Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebrospinal fluid (CSF) from 20 male patients with nonneurologic disease (age 64.5 +/- 2.8 SEM) was analyzed for the presence of the serpin alpha 1-antichymotrypsin (alpha 1-ACT). A chymotrypsin-specific chromogenic substrate (succinyl-Ala-Ala-Pro-Phe-p-nitroanilide) was used to examine the CSF samples. All CSF samples showed inhibitory activity ranging from 45 to 80% inhibition. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the samples revealed the presence of a 68-kDa protein migrating identical to authentic human plasma alpha 1-ACT. Complex formation was performed with iodinated bovine chymotrypsin for several representative CSF samples having the highest chymotrypsin inhibitory activity. Comparison was made with complex formation performed with commercially available authentic human plasma alpha 1-ACT. These studies showed the formation of complexes at 37 degrees C, regardless of whether the sample was subsequently boiled or not. In the case of CSF, two complex bands, mass smaller than with plasma alpha 1-ACT, were formed at the lower temperature whereas a single higher Mr band was formed when the samples were boiled. To determine whether cleavage of the serpin occurred, these studies were repeated using human neutrophil cathepsin G as target protease. A complex of approximately 90 kDa was formed with human alpha 1-ACT under these same conditions. alpha 1-ACT has been detected in senile amyloid plaques in brains of Alzheimer's disease patients, the only plasma serine protease inhibitor localized to these structures. Another serpin, protease nexin I, is also found in these plaques, but this inhibitor does not circulate in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the serpin, alpha 1-antichymotrypsin, in normal human cerebrospinal fluid. 172 48

The anti-inflammatory influence of dapsone may involve suppression of neutrophil chemotaxis to selected attractants, but other actions of the drug are likely also involved. We have discovered that dapsone may suppress migration of neutrophils to extravascular sites through inhibition of adherence functions required for neutrophil recruitment. Neutrophil adherence mediated by integrins (CD11/CD18 or Mac-1 family receptors) was measured in vitro in terms of binding of stimulated cells to albumin-coated wells of microtiter plates, using phorbol myristate acetate (PMA) and N-formylmethionyl-leucyl-phenylalanine (FMLP) as stimuli. Adherence was assessed by staining attached cells with crystal violet dye and measuring the dye concentration at OD590 using an automated plate reader. The role of integrins in this assay was confirmed by the ability of anti-integrin antibody to suppress stimulated neutrophil adherence. The OD590 value for cells adhering to albumin in the absence of stimulus and dapsone averaged 0.2 +/- 0.04 (SEM) over five experiments. In the presence of 0.1 microM PMA or 10(-6) M FMLP, the OD590 values averaged 0.88 +/- 0.1 and 0.75 +/- 0.12, respectively. Dapsone did not affect unstimulated neutrophil adherence but, when present with stimulus, produced a dose-related inhibitory effect on adherence. Fifty percent inhibitory doses were approximately 150 micrograms/ml dapsone for both stimuli. Sulfapyridine reproduced the inhibitory effect of dapsone, but two structurally related compounds, hydrochlorothiazide and furosamide, did not. The observed ability of dapsone to inhibit neutrophil chemotaxis under agarose to FMLP and interleukin-8 may also be explained by interference with integrin-mediated adherence required for motility in this assay system. To consider if dapsone might have a similar inhibitory influence on neutrophil adherence in vivo, we tested the stimulated adherence function of neutrophils isolated from three individuals on dapsone therapy for dermatitis herpetiformis. Stimulated adherence of patients' cells averaged less than 40 percent of the control value. Suppression of leukocyte integrin function may therefore also contribute to the ability of dapsone to inhibit neutrophil infiltration in neutrophilic dermatoses.
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PMID:Dapsone suppresses integrin-mediated neutrophil adherence function. 173 79

Activation of leukocytes in vivo produces marked constriction of large arteries in atherosclerotic, but not in normal, monkeys. We tested the hypotheses that vasoconstrictor responses to activated leukocytes in vivo may be abnormal during hypercholesterolemia before the development of atherosclerotic lesions and that responses may return to normal after the regression of atherosclerosis. Leukocytes were activated by injection of the chemotactic peptide formyl-methionine-leucine-phenylalanine (fMLP) into the blood-perfused hind limb of four groups of cynomolgus monkeys: monkeys fed a normal diet (normal group, n = 18), monkeys fed an atherogenic diet for 3-4 months (hypercholesterolemic group, n = 6), monkeys fed an atherogenic diet for 20 months (atherosclerotic group, n = 19), and monkeys fed an atherogenic diet for 18 months, followed by a normal diet for 20 months (regression group, n = 14). Baseline resistance of large arteries was 1.5 +/- 0.2 (mean +/- SEM), 2.0 +/- 0.6, 3.5 +/- 0.4 (p less than 0.05 versus normal), and 1.7 +/- 0.2 mm Hg/ml/min per 100 g tissue for the normal, hypercholesterolemic, atherosclerotic, and regression groups, respectively. Injection of fMLP did not change resistance of large arteries in normal or hypercholesterolemic monkeys. Injection of fMLP increased resistance of large arteries by 3.0 +/- 0.7 mm Hg/ml/min per 100 g tissue in atherosclerotic monkeys and by 1.3 +/- 0.4 mm Hg/ml/min per 100 g tissue in regression monkeys (p less than 0.05 versus atherosclerotic and normal). Thus, abnormal vasoconstriction in response to activation of leukocytes persists, but to a lesser extent, after regression. In contrast, vasoconstrictor responses to serotonin, which were potentiated in atherosclerotic monkeys, were normal after regression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular responses to activated leukocytes after regression of atherosclerosis. 173 39

We have utilized specific, irreversible inhibitors of cysteine proteinases to examine the role of renal cathepsin B and cathepsin L in the proteinuria which occurs in an experimental model of human glomerular disease. Administration of trans-epoxysuccinyl-L-leucylamido-(3-methyl)butane (Ep475) a specific, irreversible inhibitor of cysteine proteinases, including cathepsins B and L, significantly reduced proteinuria in rats with experimentally induced, neutrophil-independent, anti-GBM antibody disease (controls: 10 +/- 1 mg/24 h, N = 8; anti-GBM antibody disease: 203 +/- 30 mg/24 h, N = 8; anti-GBM antibody disease + Ep475: 112 +/- 13 mg/24 h, mean +/- SEM, N = 6, P less than 0.05). There was a marked reduction in the activity of both cathepsin B and cathepsin L in renal cortices obtained from Ep475-treated rats compared to either saline-treated controls or rats treated with anti-GBM IgG only. Administration of Z-Phe-Tyr(O-t-butyl)CHN2, a specific, irreversible cysteine proteinase inhibitor with a high degree of selectivity toward cathepsin L, also caused a reduction in anti-GBM antibody-induced proteinuria (90 +/- 18 mg/24 h, N = 6, P less than 0.05). This reduction in proteinuria was accompanied by a marked decrease (-84%) in the specific activity of renal cortical cathepsin L in Z-Phe-Tyr(O-t-butyl)CHN2-treated rats. However, cathepsin B activity was unchanged. There was no significant change in the renal anti-GBM antibody uptake, plasma urea nitrogen, or plasma creatinine values in the Z-Phe-Tyr(O-t-butyl)CHN2-treated rats compared to rats treated with anti-GBM IgG only or saline-treated controls. These data document the ability of cysteine proteinase inhibitors to decrease the proteinuria which occurs in a neutrophil-independent model of human anti-GBM antibody disease and suggest an important role for cathepsin L in the pathophysiology of the proteinuria which occurs in this model.
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PMID:Evidence suggesting a role for cathepsin L in an experimental model of glomerulonephritis. 189 42

We investigated the correlation between amino acid level and hepatic graft function. Plasma amino acid levels were measured at three time periods during canine orthotopic liver transplantation. During the anhepatic phase, plasma amino acid levels rose except for tryptophan. Cystine and alanine (Ala) increased significantly to 210 +/- 28% (n = 20, mean +/- SEM) and 203 +/- 11% from preoperative values (100%), respectively. In animals successfully surviving without hepatic insufficiency after transplantation of fresh livers (n = 7), plasma amino acid levels were restored to preoperative values within 3 hr following reperfusion. On the other hand, in animals that died from hepatic insufficiency within 5 days after grafting of warm ischemically damaged livers (n = 8), plasma amino acids, especially Ala, phenylalanine, total free plasma amino acids, and aromatic amino acids progressively increased to 216 +/- 25, 274 +/- 36, 152 +/- 15, and 152 +/- 15% at 3 hr after reperfusion. These were significantly higher compared to those of the group of animals transplanted with fresh livers (P less than 0.01-0.05). Furthermore, higher values were found in those dogs transplanted with warm ischemically damaged livers surviving for shorter periods. Also in dogs that died from hepatic insufficiency within 8 hr after grafting of livers preserved for 24 hr (n = 5), amino acid levels were at high values at 3 hr. These results suggest that in animals having good graft function, plasma amino acid levels are restored to preoperative values by 3 hr after reperfusion. In other cases, primary nonfunction should be strongly suspected after liver transplantation.
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PMID:Evaluation of initial hepatic allograft function with changes of free plasma amino acids in canine orthotopic liver transplantation. 199 Feb 18

The role of bradykinin in the ovulatory process was investigated using an in vitro-perfused rat ovary model. Stimulation with LH (0.1 micrograms/ml) resulted in 2.6 +/- 0.5 (mean +/- SEM) ovulations per ovary, whereas no ovulations occurred in the nonstimulated control group. Bradykinin (5 microM) added to the perfusion system hourly for 10 h induced 2 of 5 ovaries to ovulate, with 2 and 3 ovulations, respectively. When bradykinin (5 microM) was given as a single dose at 5 or 10 h after LH, the ovulation rate was significantly increased to 11.0 +/- 2.8 and 8.6 +/- 2.0 ovulations per ovary, respectively. A competitive bradykinin antagonist, phenylalanine bradykinin, inhibited the bradykinin-induced increase in LH-stimulated ovulations. The addition of LH, but not of bradykinin, increased the levels of prostaglandin endoperoxide synthase in granulosa cells, but the levels of the enzyme in the residual ovarian tissue were negligible. In contrast, prostacyclin synthase was predominantly located in the residual ovarian tissue. This enzyme was not affected by LH or bradykinin. LH increased the tissue levels of prostaglandins, predominantly prostaglandin E2 (PGE2), at 7 h, whereas the stimulatory effect of bradykinin was smaller, with a preferential increase in prostacyclin (prostaglandin I2) levels. This study indicates a modulatory role of bradykinin, possibly involving prostacyclin late in the ovulatory process, in the rat.
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PMID:Stimulatory effects of bradykinin on the ovulatory process in the in vitro-perfused rat ovary. 200 29

The goal of this study was to test the hypothesis that atherosclerosis alters responses of cerebral arteries and the ocular circulation to the activation in vivo of leukocytes and platelets. We measured blood flow to the brain and eye using microspheres and pressure in the cerebral microvessels of normal and atherosclerotic monkeys. The intracarotid injection of 10(-7) M N-formyl-L-methionyl-L-leucyl-L-phenylalanine to activate leukocytes did not alter cerebral blood flow in 11 normal or 10 atherosclerotic monkeys but increased the resistance of large cerebral arteries by 46 +/- 11% (mean +/- SEM) in the atherosclerotic animals. The injection of N-formyl-L-methionyl-L-leucyl-L-phenylalanine did not alter blood flow to the eye in 10 normal monkeys but decreased blood flow to the choroid by 38 +/- 9% in 11 atherosclerotic monkeys. The intracarotid injection of 3 x 10(-9) M prostaglandin E2, a leukocyte product, produced an increase in the resistance of large cerebral arteries in five atherosclerotic but not in six normal monkeys. Prostaglandin E2 reduced blood flow to the retina and choroid in the atherosclerotic monkeys by 62 +/- 22% and 65 +/- 17%, respectively. The intracarotid infusion of 25 micrograms/min collagen to activate platelets increased cerebral blood flow by 21 +/- 5% in 10 normal monkeys but did not alter it in 11 atherosclerotic monkeys. Collagen did not alter blood flow to the choroid in 10 normal monkeys but decreased it by 29 +/- 8% in 11 atherosclerotic monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of atherosclerosis on cerebral vascular responses to activation of leukocytes and platelets in monkeys. 205 80

A stable isotope technique depending on the use of [15N]phenylalanine and [1-13C]leucine to assess exchange was utilized to measure the components of protein turnover of the human leg and the effects of amino acid infusion. Eight healthy subjects (28.5 +/- 2.5 years) were studied when post-absorptive in the basal state and again during infusion of a mixed amino acid solution (55 g l-1, 1.52 ml kg-1 h-1). During the basal period leucine oxidation by the leg was 4.4 +/- 2.0 nmol 100 g-1 min-1 and this increased threefold during amino acid infusion (13.6 +/- 3.1 nmol 100 g-1 min-1, mean +/- SEM, P = 0.003). Amino acid infusion abolished the net negative balance between incorporation of leucine into, and release from, protein (basal, -31.8 +/- 5.8; during infusion, +3.1 +/- 7.1 nmol 100 g-1 P = 0.001). Phenylalanine exchange showed a similar pattern (basal, -13.7 +/- 1.8; during infusion, -0.8 +/- 3.0 nmol 100 g-1 min-1, P = 0.003). Basal entry of leucine into leg protein (i.e. protein synthesis) was 70.0 +/- 10.8 nmol 100 g-1 min-1 and this increased during amino acid infusion to 87.3 +/- 14.1 nmol 100 g-1 min-1 (P = 0.11). Phenylalanine entry to protein also increased with amino acid infusion (29.1 +/- 4.5 vs. 38.3 +/- 5.8 nmol 100 g-1 min-1, P = 0.09). Release from protein of leucine (101.8 +/- 9.1 vs. 84.2 +/- 9.1 nmol 100 g-1 min-1, P = 0.21) and of phenylalanine (42.8 +/- 4.2 vs. 39.1 +/- 4.2 nmol 100 g-1 min-1, P = 0.50) was unchanged by amino acid infusion. The results suggest that, in the post-absorptive state in man, infusion of mixed amino acids, without additional energy substrates; reverses negative amino acid balance by a mechanism which includes stimulation of muscle protein synthesis but which does not alter protein breakdown. Interpretation of the results obtained concurrently on whole-body protein turnover suggests that the increase in muscle protein synthesis contributes substantially to the whole-body increase, but the fall in whole-body breakdown with exogenous amino acids is independent of changes in muscle.
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PMID:The effect of amino acid infusion on leg protein turnover assessed by L-[15N]phenylalanine and L-[1-13C]leucine exchange. 210 36

Developmental defects in neutrophil function, including diminished expression of plasma membrane receptors, may play an important role in the susceptibility of the newborn infant to infection. We used monoclonal antibodies and flow cytometry to study the expression of complement receptor type one (CR1), complement receptor type three (CR3), and Fc gamma receptor type three (FcRIII) on neutrophils from six fetuses with Rh disease, 10 preterm infants, nine term infants, and nine adults. Expression of the complement receptors on unstimulated cells was similar for all groups, but significant differences in complement receptor expression were observed after stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP). Fetal, preterm, and term infant neutrophils expressed less CR3 than FMLP-stimulated neutrophils of adults [61 +/- 2, 48 +/- 4, and 66 +/- 4% (mean +/- SEM) of the mean for adults, p less than 0.05]. FMLP-stimulated CR1 expression for these groups was 61 +/- 6, 73 +/- 6, and 91 +/- 9% of the adult mean (p less than 0.05, fetal versus term infant and adult). Expression of both CR3 and CR1 increased with postconceptional age in the infants (r2 = 0.49, p less than 0.001 for CR3; r2 = 0.23, p less than 0.05 for CR1). Neutrophils of the preterm and term infants expressed less FcRIII than adult neutrophils (68 +/- 10 and 77 +/- 7% of the adult mean, p less than 0.05, for FMLP-stimulated cells), whereas fetal neutrophil FcRIII expression did not differ from that of the adult.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of the complement receptors CR1 and CR3 and the type III Fc gamma receptor on neutrophils from newborn infants and from fetuses with Rh disease. 214 35

Alterations in proteoglycans (PG) located in the pulmonary interstitium may influence extracellular matrix (ECM) structure and assembly during the development of diseases in which increased numbers of neutrophils enter the lung. To evaluate potential mechanisms of PG degradation, neutrophils or purified neutrophil products were incubated with ECM that had been produced by cultured neonatal rat vascular smooth muscle cells (SMC) or lung fibroblasts (LF) and metabolically labeled with 35SO4. Matrix PG solubilization was expressed as a percentage of the spontaneous [35SO4]PG solubilization that occurred in the presence of buffer alone. Solubilization by unstimulated neutrophils was 105.8 +/- 3.1% (mean +/- SEM, n = 6) and 101.7 +/- 3.05 (n = 8) using ECM that had been produced by LF and SMC, respectively. Solubilization by neutrophils that had been stimulated with formyl-methionine-leucine-phenylalanine (FMLP) in the presence of cytochalasin B (CB) was 189.7 +/- 5.8% and 298.2 +/- 26.2% using ECM produced by LF and SMC, respectively. Matrix that had been produced by SMC was used to evaluate which neutrophil products were responsible for the degradation of PG. Addition of a specific inhibitor of neutrophil elastase (NE) to stimulated polymorphonuclear leukocytes (PMN) reduced PG solubilization by 88.3 +/- 4.8% (n = 8). Addition of an inhibitor of cathepsin G (CG), as well, did not further reduce PG degradation. Purified CG and myeloperoxidase solubilized significantly more PG, 125.8 +/- 6.2% (n = 9) and 143.2 +/- 8.1% (n = 6), respectively (P less than 0.01), than was solubilized spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of extracellular matrix proteoglycan degradation by human neutrophils. 215 32


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