Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vibrio vulnificus strains isolated from septicemia cases and from the environment show a wide variety of capsular types. In an attempt to find common structural features which can be correlated with pathogenicity and toxicity, we have determined structures of the capsular polysaccharides (CPS) from several pathogenic strains. We report the complete structure of the polysaccharide from the pathogenic V. vulnificus strain ATCC 27562 using a combination of homonuclear and heteronuclear one-dimensional and two dimensional NMR experiments. The 13C and 1H NMR spectra, including the exchangeable amide proton resonances, have been completely assigned. The amide linkage between Ser and C6 of GalA has been unambiguously determined by water-suppressed 2D NOESY. To verify the structure established by NMR, we have fragmented the polymer employing the Smith degradation procedure. The Smith product identified by NMR and matrix-assisted laser desorption mass spectrometry is consistent with the proposed structure for the CPS, which is composed of D-GlcNAc, MurNAc, D-GalA, L-Rha and is serine-linked as shown: [formula: see text]
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PMID:Structure of a muramic acid containing capsular polysaccharide from the pathogenic strain of Vibrio vulnificus ATCC 27562. 972 Feb 37

A novel copper-binding protein was identified in the liver supernatant (100,000 x g) of Indian childhood cirrhosis (ICC), purified to apparent homogeneity and characterized [corrected]. Purified major copper-binding protein (MCuBP) is solely responsible for binding about 35% of the total supernatant copper. Elution profile of ICC liver supernatant on Sephadex G-75 column chromatography showed three peaks. About 60% of the total supernatant copper was resolved in peak II, whereas zinc content was insignificant in this peak. But peak II was almost missing in a gel elution profile of control liver supernatant. The control group included cases of various liver diseases viz. neonatal hepatitis, septicemia, and mixed nodular cirrhosis. Copper-binding proteins of peak II further purified on ion-exchange chromatography and elution profile showed that peak II was a MCuBP with high copper-binding capacity (10 g atoms/mol of native protein). SDS-PAGE of this protein also revealed the existence of a single band with molecular mass of about 50 kD. UV spectra of MCuBP showed the maximal absorbance at 254 nm. Unlike the classical metallothionein, the amino acid composition of MCuBP revealed the presence of aromatic amino acids and higher content of glutamic acid and aspartic acid followed by glycine and serine. The ratio (0.3) of basic amino acids to acidic amino acids strongly indicates that it is an acidic protein. The cysteine content in this protein was insignificant, which further corroborates the possibility that the acidic amino acids might be prominent candidates for binding copper. Thus, the 50-kD MCuBP apparently makes a major contribution to the total copper-binding activity in ICC liver cytosol and may play a significant role in hepatic intracellular copper accumulation.
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PMID:Identification of a novel copper-binding protein from the liver of Indian childhood cirrhosis: purification and physicochemical characterization [corrected]. 980 48

Sequestration of neutrophils and release of histotoxic mediators are considered important for the development of pathologic alterations of the lung defined as adult respiratory distress syndrome. Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease. In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus. In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-gamma, but independent of tumor necrosis factor (TNF). Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1. Expression of MIP-2, KC, MIP-1alpha and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery. Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.
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PMID:Mechanisms of acute inflammatory lung injury induced by abdominal sepsis. 1006 20

Sepsis and major trauma are the two most common causes of disseminated intravascular coagulation (DIC) and are characterized by a sudden increase in inflammatory mediators. In general, the outcome of the patient is determined by the degree of the inflammatory response. In severe cases of sepsis and trauma, cascade systems, such as the coagulation, fibrinolytic and complement systems, are activated beyond the capacity of the autoregulatory mechanisms. During DIC, plasma levels of antithrombin (AT)--a serine protease inhibitor that acts mainly on the serine proteases of the coagulation system--decrease due to the formation and subsequent elimination of complexes between AT and activated coagulation factors. The consumption of AT may start a vicious circle by facilitating further intravascular fibrin formation, followed by ischaemic tissue injury and accelerated activation of blood coagulation. Infusion of AT has an anti-inflammatory effect through its ability to counteract microvascular thrombosis. Furthermore, AT induces the release of prostacyclin from the vessel wall by binding to glycosaminoglycans on the surface of endothelial cells. Prostacyclin has a marked anti-inflammatory effect as a result of its inhibitory effect on neutrophils, monocytes and platelets.
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PMID:The effect of antithrombin on the systemic inflammatory response in disseminated intravascular coagulation. 1010 94

Solvent/detergent (S/D)-treated plasma is currently marketed by the American Red Cross as a virally inactivated alternative to fresh-frozen plasma (FFP). The serpin-type serine proteinase inhibitors have a flexible reactive site loop (RSL) that can convert from the active conformation to the inactive latent or polymerized conformations when exposed to heat and/or detergents. We have compared the conformational stability and inhibitory activity of 3 plasma serpins-antithrombin, antitrypsin, and antiplasmin-in S/D plasma and FFP. In S/D plasma, virtually 100% of the antiplasmin and approximately 50% of the antitrypsin are in either the latent or polymerized conformation and lack inhibitory activity, while in FFP only the active conformation is present. Interestingly, antithrombin is not affected by S/D treatment and remains fully active. These data demonstrate that S/D plasma is not simply a virally inactivated equivalent of FFP. The lack of antiplasmin activity and decreased antitrypsin activity in S/D plasma suggest that it may not be as effective as FFP for the treatment of bleeding in patients with systemic activation of proteolytic cascades, such as disseminated intravascular coagulation and sepsis, acquired fibrinolytic states, and large-volume transfusion. Although there has been extensive use of S/D plasma in several European countries with no reports of adverse effects, clinical studies directly comparing the efficacy of these 2 plasma products are needed to directly evaluate the relative therapeutic efficacy of FFP and S/D plasma for the treatment of these diseases.
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PMID:Solvent/detergent-treated plasma has decreased antitrypsin activity and absent antiplasmin activity. 1057 9

IL-1beta stimulation of cultured epithelial cells induces the degradation of IkappaBalpha and the consequent nuclear translocation of NF-lambdaB, a critical proinflammatory transcription factor in the mucosal host immune response. The role of reactive oxygen intermediates, serine protease activity, and tyrosine kinase activity in the activation of NF-kappaB is weakly conserved across various cell lineages and has not been defined in human enterocytes, a major target of oxidant stress in sepsis, thermal injury, and hemorrhagic shock. We report here that in Caco-2BBe cells, a transformed human colon cancer cell line with features of small intestinal epithelial cells in culture, exposure to oxidant stress (hydrogen peroxide 1-10 mM) did not induce NF-kappaB activation. Similarly, scavenging of free radicals and oxidants by pyrrolidine dithiocarbamate and dimethyl sulfoxide did not block IL-1beta-induced IkappaBalpha degradation and NF-kappaB activation. Genistein, a nonspecific tyrosine kinase inhibitor, also had no effect on IL-1beta-mediated effects on NF-kappaB. Serine protease inhibition by tosyl-lysine-chloromethylketone and tosyl-phenylalanine-chloromethylketone inhibited IkappaBalpha degradation and NF-kappaB activation stimulated by IL-1beta. Our data highlight the strong divergence between epithelial and mononuclear cells in the signal transduction pathways relating IL-1beta stimulation and NF-kappaB nuclear translocation.
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PMID:IL-1beta induction of NF-kappaB activation in human intestinal epithelial cells is independent of oxyradical signaling. 1063 62

C1-esterase inhibitor (C1-Inh) therapy was introduced in clinical medicine about 25 years ago as a replacement therapy for patients with hereditary angioedema caused by a deficiency of C1-Inh. There is now accumulating evidence, obtained from studies in animals and observations in patients, that administration of C1-Inh may have a beneficial effect as well in other clinical conditions such as sepsis, cytokine-induced vascular leak syndrome, acute myocardial infarction, or other diseases. Activation of the complement system, the contact activation system, and the coagulation system has been observed in these diseases. A typical feature of the contact and complement system is that on activation they give rise to vasoactive peptides such as bradykinin or the anaphylatoxins, which in part explains the proinflammatory effects of either system. C1-Inh, belonging to the superfamily of serine proteinase inhibitors (serpins), is a major inhibitor of the classical complement pathway, the contact activation system, and the intrinsic pathway of coagulation, respectively. It is, therefore, endowed with anti-inflammatory properties. However, inactivation of C1-Inh occurs locally in inflamed tissues by proteolytic enzymes (e.g., elastase) released from activated neutrophils or bacteria thereby leading to increased local activation of the various host defense systems. Here we will give an overview on the biochemistry and biology of C1-Inh. We will discuss studies addressing therapeutic administration of C1-Inh in experimental and clinical conditions. Finally, we will provide an explanation for the therapeutic benefit of C1-Inh in so many different diseases.
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PMID:C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. 1069 56

In the course of the past two decennia, a 3rd route of complement activation (next to the classical and the alternative routes) has been identified: the lectin route in which mannose-binding lectin (MBL) plays an essential role. MBL is produced in the liver. From the phylogenetic and functional points of view, complement activation via MBL falls in between the alternative and the classical routes and combines the advantages of the former (an early response, without the intervention of antibodies) with those of the latter (high specificity). The binding of MBL to the surface of a microorganism results in the activation of two serine proteases (MASP1 and MASP2) that are coupled to MBL. These enzymes can activate C4 and C2 so that, via the MBL route, the C3-convertase of the classical route (C4b2b) is produced long before there are any specific antibodies. The gene for MBL is located on the long arm of chromosome 10 and consists of a promoter gene and 4 exons coding for the protein. The prevalence of mutations in the MBL gene is about 10%, but in Africa South of the Sahara it is as high as 30%. MBL deficiency predisposes both children and adults to all sorts of infectious diseases, chronic diarrhoea, tonsillitis, otitis media, pneumonia, (meningococcal) meningitis, sepsis and osteomyelitis. Remarkably, MBL deficiency may actually be advantageous in some infections, because certain microorganisms use MBL or complement to invade the cell.
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PMID:[Immunology in the medical practice. XXVII. Mannose-binding lectin, an important link for nonspecific or hereditary immune reaction]. 1107 14

T4-binding globulin (TBG), the principal thyroid hormone-binding protein of serum, is a member of the serine protease inhibitor (serpin) superfamily. We report a characteristic serpin cleavage product of TBG in sepsis sera. At 49-50 kDa, the TBG remnant is 4-5 kDa smaller than the intact protein and is the same molecular mass as a TBG cleavage product produced by incubation with polymorphonuclear elastase. Incubation with polymorphonuclear leukocytes also produces the 49- to 50-kDa remnant, and this proteolysis is stimulated by zymosan activation. Polymorphonuclear cell cleavage of TBG increases the ratio of free/bound T4. As previously described, in vitro cleavage of TBG by elastase also increases free/bound T4. These findings are consistent with the hypothesis that serine proteases present at inflammatory sites cleave TBG, releasing its hormonal ligands.
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PMID:A characteristic serpin cleavage product of thyroxine-binding globulin appears in sepsis sera. 1109 20

Reperfusion injury is defined as the enhancement of the damage that occurs in ischaemic cells during the reperfusion period. Cellular damage to the brain occurs not only during the ischaemic period, but also during the reperfusion period. Such injury occurs when blood flow is restored to heart, brain or other tissue after flow has been blocked. Several mechanisms appear to play a role in the generation of reperfusion injury. To a greater or lesser extent, most involve neutrophils. The infiltration of neutrophils into the previously ischaemic area has been implicated as playing major role following reperfusion. Microscopic examination of tissue has shown a direct correlation between the duration of oxygen deprivation with the amount of damage, and the extent of activated neutrophil recruitment. Activated neutrophils are responsible for the release of serine proteases, which directly lead to tissue damage. Activated neutrophils also contain a newly assembled enzyme that produces tissue damaging free radicals. However, a preliminary and necessary step is to attach the activated neutrophil on to the lining of the blood vessels, a process requiring proteolytic activity. Administration of a drug that prevents neutrophil transmigration would reduce reperfusion injury. SuperGen is developing a drug, LEX 032, with a unique spectrum of activities, including the ability to inhibit binding of neutrophils to the vascular surface by blocking this proteolytic activity. In addition, this drug inhibits free radical production by neutrophils, and inhibits the activity of released serine proteases. Therefore, LEX 032 is expected to prevent or minimise neutrophil mediated reperfusion injury. Blockade of all three destructive inflammatory responses should limit the amount of damaged tissue and save viable tissue. A drug with these capabilities might find use in the treatment of myocardial infarction, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation. Since LEX 032 has no inhibitory activity against thrombin and plasmin, it represents an ideal drug for use in the treatment of ischaemic stroke. Recently, data have been published demonstrating that ischaemic stroke patients given the thrombolytic drug tPA were at least 30% more likely to have minimal or no disability at three months, as measured by outcome scales, when compared to placebo-treated patients. Presumably, this action was because of the hastening of brain reperfusion, and may have been limited due to reperfusion injury. The FDA approved the use of tPA for the limited treatment of acute ischaemic stroke. Since LEX 032 has been shown to limit neutrophil mediated reperfusion damage, it may find use either alone, to ameliorate damage occurring spontaneously during ischaemic stroke, or in combination therapy with tPA to reduce reperfusion injury secondary to thrombolytic therapy. This unique approach may have broad therapeutic potential in the treatment of neutrophil mediated diseases since, unlike a monoclonal antibody for example, it is independent of the specific adhesion molecule(s). These diseases include inflammatory diseases which are, at least in part, caused or exacerbated by excessive neutrophil proteases, such as acute pancreatitis, arthritis, allograft rejection, sepsis, meningitis, acute pulmonary inflammation, psoriasis and damage caused by burns. This is in addition to reperfusion-related diseases such as myocardial infarction, stroke, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation.
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PMID:LEX 032: a novel recombinant human protein for the treatment of ischaemic reperfusion injury. 1113 33


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