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

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Query: EC:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurologic symptoms in human shigellosis have often been attributed to Shiga toxin, although its exact role has not been determined. By use of a [3H] thymidine-labeled HeLa cell assay, cytotoxic activity was demonstrated in stool but not cerebrospinal fluid or serum from five patients with shigellosis presenting with seizures or encephalopathy. Bacterial isolates produced 16.0-88.2 CD50 (50% cytotoxic dose) of cytotoxin/mg of protein. The toxin activity in stool and the cytotoxic activity of the isolates were not neutralized by antiserum to purified Shiga toxin. DNA hybridization studies showed that Shigella isolates from these patients lacked the structural genes for Shiga toxin. The cytotoxin produced was also distinct from Shiga-like toxins I and II. Sonicates of the Shigella strains injected intraperitoneally into mice caused lethargy and lethality. The toxin activity was heat-labile and sensitive to trypsin, indicating that its active component is protein. Ultrafiltration and gel filtration chromatography showed a molecular mass of 100-125 kDa. Thus Shiga toxin production is not essential for the development of neurologic manifestations of shigellosis; other toxic products may play a role.
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PMID:The association of Shiga toxin and other cytotoxins with the neurologic manifestations of shigellosis. 232 46

The multisystem involvement in acute pancreatitis (AP) is a reflection of the pancreatic gland's capacity to produce a number of potent vasoactive peptides, hormones, and enzymes. The various prognostic criteria are early evaluations of these metabolic derangements. The pathogenesis of hypocalcemia, long recognized as an indicator of severity of AP, is multifactorial. Imbalances of parathyroid hormone (PTH)-calcitonin, the interactions of glucagon, gastrin and other pancreatic hormones with PTH-calcitonin, the role of free fatty acids in binding serum calcium with albumin, and the translocation of calcium ion in muscles and liver, have been recently described but remain conflicting theories. Yet, the time-honored theory of calcium-soap formation enjoys wide acceptance. Hyperglycemia, hypoglycemia, and occasional ketoacidosis in acute pancreatitis have been studied thoroughly. The complex cause-and-effect relationship between hyperlipidemia with acute pancreatitis needs further study. The coagulation abnormalities seem to be initiated by activated trypsin, and their role in microvascular coagulation appears to form a unifying hypothesis for major organ dysfunction, but this requires further investigation. Adult respiratory distress syndrome may be the result of active enzymes that digest pulmonary surfactant and/or microvascular thrombosis. The depression of cardiac function and shock are suspected to be secondary to vasoactive peptides such as bradykinin, or myocardial depressant factor, whose structure has yet to be elucidated. The renin-angiotensin alterations and renal complications in acute pancreatitis have received scant attention in the literature. The onset of moderate visual disturbances, or even blindness, in a patient with acute pancreatitis as a result of retinal vessel thrombosis is fortunately uncommon. Rare but interesting are the manifestations such as subcutaneous fat necrosis, arthralgia, and pancreatic encephalopathy. Despite the extensive literature on the complexities of the pathogenesis of complications of acute pancreatitis, there have been very few advances in the prevention and management of specific complications. It is hoped that further work on modification of enzymatic disturbances induced in acute pancreatitis will result in its effective treatment and prevention of serious complications.
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PMID:Systemic complications of acute pancreatitis. 328

Two infants are described with a fulminant disorder characterised by profound circulatory collaps and shock, generalised convulsions and unremitting coma, bleeding due to severe DIC, fever, diarrhoea, metabolic acidosis and renal and hepatic failure. Both infants died shortly after onset of the symptoms. Autopsy mainly revealed haemorrhages in different organs, anoxaemic lesions in the brain and a normal structure of liver and pancreas. No causative agent could be demonstrated. We believe that both patients suffered from haemorrhagic shock and encephalopathy, a mostly fatal disorder which has recently been described. Although the clinical and biochemical features are very distinctive, this syndrome is probably heterogeneous and its differentiation from some other disorders may be difficult. Its pathogenesis is unknown but there are some indications that intravascular activity of trypsin may play a role. During a study of the two families we obtained abnormal results of immunologic tests in most members: the interpretation of this finding remains conjectural. Haemorrhagic shock and encephalopathy may occur more frequently than the restricted literature on this subject suggests. Future studies will have to deal with the question of identity and pathogenesis.
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PMID:Haemorrhagic shock and encephalopathy. 373 33

In the past year, ten infants have been admitted to hospital with a new or previously unrecognised disorder, characterised by an acute onset of encephalopathy, fever, shock, watery diarrhoea, severe disseminated intravascular coagulation, and renal and hepatic dysfunction. Seven of the infants died. No specific causative agent has been identified, but preliminary studies suggest that the pathophysiology of the disease may involve release of proteolytic enzymes (such as trypsin) into the circulation, with destruction of the microcirculation.
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PMID:Haemorrhagic shock and encephalopathy: a new syndrome with a high mortality in young children. 613 58

Cleavage of the hemagglutinin (HA) molecule by proteases is a prerequisite for the pathogenicity and even for the neurovirulence of influenza A viruses. WSN, a neurovirulent virus, adapted to mouse brain, grew in vitro in several types of cells including neuroblastoma cells in the absence of trypsin. When mice were intracerebrally inoculated with WSN, the viral antigen was found in the substantia nigra zona compacta and hippocampus. The mice inoculated with viruses isolated from children with acute encephalopathy associated with an influenza virus infection, on the other hand, showed no neurological symptoms. Furthermore, these viruses did not grow in the human neuroblastoma and glioblastoma cells. Since 1991, most of the human influenza A viruses have not agglutinated chicken erythrocytes. Whether this altered receptor binding specificity is related to the occurrence of influenza encephalitis and encephalopathy is now under investigation.
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PMID:[Influenza encephalopathy and encephalitis]. 1072 90

Dengue viruses (DEN) cause a broad spectrum of clinical manifestations including potentially life-threatening conditions such as hemorrhagic shock syndrome and less frequently acute hepatitis with liver failure and encephalopathy. In addition, dengue viruses provide a potential model to understand the initiation of hepatocyte infection by the structurally closely related hepatitis C virus (HCV), because this virus at present cannot be grown in cell culture. Although the initial steps of viral infection are a critical determinant of tissue tropism and therefore pathogenesis, little is known about the molecular basis of binding and endocytic trafficking of DEN or of any other flavivirus. Our studies revealed that binding of radiolabeled DEN to the human hepatoma cell line HuH-7 was strictly pH dependent and substantially inhibitable by the glycosaminoglycan heparin. Ligand-blot analysis, performed as a viral overlay assay, showed two heparan sulfate (HS) containing cell-surface binding proteins resolving at 33 and 37 kd. Based on the sensitivity of unprotected virus and the viral binding site on the cell surface to trypsin, viral internalization was quantified as an increase in trypsin protected virus over time. Virus trafficking to the site of degradation was inhibited by pH dissociation of the clathrin coat and dependent on IP(3)-mediated homotypic endosomal fusion. These findings confirm the hypothesis that binding and internalization of DEN by hepatocytes are mediated primarily by HS containing proteoglycans and suggest that flaviviruses traffic the major clathrin-dependent endocytic pathway during infection.
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PMID:Heparan sulfate proteoglycans initiate dengue virus infection of hepatocytes. 1105 58

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant dementia that is characterized by intraneuronal inclusions of mutant neuroserpin. We report here the expression, purification, and characterization of wild-type neuroserpin and neuroserpin containing the S49P mutation that causes FENIB. Wild-type neuroserpin formed SDS-stable complexes with tPA with an association rate constant and K(i) of 1.2 x 10(4) m(-1) s(-1) and 5.8 nm, respectively. In contrast, S49P neuroserpin formed unstable complexes with an association rate constant and K(i) of 0.3 x 10(4) m(-1) s(-1) and 533.3 nm, respectively. An assessment by circular dichroism showed that S49P neuroserpin had a lower melting temperature than wild-type protein (49.9 and 56.6 degrees C, respectively) and more readily formed loop-sheet polymers under physiological conditions. Neither the wild-type nor S49P neuroserpin accepted the P7-P2 alpha(1)-anti-trypsin or P14-P3 antithrombin-reactive loop peptides that have been shown to block polymer formation in other members of the serpin superfamily. Taken together, these data demonstrate that S49P neuroserpin is a poor proteinase inhibitor and readily forms loop-sheet polymers. These findings provide strong support for the role of neuroserpin polymerization in the formation of the intraneuronal inclusions that are characteristic of FENIB.
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PMID:Mutant Neuroserpin (S49P) that causes familial encephalopathy with neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro. 1188 Mar 76

The infectivity and pathogenicity of influenza virus are primarily determined by host cellular trypsin-type processing proteases which cleave the viral membrane fusion glycoprotein hemagglutinin (HA). Therefore the distribution of the processing protease is a major determinant of the infectious organ tropism. The common epidemic human influenza A virus is pneumotropic and the HA processing proteases tryptase Clara, mini-plasmin, tryptase TC30 and ectopic anionic trypsin have all been isolated from mammalian airways. However, the pneumotropic influenza virus occasionally causes severe brain edema, particularly in children presenting with Reye's syndrome treated with aspirin, or in children with influenza-associated encephalopathy without antipyretic treatment. We have observed that, after influenza virus infection, the accumulation of mini-plasmin in the cerebral capillaries in mice with a congenital or acquired abnormality of mitochondrial beta-oxidation mimicking the pathological findings of Reye's syndrome, causes an invasion and multiplication of the pneumotropic influenza virus at these same locations. From these findings, we hypothesize that the accumulated mini-plasmin modifies the brain capillaries from a non-permissive to a permissive state, thereby allowing multiplication of pneumotropic influenza virus. In addition, mini-plasmin proteolytically destroys the blood-brain barrier. These pathologic findings, consistent with encephalopathy in mice with a systemic impairment of beta-oxidation, may have implications for human influenza encephalopathy.
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PMID:Accumulation of mini-plasmin in the cerebral capillaries causes vascular invasion of the murine brain by a pneumotropic influenza A virus: implications for influenza-associated encephalopathy. 1525 80

Extracellular cleavage of virus envelope fusion glycoprotein hemagglutinin (HA0) by host trypsin-like proteases is a prerequisite for the infectivity and pathogenicity of human influenza A viruses and Sendai virus. The common epidemic influenza A viruses are pneumotropic, but occasionally cause encephalopathy or encephalitis, although the HA0 processing enzyme in the brain has not been identified. In searching for the brain processing proteases, we identified a processing enzyme in rat brain that was inducible by infection with these viruses. The purified enzyme exhibited an apparent molecular mass of approximately 22 kDa on SDS-PAGE and the N-terminal amino acid sequence was consistent with that of rat pancreatic trypsin I. Its substrate specificities and inhibition profiles were the same as those of pancreatic trypsin I. In situ hybridization and immunohistochemical studies on trypsin I distribution revealed heavy deposits in the brain capillaries, particularly in the allocortex, as well as in clustered neuronal cells of the hippocampus. The purified enzyme efficiently processed the HA0 of human influenza A virus and the fusion glycoprotein precursor of Sendai virus. Our results suggest that trypsin I in the brain potentiates virus multiplication in the pathogenesis and progression of influenza-associated encephalopathy or encephalitis.
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PMID:Identification of trypsin I as a candidate for influenza A virus and Sendai virus envelope glycoprotein processing protease in rat brain. 1660 46

To assess the etiology of influenza-associated encephalopathy(IAE), a surveillance effort was conducted during 2000-2005 in Japan. Over half of fatal and handicapped IAE patients exhibited a disorder of mitochondrial beta-oxidation and ATP generation evoked by the thermolabile phenotype of carnitine palmitoyltransferase II variations with transiently elevated serum acylcarnitine during high-grade fever. Model mice having impaired mitochondrial beta-oxidation exhibited significant accumulation of mini-plasmin and up-regulation of trypsin in the cerebral capillaries after infection with influenza A virus, resulting in the destruction of blood-brain barrier and increased brain vascular permeability. Trypsin up-regulation was also evident in the neuronal cells in the hippocampus, suggesting a severe neurologic complication of IAE.
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PMID:[Analysis of SNPs and enzymatic disorder in the patients of influenza-associated encephalopathy: disorder of fatty acid metabolism in mitochondria induced by high fever]. 1703 63


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