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:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetracyclines are potent inhibitors of 2 major matrix metalloproteinases which have been implicated in connective tissue degradation: collagenase and Type IV collagenase/gelatinase. We directly identified these enzyme activities in extracts of inflamed paw tissue from rats with adjuvant arthritis. Oral tetracycline therapy suppressed metalloproteinase activity in arthritic tissue, but even very high doses failed to exhibit substantial antiinflammatory efficacy (reduced joint swelling and paw diameter). Flurbiprofen, a conventional nonsteroidal antiinflammatory drug, reduced inflammatory indices as expected. The combination of the 2 agents administered orally completely inhibited collagenase activity, significantly inhibited gelatinase activity and produced substantial normalization of radiographic joint damage, far greater than either drug alone. Tetracycline inhibition curves in vitro suggest that the collagenase in this tissue is not of fibroblast origin. Tetracycline derivatives might be useful adjuncts to prevention of tissue damage in chronic inflammatory arthritides.
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PMID:Tetracyclines suppress matrix metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorate bone damage. 140 31

Tetracycline antibiotics (TETs) have a recently discovered novel action: inhibition of extracellular metalloproteinase activity, especially that of collagenase and gelatinase. This property, now confirmed in 8 different laboratories using > 40 tissue sources, includes natural and semi-synthetic TETs as well as a chemically modified TET (CMT) devoid of antimicrobial activity. We have used 14C-Tyr biosynthetically labelled intracellular proteins in L-6 myoblast culture as a test system to assess intracellular proteolysis. Starvation accelerates proteolysis, which can be suppressed by agents such as insulin or serum. Minocycline, doxycycline, and CMT all retarded the rate of intracellular protein degradation in a dose dependent manner. These agents also demonstrated marked synergism with insulin. A CMT derivative (pyrazole) stripped of one of its metal chelation sites and lacking anti-collagenase activity, also lost its antiproteolytic effect. CMT at physiologic concentrations (< or = 5 micrograms/ml) had no effect on protein synthesis, but at 15 micrograms/ml (pharmacologic), a suppressive effect was noted. These findings demonstrate that TETs can inhibit protein degradation as well as synthesis in a mammalian muscle-derived cell line.
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PMID:Tetracyclines inhibit intracellular muscle proteolysis in vitro. 144 21

Tetracycline inhibition of neutrophil-associated collagenolysis has been the focus of a number of investigations. Evidence has suggested that this inhibition results from the ability of this family of antimicrobial drugs to bind divalent cations such as Ca2+ and Zn2+, two cations that are required for full expression of activity of metalloproteinases such as collagenase and gelatinase. Data presented in this study demonstrate that tetracyclines can also inhibit neutrophil-mediated RBC lysis, superoxide anion synthesis, degranulation and migration. To some extent, tetracycline inhibition of neutrophil functions is mimicked by the Ca2+ binding agents, EDTA and TMB-8. However, Ca2+ enrichment restored full function to EDTA- and TMB-8-treated cells but not to tetracycline-treated neutrophils. This suggests that Ca2+ binding plays a role but is not the critical effect leading to tetracycline suppression of neutrophil functions. It has been suggested that tetracyclines can suppress leukocyte-associated tissue damage. Host tissues are protected from neutrophil-mediated damage by two mechanisms: 1. Neutrophil granule-associated enzymes are secreted in an inactive state; and, 2. tissues are protected from these enzymes by a potent inhibitor shield. Neutrophils can bypass these protective elements by activating enzymes and by destroying the shield through the synthesis of oxygen radicals. Therefore, tetracyclines may suppress neutrophil-mediated tissue damage by inhibiting their migration and degranulation and, potentially more importantly, by suppressing synthesis of oxygen radicals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Suppression of human neutrophil functions by tetracyclines. 184 18

Tetracycline has anticollagenase activity in human and animal tissues. Recent evidence shows collagenase to be instrumental in the progression of infectious and noninfectious corneal ulceration. We investigated the effect of systemic tetracycline on the incidence of corneal perforation in Pseudomonas aeruginosa ulcerative keratitis in rabbits. Twenty rabbits were assigned randomly to two groups in a masked fashion. All corneas were inoculated with 10(6) P. aeruginosa organisms. Ten rabbits (20 eyes) received intramuscular tetracycline 50mg/kg/day in a saline vehicle (treatment group), and ten rabbits (20 eyes) received saline alone (control group) for ten days. The incidence of corneal perforation in the treatment group (45%) was significantly lower than that in the control group (80%, P less than .02). This appeared to be independent of any antimicrobial effect from tetracycline. Administration of tetracycline may be a useful adjunct in the treatment of P. aeruginosa corneal ulcers.
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PMID:Effect of systemic tetracycline on progression of Pseudomonas aeruginosa keratitis in the rabbit. 211 13

Tetracycline resistance in the Enterobacteriaceae is mediated by a number of genetically related, usually plasmid-borne, determinants which specify an efflux system involving an inner membrane protein, Tet. Attempts to overproduce the Tn10 (Class B)-encoded Tet in Escherichia coli by cloning the structural gene tet downstream of the lambda PL promoter under regulation by temperature-sensitive lambda repressor cI857 were unsuccessful; induction at 42 degrees C resulted in filamentous, non-viable cells containing little detectable overproduction of the protein. However, cells containing tet fused to lacZ were resistant to tetracycline at 30 degrees C and synthesized modest amounts of a large fusion protein when induced at 42 degrees C. Fusion of the N-terminal half or the first 38 amino acids of tet to lacZ did lead to increased production of fusion proteins. Fusions could be purified by size or by LacZ immunoaffinity or substrate-affinity chromatography. In the latter method, selected detergents were required to counteract nonspecific binding of Tet to the adsorbant. Amino acid sequencing of the N-terminus of Tet-LacZ fusion proteins indicated that most molecules were blocked at this terminus. The sequence of an unblocked subpopulation was consistent with that expected from the nucleotide sequence. A collagen peptide linker, genetically placed between tet and lacZ, allowed recovery of purified Tet protein after collagenase treatment of the purified fusion protein.
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PMID:Overproduction and purification of the Tn10-specified inner membrane tetracycline resistance protein Tet using fusions to beta-galactosidase. 217 17

Invasion of the laryngeal framework by cancer implies a tumor that has spread beyond the bounds of the organ of origin, which may affect the outcome of the disease. Framework invasion almost invariably takes place in ossified or calcified cartilage, and the reason for this has never before been adequately explained. The finding of increased density on some computerized tomography scans where the tumor was invading the framework stimulated this study of the mechanisms of this type of spread. One hundred fifty-eight consecutive laryngeal specimens were examined by a serial sectioning method to elucidate this. Several laryngeal specimens were examined for alkaline phosphatase in the tissues, and two specimens were examined for collagenase. A method of tetracycline labeling was used to measure the amount of osteoblastic activity in another two specimens. Framework invasion occurred mainly at the glottic level and exclusively in ossified or calcified cartilage. This type of invasion was associated with osteoblastic activity which appeared to be at least partially mediated by tumor-produced alkaline phosphatase. Osteoclastic activity took place hand-in-hand with the former process, and at this stage, tumor remained outside the perichondrium. Tetracycline labeling confirmed active bone deposition in these areas and appeared to explain the finding of increased ossification seen on computerized tomography scans where early invasion was taking place.
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PMID:Framework invasion by laryngeal carcinoma. 311 72

Human fetal kidney explants can be maintained during 5 days in Leibovitz's L15, a basic serum-free medium. Because culture conditions are minimal for growth and differentiation, DNA synthesis drastically decreases during the first 48 h, but stabilizes thereafter. The addition of insulin plus transferrin significantly restores this important cellular function in kidneys of fetuses younger than 16 wk. However, renal explants from older fetuses are more difficult to culture: they respond less to growth factors and are more prone to necrosis. The objective of this study was to verify the influence of tetracycline, an antibiotic with anti-collagenase potential, on cultured kidney explants aged 17 to 20 wk. The addition of 20 micrograms/ml tetracycline did not influence DNA synthesis nor the effectiveness of insulin plus transferrin on cell proliferation. Nor did it change the activities of alkaline phosphatase and gamma-glutamyltransferase, two enzymic markers of brush border differentiation. After 5 days in L15 alone, explants often showed necrosis and an important reduction in both weight and volume. Insulin plus transferrin significantly restored these parameters to control values observed at Day 0, but evidence of necrosis was still present. Tetracycline alone markedly reduced explant necrosis resulting in a significant increase in weight and volume. The effectiveness of insulin plus transferrin on explant morphometry was not improved when tetracycline was added as third factor. These results indicate that insulin plus transferrin restores explant mass through cell proliferation, whereas tetracycline does so possibly through a reduction in extracellular matrix degradation. The two effects are not additive in cultured mid-term fetal kidneys.
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PMID:Positive influence of tetracycline on human fetal kidney in serum-free organ culture. 791 74

Many studies show a strong association between diabetes mellitus and risk for periodontal disease destruction. Patients with non-insulin-dependent diabetes mellitus have an increased risk of developing destructive periodontal disease. Under similar plaque conditions, adult patients with long-term, poorly controlled diabetes mellitus have more attachment and bone loss than controlled diabetic patients. Most patients with diabetes mellitus respond to conventional periodontal treatment, but in some cases the response may be related to the degree of metabolic control. Periodontal treatment may have a beneficial effect on the metabolic status of poorly controlled diabetes. Tetracycline therapy may be an effective adjunctive treatment in the management of periodontal disease in diabetic patients by blocking collagenase-dependent periodontal tissue destruction. Pyostomatitis vegetans is frequently associated with chronic inflammatory bowel disease and is a marker for the disease. Plaque control with chlorhexidine gluconate should be preceded by mechanical removal of plaque and calculus in patients with leukemia undergoing chemotherapy. A distinct gingival lesion is associated with Wegener's granulomatosis, a potentially fatal disease that, if detected early, has a favorable prognosis.
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PMID:Periodontal manifestations of systemic disease and management of patients with systemic disease. 840 43

Degradation of type I collagen by Porphyromonas gingivalis was monitored by fluorogenic, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and growth assays. All three assays showed that inactivation of both the rgpA and rgpB genes was necessary to completely eliminate the capacity of P. gingivalis to cleave type I collagen. Leupeptin, an Arg-gingipain-specific protease inhibitor, almost completely inhibited collagen degradation by P. gingivalis cells whereas cathepsin B inhibitor II, a Lys-gingipain inhibitor, did not. A purified preparation of Arg-gingipains A and B hydrolyzed gelatin but did not cleave type I collagen, suggesting that the enzymes must be attached to the cell surface to exert collagenase activity. A number of substances used as adjuncts in periodontal therapy were also tested for their capacity to inhibit collagenase activity of P. gingivalis. Tetracycline, doxycycline, and chlorhexidine strongly inhibited collagenase activity.
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PMID:The collagenase activity of Porphyromonas gingivalis is due to Arg-gingipain. 1272 24

Tetracycline, metronidazole, and chlorhexidine have been tested for their effectiveness in the treatment of periodontitis in dogs under experimental conditions. Tetracycline has been effective in reducing bone resorption in dogs with periodontitis when used in the long-term. When used for short times, it can result in reduction of the numbers of microorganisms that are associated with disease. Tetracycline can inhibit the activity of mammalian collagenase thought responsible for the destruction of alveolar bone and it may be capable of inhibiting the adherence of microorganisms and thus preventing infection. In some experiments, metronidazole was more effective than tetracycline in eliminating spirochetes from the periodontal flora, and it has been found effective in preventing the inflammation and the development of the bacterial flora usually associated with the natural accumulation of plaque. Chlorhexidine (0.2% aqueous solution) has been found effective in preventing the normal progression of periodontal disease when used as a spray for the long-term treatment of dogs. It could prove to be as effective as brushing for the long-term control of periodontitis in the dog. Limited information is available on the use of clindamycin, spiramycin, and vancomycin.
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PMID:A review of the experimental use of antimicrobial agents in the treatment of periodontitis and gingivitis in the dog. 1742 14


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