, factor C, by forming a covalent 1:1 complex with the protease. The second-order rate constant for inhibition of factor C was 2.5 x 10(6) M-1 s-1 at 37 degrees C. LICI also inhibited human alpha-thrombin, rat salivary kallikrein, bovine plasmin, and trypsin but not Limulus clotting enzyme, Limulus factor B, bovine factor Xa, human factor XIa, human tissue plasminogen activator, human urokinase, chymotrypsin, elastase, and papain. Glycosaminoglycans such as heparin and heparan sulfate had no effect on the inhibitory activity. A cDNA coding for LICI was isolated from a hemocyte cDNA library. The open reading frame of the 1,257-base pair cDNA codes for the mature protein of 394 amino acids, of which 223 residues were confirmed by amino acid sequence analysis. LICI shows significant sequence identities to members of the serpin superfamily, such as human plasminogen activator inhibitor type 2 (40%) and human monocyte/neutrophil elastase inhibitor (39%). LICI contains a putative reactive site, -Arg-Ser-, at the corresponding position present in several inhibitors of the serpin superfamily. The subcellular localization, determined using an anti-LICI polyclonal antibody, indicated that LICI colocates with the Limulus serine protease zymogens in large granules in the hemocyte.
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PMID:A Limulus intracellular coagulation inhibitor with characteristics of the serpin superfamily. Purification, characterization, and cDNA cloning. 827 48

The same 70-kDa protein, present on the surface of mouse lymphocytes, served as the predominant binding site for heparin, heparinoids, and bacterial lipoteichoic acids, as well as peptidoglycan and lipopolysaccharides. This conclusion was supported by the following results: (a) all of these compounds photoaffinity cross-linked to one major 70-kDa 6.5-7.0 pI protein that co-migrated on two-dimensional polyacrylamide gel electrophoresis; (b) peptide maps of the 70-kDa proteins digested with chymotrypsin, subtilisin, protease V, or papain yielded the same peptides for heparin-, lipoteichoic acid-, peptidoglycan-, and lipopolysaccharide-binding proteins; (c) cross-linking of peptidoglycan, lipopolysaccharide, lipoteichoic acid, and heparin was competitively inhibited by the same compounds with the same order of potency, i.e. carboxyl-reduced sulfated heparin > peptidoglycan > pentosan polysulfate > heparin > chitin > dextran sulfate > trestatin sulfate > polyanetholesulfonate > fucoidan > beta-cyclodextrin tetradecasulfate > heparan sulfate > carrageenan lambda > lipoteichoic acids > Re-lipopolysaccharide > lipopolysaccharide > lipid A > polygalacturonic acid; and (d) cross-linking of each of these ligands was not inhibited by carboxyl-reduced heparin, dextran, beta-cyclodextrin, trestatin, carrageenan kappa, chondroitin 4-sulfate, chondroitin 6-sulfate, beta-D-glucan, carboxy-methylcellulose, levan, alpha-D-mannan, and glycogen. The minimum size of the molecule that bound was 7-9 glycan residues, whereas, di- and trisaccharides did not bind. There was a logarithmic linear relationship between the strength of the binding and the length of the polymer (up to > 1500 glycan residues), which indicates an avidity effect of the cooperative binding of one polymeric molecule to several receptor molecules on the cell surface. The 70-kDa receptor, therefore, has a broad, but limited specificity of binding for non-charged (peptidoglycan and chitin), highly negatively charged (heparin and heparinoids), and weakly negatively charged (lipoteichoic acids, lipopolysaccharides, and lipid A) ligands.
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PMID:Heparin, sulfated heparinoids, and lipoteichoic acids bind to the 70-kDa peptidoglycan/lipopolysaccharide receptor protein on lymphocytes. 829 63

The effects of the inflammatory mediators lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF) and unstimulated and activated neutrophils (PMNs) on endothelial cell (EC) necrosis were studied using the cultured human EC line (ECV-304) and human PMNs in vitro. LPS and TNF alone or their combination failed to induce EC necrosis. Activated PMNs, as evidenced by augmentations in CD11b expression and respiratory burst, induced significant EC necrosis commencing at 12 hr of coculture, which was strongly dependent on the ratio of PMN:ECs and the duration of PMN:EC coculture. In contrast, unstimulated PMNs induced no significant increases in EC necrosis. To examine the mechanisms of activated PMN-mediated EC necrosis, the oxygen radical scavengers superoxide dismutase (SOD) and catalase, as well as the protease inhibitors phenylmethylsulfonyl fluoride (PMSF), alpha 1-antitrypsin (alpha 1-AT), soybean trypsin-chymotrypsin inhibitor (TCI), and aprotinin, were studied in coculture experiments. EC necrosis induced by activated PMNs could be markedly attenuated by SOD, PMSF, alpha 1-AT, TCI, aprotinin, or their combinations. Although aprotinin enhanced respiratory burst, this agent inhibited necrosis by downregulating PMN CD11b and PMN-EC adhesion. These results demonstrate that the inflammatory mediators LPS and TNF and quiescent PMNs fail to induce EC necrosis. However, PMNs activated by inflammatory mediators can induce EC necrosis through oxidative and nonoxidative mechanisms and this process is dependent on PMN-EC adhesion.
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PMID:Mechanisms involved in the induction of human endothelial cell necrosis. 859 44

Bacterial lipopolysaccharide (LPS) attachment at the hemocyte surface is based on the crosslinking of surface associated p47 to LPS, via the intermediacy of tyrosine derivatives generated by the action of phenoloxidase (PO). This attachment is an initial step for LPS internalization from hemocytes (Charalambidis et al., 1996). The results presented clearly show the critical role of hemocyte associated PO activity in the above processes. Biochemical and immunofluorescent analysis demonstrated unambiguously the presence of prophenoloxidase (proPO) on the hemocyte surface. The cell-surface expression of proPO appeared to be LPS-independent, whereas its activation was LPS-dependent. The activation of cell surface proPO involves a limited proteolysis, since upon activation with chymotrypsin proPO is converted to a set of smaller molecular weight proteins with PO activity. The activation appears to be due to enzyme activators, serine proteases, released upon LPS-stimulation. This hypothesis was supported from the activation of membrane proPO by the culture medium of hemocytes which have been triggered with LPS. In addition, proPO, activation was abolished by inhibitors of secretion and PMSF. The release of proPO activators upon LPS-stimulation is mediated via protein tyrosine phosphorylation, as genistein inhibited proPO activation, a situation similar to that reported by us for the release of the effector protein p47 (Charalambidis et al., 1995). The LPS-stimulated activation of cell-surface proPO is a prerequisite for LPS (either cell associated or cell free) internalization, as judged by the resistance of LPS binding to dissociation by proteinase K.
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PMID:Hemocyte surface phenoloxidase (PO) and immune response to lipopolysaccharide (LPS) in Ceratitis capitata. 901 31

We purified a chymotrypsin inhibitor, designated cytin, from the rhynchobdellid leech Theromyzon tessulatum. This 7.4-kDa peptide was purified to apparent homogeneity by gel-permeation and anion-exchange chromatographies, followed by reverse-phase HPLC. The structure of cytin was determined by reduction, S-beta-pyridilethylation, automated Edman degradation, and electrospray mass spectrometry. Cytin is formed by the association of two protein chains, which are linked by a disulfide bridge. Chain A consists of 43 and chain B of 22 amino acid residues. Chain B exhibits 40-63% sequence similarity with the N-terminal sequences of subtilisin/chymotrypsin inhibitors isolated from barley seeds. Cytin inhibited chymotrypsin (Ki 600 pM) and weakly inhibited trypsin (Ki 350 nM). This chymotrypsin inhibitor, in contrast to others isolated from leeches, does not inhibit elastase or cathepsin G. Furthermore, cytin (10 microM) significantly diminishes the level of human granulocyte and monocyte activation induced by lipopolysaccharide (1 U/ml) in a manner similar to that of aprotinin. These data indicate that this chymotrypsin inhibitor may be biomedically significant.
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PMID:Amino-acid-sequence determination and biological activity of cytin, a naturally occurring specific chymotrypsin inhibitor from the leech Theromyzon tessulatum. 939 20

Tepoxalin is a structurally and functionally novel non-steroidal anti-inflammatory drug (NSAID) with potent anti-inflammatory and analgesic properties. Apart from its inhibitory effect on cyclooxygenase activity, tepoxalin is able to inhibit production of cytokines in peripheral cells outside the CNS. No data, however, are available concerning the effects of this drug in the CNS. Since cytokines such as interleukin-1 (IL-1) or interleukin-6 (IL-6) as well as acute-phase proteins such as alpha1-anti-chymotrypsin (ACT) participate in the etiopathology of Alzheimer's disease (AD), we were interested whether tepoxalin is able to inhibit the synthesis of these immunomodulators in primary rat microglia and astrocytes as well as in the human astrocytoma cell line U373 MG. We found that tepoxalin markedly inhibits IL-1beta-induced IL-6 and ACT synthesis in astrocytes and the synthesis of IL-1beta and IL-6 in lipopolysaccharide (LPS)-stimulated microglial cells. Electrophoretic mobility shift and reporter gene assays revealed that tepoxalin exerts its inhibitory effect through the inhibition of nuclear factor kappaB (NF-kappaB), a transcription factor involved in the induction of IL-1, IL-6 and ACT gene expression. We show that inhibition of NF-kappaB activation by tepoxalin is mediated by preventing IkappaB-alpha degradation. Based on this inhibitory effect of tepoxalin on cytokine and ACT synthesis and the documented therapeutic efficacy of NSAIDs in AD, we conclude that tepoxalin may be of therapeutic benefit for the treatment of AD patients and should therefore be tested in clinical trials.
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PMID:The non-steroidal anti-inflammatory drug tepoxalin inhibits interleukin-6 and alpha1-anti-chymotrypsin synthesis in astrocytes by preventing degradation of IkappaB-alpha. 1047 Oct 86

We investigated the expression of interferon gamma (IFN-gamma)-regulated subunits and the enzymatic activity of proteasomes purified from tumor-derived and normal B lymphocytes representing different stages of B-cell activation/differentiation. The catalytic beta subunits (Lmp2 and Lmp7) and the regulatory subunits (PA28alpha and PA28beta) were expressed at equally high levels in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs), freshly isolated B-chronic lymphocytic leukemia (B-CLL) cells and normal CD23(-) B lymphocytes. Lmp2 and Lmp7 were selectively down-regulated in germinal center cell-derived Burkitt's lymphoma (BL) and Hodgkin's lymphoma (HD) cell lines. There was a direct correlation between the expression of Lmp2/7 and the chymotrypsin and trypsin-like activities in proteasomes purified from LCLs, BLs and CLL cells, whereas 5 HD cell lines expressing B or T-cell markers exhibited a variable pattern of subunit expression and enzymatic activity. Poor hydrolysis of the fluorogenic substrates by proteasomes from BL cells correlated with a distinct pattern of cleavage of a reference 50mer peptide, production of different sets of degradation products and significantly reduced recovery of a known cytotoxic T-lymphocyte (CTL) target epitope. The enzymatic activity of proteasomes from normal CD23(-) "resting" B lymphocytes resembled that of BL cells in spite of high Lmp2/7 expression. This pattern was not reversed by treatment with the B-cell mitogen, lipopolysaccharide (LPS). The results suggest that different stages of B-cell activation/differentiation are associated with distinct profiles of IFN-gamma-regulated subunit composition and enzymatic activity of the proteasome. This may have important implications for the analysis and manipulation of tumor-specific immune responses.
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PMID:Variations in proteasome subunit composition and enzymatic activity in B-lymphoma lines and normal B cells. 1109 9

Intra-acinar cell nuclear factor-kappaB (NF-kappaB) and trypsinogen activation are early events in secretagogue-induced acute pancreatitis. We have studied the relationship between NF-kappaB and trypsinogen activation in rat pancreas. CCK analogue caerulein induces early (within 15 min) parallel activation of both NF-kappaB and trypsinogen in pancreas in vivo as well as in pancreatic acini in vitro. However, NF-kappaB activation can be induced without trypsinogen activation by lipopolysaccharide in pancreas in vivo and by phorbol ester in pancreatic acini in vitro. Stimulation of acini with caerulein after 6 h of culture results in NF-kappaB but not trypsinogen activation. Protease inhibitors (AEBSF, TLCK, and E64d) inhibit both intracellular trypsin activity and NF-kappaB activation in caerulein stimulated acini. A chymotrypsin inhibitor (TPCK) inhibits NF-kappaB activation but not trypsin activity. The proteasome inhibitor MG-132 prevents caerulein-induced NF-kappaB activation but does not prevent trypsinogen activation. These findings indicate that although caerulein-induced NF-kappaB and trypsinogen activation are temporally closely related, they are independent events in pancreatic acinar cells. NF-kappaB activation per se is not required for the development of early acinar cell injury by supramaximal secretagogue stimulation.
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PMID:Relationship between NF-kappaB and trypsinogen activation in rat pancreas after supramaximal caerulein stimulation. 1116 28

This study was undertaken to investigate the antitumor effect of liposomal hexadecylphosphocholine (L-HPC), a synthetic phospholipid encapsulated into multilamellar vesicles (MLV). The effect of these liposomes was tested in an orthotopic nude mouse model using the human mammary carcinomas MDA-MB 435 and 231. The main interest of the investigation was to study whether activated macrophages are substantially involved in the tumor growth inhibition mechanism. The growth of both MDA-MB 435 and 231 tumors in the mammary fat pad was significantly inhibited by a 14-day intraperitoneal therapy with L-HPC. The remaining tumors were shown to be heavily infiltrated with macrophages. In vitro studies of mPEM demonstrated a significant induction of macrophage-mediated tumor cytotoxicity (MMCTX) against the 2 cell lines by L-HPC. The L-HPC-mediated activation mechanism was characterized to be IL-6 and TNFalpha dependent but rather independent of IL-1alpha and nitric oxide (NO). NMA, a specific inhibitor of NO production, did not inhibit L-HPC-induced MMCTX. Furthermore, L-HPC was shown to upregulate the matrixmetalloproteinases MMP-9 and MMP-2 secretion into the supernatant. Considering cytokine release and production of collagenases, the L-HPC-induced macrophage activation cascade is assumed to be comparable with that of classical activators such as lipopolysaccharide (LPS) and interferon (IFN) gamma. As far as NO production is considered, the L-HPC activation mechanism differs from that caused by LPS and IFN gamma.
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PMID:Growth inhibition of human mammary carcinoma by liposomal hexadecylphosphocholine: Participation of activated macrophages in the antitumor mechanism. 1129 Oct 82

Irreversible binding of T-even bacteriophages to Escherichia coli is mediated by the short tail fibres, which serve as inextensible stays during DNA injection. Short tail fibres are exceptionally stable elongated trimers of gene product 12 (gp12), a 56 kDa protein. The N-terminal region of gp12 is important for phage attachment, the central region forms a long shaft, while a C-terminal globular region is implicated in binding to the bacterial lipopolysaccharide core. When gp12 was treated with stoichiometric amounts of trypsin or chymotrypsin at 37 degrees C, an N-terminally shortened fragment of 52 kDa resulted. If the protein was incubated at 56 degrees C before trypsin treatment at 37 degrees C, we obtained a stable trimeric fragment of 3 x 33 kDa lacking residues from both the N- and C-termini. Apparently, the protein unfolds partially at 56 degrees C, thereby exposing protease-sensitive sites in the C-terminal region and extra sites in the N-terminal region. Well-diffracting crystals of this fragment could be grown. Our results indicate that gp12 carries a stable central region, consisting of the C-terminal part of the shaft and the attached N-terminal half of the globular region. Implications for structure determination of the gp12 protein and its folding are discussed.
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PMID:Identification and crystallisation of a heat- and protease-stable fragment of the bacteriophage T4 short tail fibre. 1153 Sep 35


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