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)

We have studied cells dispersed with proteolytic enzymes from rheumatoid arthritic synovectomy specimens to determine the cell type(s) responsible for joint destruction. Initially 10-50% of these cells adhered to culture dishes within 24 hr and were of two main types: small, round cells and larger, stellate cells. During 1-4 days of culture, 5-25% had Fc receptors and 25-50% showed brisk phagocytosis. Daily producition, per 10(6) cells of collagenase (EC 3.4.24.3) (after trypsin pretreatment) was up to 70 mug of collagen fibrils lysed per min at 37 degrees (70 units), of prostaglandin (PGE2), up to about 1200 ng, and of lysozyme, up to about 100 mug. Under identical conditions of assay, fibroblasts grown from explants of synovium produced no detectable collagenase or lysozyme, and PGE2 was only 2-4 ng. With the dispersed cell preparations, macrophage markers (Fc receptors and lysozyme) were undetectable after 4 days and PGE2 decreased rapidly after about 7 more days. However, collagenase production continued for 3-25 weeks, and in some cultures, after cell passage. At these later stages, large, slow-growing stellate cells were predominant and could phagocytose carbon particles if incubated for greater than 6-8 hr. Indomethacin (14 muM) inhibited PGE2 but stimulated collagenase production whereas dexamethasone (10 nM) inhibited both. Production of PGE2 and collagenase in large amounts in vitro by these cells suggests that they may be involved in joint destruction in vivo. The precise origin of these synovial cells and the mechanisms responsible for the sustained production of collagenase at a high rate remain unidentified.
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PMID:Production of collagenase and prostaglandins by isolated adherent rheumatoid synovial cells. 17 63

1 The effects of purported prostaglandin synthesis inhibitors on steroid and prostaglandin (E and F) release from trypsin-dispersed cat adrenocortical cells were investigated. 2 Low indomethacin concentrations potentiated adrenocorticotrophin (ACTH)-evoked prostaglandin and steroid release, whereas higher concentrations depressed both responses to ACTH. The steroidogenic response to exogenous prostaglandin E2 was not markedly altered over a wide range of indomethacin concentrations. 3 Indomethacin enhanced basal steroid release but did not enhance basal prostaglandin E or F release. 4 5,8,11,14-Eicosatetraynoic acid (ETA) elicited a concentration-dependent inhibition of ACTH-induced steroid release, but had little effect on prostaglandin E2-induced steroid release. A high concentration of ETA inhibited prostaglandin E and F release. 5 These data are discussed in relation to the concept that prostaglandins provide a critical link in ACTH-induced corticosteroidogenesis.
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PMID:Indomethacin-induced alterations in corticosteroid and prostaglandin release by isolated adrenocortical cells of the cat. 18 Nov 10

The existence of a new factor (AF) in mice acting synergistically with known proaggregatory stimuli has been suggested by the present study in the plasma of mice challenged with intravenous collagen and adrenaline. Indomethacin, nordihydroguaretic acid (NDGA), BW 755C, phentolamine, cimetidine and ketanserin could not block the response of AF. Activity of the factor remained unaltered after treatment with pancreatic phospholipase A2, collagenase, CP/CPK, trypsin and heparin. Fractionation of the plasma indicated the presence of AF in acetone precipitate. Activity was destroyed by pronase and it was lost after dialysis and charcoal treatment. Existence of such a factor which is heat resistant, is of low molecular weight and is proaggregatory in nature in the thrombotic mice plasma and which requires calcium ions for the expression of its activity, has not been reported earlier.
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PMID:Evidence for the presence of a new plasma factor which acts synergistically to ADP induced platelet aggregation. 211 90

Prostaglandin H synthase catalyzes two reactions: the bis-dioxygenation of arachidonic acid to form prostaglandin G2 (cyclooxygenase activity), and the reduction of hydroperoxides to the corresponding alcohols (peroxidase activity). The cyclooxygenase activity can be selectively inhibited by many nonsteroidal antiinflammatory agents including indomethacin. In the native synthase, there is a single prominent protease-sensitive region, located near Arg253; binding of the heme prosthetic group makes the synthase resistant to proteases. To investigate the spatial relationship between the area of the synthase which interacts with indomethacin and the protease-sensitive region, the effects of indomethacin and similar agents on the protease sensitivity of the two enzymatic activities and of the synthase polypeptide were examined. Incubation of the synthase apoenzyme with trypsin (3.6% w/w) resulted in the time-dependent coordinate loss (75% at 1 h) of both enzymatic activities and the cleavage (85% at 1 h) of the 70-kDa subunit into 38- and 33-kDa fragments, indicating that proteolytic cleavage of the polypeptide at Arg253, destroyed both activities of the synthase simultaneously. Indomethacin, (S)-flurbiprofen, or meclofenamate (each at 20 microM) rendered both activities and the synthase polypeptide (at 5 microM subunit) resistant to attack by trypsin or proteinase K; these agents also inhibited the cyclooxygenase activity of the intact synthase. Two reversible cyclooxygenase inhibitors, ibuprofen and flufenamate, also made both of the activities and the synthase polypeptide more resistant to trypsin. Titration of the apoenzyme with indomethacin (0-3 mol/mol of synthase dimer) resulted in proportional increases in the inhibition of the cyclooxygenase and in the resistance to attack by trypsin. (R)-Flurbiprofen did not increase the resistance to protease or appreciably inhibit the cyclooxygenase. These results suggest that the same stereospecific interaction of these agents with the synthase that produced inhibition of the cyclooxygenase led to a decreased accessibility of the Arg253 region to proteases. Aspirin treatment made the synthase less resistant to trypsin; aspirin-treated synthase became more resistant to trypsin when it was incubated with indomethacin before addition of the protease. The presence of 50 microM arachidonate during digestion of apoenzyme or aspirin-treated apoenzyme with trypsin did not decrease the cleavage of the synthase subunit.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Topography of prostaglandin H synthase. Antiinflammatory agents and the protease-sensitive arginine 253 region. 250 12

The therapy with thymus extracts, oral and parenteral, reduced the frequency and the intensity of recurrences of herpes labialis infections. The duration of the effect was at least 6 month after interruption of the therapy. Indomethacin was effective and developed and intensive effect only during the therapy. The skin test with recall-antigens and the neopterin-elimination were altered at the first day of the menstruation during the recurrence. The normalisation succeeded during therapy. In patients with recurrences in the perimenstrual time we observed a reduced T-helper/T-suppressor index during the first day of menstruation. Normal data were registered out of the recurrence time and/or under therapy. Inhibitors of the lymphokine: leucocyte/migration inhibitory factor (LIF) with a molecular weight of 6-12 KD were obtained with the specific stimulation of mononuclear cells of patients with recurrent infections with herpes labialis using the herpes-virus-1 antigen. The inhibition of fibrinolysis/proteolysis with aprotinin, tranexamic acid, phenyl-methyl-sulphonyl-fluoride and di-isopropyl-fluorophosphate could prevent the appearance of inhibitors. Inhibitors could be produced by splitting the LIF-molecule with urokinase and plasminogen but not with trypsin. The production, but not the activity, of present LIF-inhibitors are blocked in vivo and in vitro by indomethacin and thymus peptides.
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PMID:[Recurrent herpes labialis infections: cellular immunity and immunomodulation]. 253 31

Collagenolytic activity in ovarian follicles was previously demonstrated by using synthetic peptides and reconstituted collagen fibers. However, attempts to demonstrate degradation of ovarian collagen and to correlate collagenase activity with ovulation were not successful. By administration of L-(5-3H) proline, we have labeled ovarian and follicular collagen and followed collagenolytic activity by separation of 3H-hydroxyproline (3H-Hyp) from acid hydrolyzates of ovarian tissue by HPLC. The level of ovarian and follicular 3H-Hyp decreased by about 40% on the afternoon of proestrus or after exogenous stimulation of ovulation by human CG (hCG), and this decrease was abolished by blocking the surge of gonadotropins with Nembutal. To verify that the observed reduction in 3H-Hyp was due to the action of a typical collagenase, the collagenous fraction was prepared from ovarian tissue and from preovulatory follicles before and after the ovulatory stimulus. The extracts were treated with trypsin (25 min, 25 C, 0.01 mg/ml) plasmin and p-amino-phenyl-mercuric acetate to fully activate the collagenase extracted along with collagen. Both, enzymatic and chemical activation of collagenase in vitro resulted in degradation of collagen. This degradation could be inhibited by cysteine and EDTA; both are classic inhibitors of mammalian collagenases. The activity of ovarian collagenase increased within 3 h after hCG-stimulation, peaked at 5-fold 6 h after hCG, and declined afterwards. Administration of cysteine (0.001-0.01 mmol) into the bursal cavity of proestrous rats blocked ovulation and breakdown of ovarian collagen in a dose-dependent manner. Cysteine effectively inhibited ovulation even when injected 7 h after the hCG stimulus. Inhibitors of arachidonic acid metabolism prevent ovulation. Indomethacin (inhibitor of cyclooxygenase) and nordihydroguaiaretic acid (inhibitor of lipoxygenase) blocked ovulation and inhibited hCG-induced ovarian collagenolysis. Collectively, these results corroborate the essential role of collagenolysis in follicular rupture in mammals.
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PMID:The involvement of collagenolysis in ovulation in the rat. 298 65

Previously it was shown that macrophages (M phi) isolated from the vigorous (Vig) or modulated (Mod) liver granulomas (Gr) of Schistosoma mansoni-infected mice restored mitogen and parasite egg antigen-induced proliferative responses to accessory cell-depleted lymphocytes. Furthermore, supraoptimal concentrations of highly activated VigGrM phi suppressed lymphoproliferation to a greater extent than did the lesser activated ModGrM phi. In this study we investigated the role of soluble mediators in GrM phi accessory/regulatory activity. Indomethacin released VigGrM phi-mediated inhibition of mitogen but not antigen-induced lymphoproliferation. Extensively dialyzed serum-free GrM phi culture supernatant nonspecifically suppressed SEA- or KLH-induced blastogenesis. Culture supernatants also reduced vesicular stomatitis virus-induced plaque formation in supernatant-pretreated L-929 fibroblasts. The 20 to 45 Kd GrM phi-derived lymphoproliferation suppressive factor (SF) and the 20 to 50 Kd viral plaque-reducing factor (PRF) were stable at low pH, but became inactivated by heat and trypsin digestion. Although freshly isolated Vig or ModGrM phi contained preformed SF and PRF, in vitro production of the factors were depressed by protein synthesis inhibitors. Moreover, SF was active only when added to cultures before day 3 of the 6-day proliferation assay. Both SF and PRF were specifically retained on rabbit anti-murine IFN-alpha/beta immunoaffinity columns. Thus, the suppressive activity of Vig or ModGrM phi is in part mediated by a monokine that shares physical, biological, and antigenic characteristics with murine IFN-alpha/beta. In contrast to the suppression of antigen-driven proliferation, GrM phi culture supernatant costimulated PHA-induced mitogenesis. The 13 to 21 Kd GrM phi-derived lymphocyte-activating factor (LAF) was stable to heat, low pH, and trypsin digestion. Freshly isolated Vig or ModGrM phi contained preformed LAF, although its in vitro production was depressed by protein synthesis inhibitors. The physical and biological characteristics of GrM phi-derived LAF appear similar to IL 1. It is concluded that both Vig and ModGrM phi secrete regulatory/accessory monokines that may contribute to the initiation and maintenance of the focal inflammatory granulomatous response.
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PMID:Characterization of regulatory (interferon-alpha/beta) and accessory (LAF/IL 1) monokine activities from liver granuloma macrophages of Schistosoma mansoni-infected mice. 310 71

The effects of indomethacin administration on hemodynamics were investigated in canine acute hemorrhagic pancreatitis (AHP). Thirteen mongrel dogs were randomly divided into a fluid treatment group, an indomethacin prophylaxis group (IMP), and an indomethacin therapy (IM) group. Indomethacin (5 mg/kg) was administered as a bolus dosage 30 min before the induction of AHP in the IMP group. In the IM group, indomethacin was also given as a bolus (5 mg/kg) in 5 min starting 30 min after the induction of AHP. AHP was induced with a mixture of trypsin and sodium taurocholate infused into the pancreatic duct. Hemodynamics were monitored during the 4.5 h of surveillance time. Heart rate did not change significantly between the groups. Indomethacin prophylaxis maintained mean arterial pressure at a significantly higher level (P less than 0.05) and prevented the initial fall in blood pressure when compared to the fluid treatment or IM group. Indomethacin increased cardiac output (P less than 0.05) in the IM group, but did not differ significantly in the IMP group in comparison with the fluid treatment group. In conclusion, the inhibition of the initial fall in blood pressure by indomethacin in AHP suggests prostaglandins to play a role in hemodynamic changes and pancreatic shock to be "septic" as evaluated by hemodynamic changes.
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PMID:Indomethacin in canine acute hemorrhagic pancreatitis. 335 85

The role of prostaglandins (PGs) in aldosterone secretion was studied in isolated rat adrenal glomerulosa cells. [14C]Arachidonic acid was metabolized to [14C]6-keto-PGF1 alpha, [14C]PGF2 alpha, [14C]PGE2, and [14C]PGD2. Pretreatment with indomethacin (5 X 10(-5) M) or U-51605 (5 micrograms/ml) inhibited the synthesis of these metabolites. Angiotensin II (AII) stimulated a concentration-related release of aldosterone and 6-keto-PGF1 alpha, but not PGE2. Significant increases in aldosterone and 6-keto-PGF1 alpha occurred at AII concentrations of 0.2 and 2 nM. The increases in 6-keto PGF1 alpha concentrations after AII treatment were small, however (278 +/- 33 pg/10(6) cells X h for control vs. 581 +/- 90 after 2 nM AII). At higher concentrations, AII further stimulated aldosterone, but 6-keto PGF1 alpha levels declined. AII stimulated the synthesis of aldosterone and 6-keto PGF1 alpha in parallel with time of incubation. Indomethacin (3 microM) decrease basal and AII-stimulated aldosterone release by 40% and 23%, respectively, and inhibited the synthesis of PGs. U-51605 (5 micrograms/ml) failed to alter aldosterone release. Arachidonic acid increased the synthesis of PGE2 and 6-keto-PGF1 alpha in a concentration-related manner without altering the synthesis of aldosterone. In contrast, PGH2 stimulated the release of PGE2, 6-keto-PGF1 alpha, and aldosterone. PGI2 and PGE2 stimulated aldosterone secretion, which was concentration related. Threshold stimulation by PGI2 and PGE2 occurred at 0.5 and 5 nM, respectively. Maximal stimulation occurred at 5 nM for PGI2 and at 5000 nM for PGE2, with PGE2 producing the greater maximal response. Treatment of the cells with trypsin eliminated the steroidogenic response to PGE2. These findings indicate that PGI2 and PGE2 are produced by the adrenal glomerulosa cells, and the synthesis of PGI2 may be stimulated by AII. However, the concentrations of PGI2 synthesized are not adequate to stimulate aldosterone secretion. Thus, PGI2 does not appear to mediate angiotensin-induced aldosterone secretion.
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PMID:Absence of prostacyclin involvement in angiotensin-induced aldosterone secretion in rat adrenal cells. 392 81

The activity of alpha-thrombin and chemically modified derivatives of this enzyme in stimulating cGMP formation in murine neuroblastoma clone N1E-115 cells is reported. The rank order potency of the compounds falls into three classes: 1) alpha-thrombin is the most potent and effective; 2) the catalytically active enzymes gamma-thrombin, trypsin, and nitro-alpha-thrombin are approximately 50-fold less potent than alpha-thrombin; and 3) active site blocked derivatives of alpha-thrombin are 100 to 1000-fold less potent than alpha-thrombin. Native alpha-thrombin consistently produces the most effective response, usually 1.5 to 3-fold greater than any of the other compounds tested. Preincubation of cells with quinacrine, an inhibitor of phospholipase A2, or with the lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid or nordihydroguaiaretic acid prior to thrombin challenge resulted in a concentration-dependent attenuation of the response. Indomethacin was without effect in modifying the response. These results suggest that thrombin stimulation of neuroblastoma cells involves the release of arachidonic acid and its metabolism by lipoxygenase. These results clearly demonstrate the activity of alpha-thrombin in stimulating a receptor-mediated response in cultured nerve cells. The results are discussed in relation to the interaction of endogenous alpha-thrombin with nerve cells following invasive trauma and to the possible presence of endogenous proteinases with a neurotransmitter-like function.
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PMID:Activation of cyclic nucleotide formation in murine neuroblastoma N1E-115 cells by modified human thrombins. 608 21


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