Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031099 (periodontitis)
 12,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombin and bradykinin stimulate production of prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1 alpha (the stable breakdown product of prostacyclin) in isolated human peripheral blood monocytes in a dose- and time-dependent manner. Since PGE2 and prostacyclin can affect the activity of immunocompetent cells and bone resorbing osteoclasts, our finding indicates that thrombin and bradykinin, both of which are formed in inflammatory processes as a consequence of activation of the Hageman factor (coagulation factor XII), may have important roles in the modulation of the inflammatory response and the loss of alveolar bone in periodontitis.
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PMID:Thrombin and bradykinin enhance prostaglandin production in human peripheral blood monocytes. 267 41

The effect of bradykinin and desArg9-bradykinin on bone was studied in cultures of calvarial bones taken from 6-7-day-old mice. Bradykinin, at and above a 3-nM concentration, caused a dose-dependent stimulation of bone mineral mobilization and matrix degradation. Bradykinin-stimulated resorption was inhibited by calcitonin, an increased concentration of phosphate in the culture medium, hydrocortisone, dexamethasone, indomethacin, meclofenamic acid, naproxen, and 5, 8, 11, 14-eicosatetraenoic acid. The results suggest that bradykinin stimulates osteoclast-mediated bone resorption by a process that is dependent on endogenous prostaglandin production. The stimulatory effect of bradykinin, but not of parathyroid hormone and prostaglandin E2, was potentiated by the angiotensin-converting enzyme inhibitor, BPP5a. Treatment with carboxypeptidase B did not affect the capacity of the peptide to stimulate 45Ca release. DesArg9-bradykinin (1 mumole/liter) stimulated 45Ca release to the same degree as did bradykinin. Bradykinin (3 microM) did not affect the degradation of cartilage proteoglycans, as assessed by the release of 35S-sulfate from prelabeled calf articular cartilage in organ culture. These findings suggest that generation of bradykinin in inflammatory lesions of rheumatoid arthritis and periodontitis may contribute to the bone resorptive process seen in the joints and alveolar bone; however, bradykinin does not directly activate chondrocytes into a catabolic state.
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PMID:Bradykinin, a new potential mediator of inflammation-induced bone resorption. Studies of the effects on mouse calvarial bones and articular cartilage in vitro. 359 36

Inflammation-induced localized bone resorption in diseases such as marginal and apical periodontitis, rheumatoid arthritis, and osteomyelitis is due to activation and recruitment of osteoclasts by locally produced cytokines and inflammatory mediators. Thus several interleukins (1, 3, 4, 6, and 11), tumor necrosis factors (alpha, beta), colony-stimulating factors (M and GM), leukemia inhibitory factor, gamma-interferon, and transforming growth factor-beta have effects on bone resorption and bone formation in vivo and in vitro. The kallikrein-kinin system and the coagulation cascade are also activated in inflammation. We have found that peptides produced in the kallikrein-kinin system (bradykinin, kallidin) and thrombin, the end product in the coagulation cascade, can stimulate bone resorption in vitro. The stimulatory effect of bradykinin is linked both to B1 and B2 bradykinin receptors. Both kinins and thrombin stimulate prostaglandin biosynthesis in bone parallel with the bone resorptive effect. The stimulatory effect of bradykinin on bone resorption is completely lost when the prostaglandin response is abolished, whereas thrombin can stimulate bone resorption both via prostaglandin-dependent and independent mechanisms. In addition, bradykinin and thrombin act in concert with interleukin-1 to synergistically stimulate bone resorption and prostaglandin biosynthesis. We also have found that one of the acute-phase reactants, haptoglobin, can stimulate bone resorption in vitro, indicating the possibility of generalized bone loss in chronic inflammatory diseases. Moreover, haptoglobin synergistically potentiates bradykinin-induced and thrombin-induced prostanoid biosynthesis in osteoblasts. These observations indicate that the rate of bone resorption in inflammation-induced bone loss may not be due to a single factor but to the concerted action of several local or systemic factors.
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PMID:Regulation of bone metabolism by the kallikrein-kinin system, the coagulation cascade, and the acute-phase reactants. 752 72

ODU Plaque-susceptible rats (ODUS/Odu) exhibit markedly heavy plaque formation in the lower incisors and develop both periodontal pockets and gingivitis after being fed a commercially available powder diet. These rats have been established as an inbred strain. We have demonstrated that the ODUS/Odu are a very suitable experimental model for studying periodontitis. We already reported about the allelic distribution, changes of plaque formation and body weight, biochemical nature, toxic activity, vascular permeability factor and bradykinin inactivating factor of the plaque, histological and immunological studies, the pH in the periodontal pocket, amount of saliva, IgA in the saliva, salivary kallikrein, the relationship between sialic acid in the saliva and the serum, leukocyte functions (chemotaxis and superoxide anion) in ODUS/Odu, histamine, mast cell, free radicals, superoxide dismutase activities in gingiva and gingival nerve fibers with substance P or calcitonin gene-related peptide, and effect of diabetes. Streptozotocin-induced diabetic ODUS/Odu may be a useful tool for studying the pathological mechanisms in the development of periodontal tissue breakdown in diabetes. ODUS/Odu should help to further establish the utility of this strain as a model for experimental periodontal disease.
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PMID:[Experimental periodontitis in rats]. 762 82

Infection with Porphyromonas gingivalis is strongly associated with adult periodontitis, and proteinases are considered to be important virulent factors of the bacterium. In order to investigate the function of proteinases in disease development we examined vesicles, a biological carrier of these enzymes, for the generation of vascular permeability enhancement (VPE) activity, believed to correlate with the exudation of gingival crevicular fluid. The vesicles generated VPE activity from human plasma in a dose-dependent manner which could be inhibited 90% by antipain, a specific inhibitor of the Arg-specific cysteine proteinases (Arg-gingipains [RGPs] from P. gingivalis. Incubation of vesicles with high-molecular-weight-kininogen (HMWK)-deficient plasma did not result in VPE activity. On this basis, RGPs associated with vesicles were assumed to be responsible for most of the VPE activity generation via plasma prekallikrein activation and subsequent bradykinin production. The secondary pathway for VPE activity production was dependent on the direct release of bradykinin from HMWK by the concerted action of RGP and a Lys-specific cysteine proteinase (Lys-gingipain [KGP]), also associated with vesicles. These results indicate that RGP and KGP are biologically important VPE factors acting either via prekallikrein activation (RGP) and/or HMWK cleavage (RGP and KGP) to release BK and, thereby, contributing to the production of gingival crevicular fluid at periodontal sites infected with P. gingivalis.
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PMID:Dependence of vascular permeability enhancement on cysteine proteinases in vesicles of Porphyromonas gingivalis. 772 14

1. Porphyromonas gingivalis is one of the bacteria likely to be related to pain in periodontitis. Several enzymes isolated from P. gingivalis have been reported to have kininogenase activity. Since kinin release could be held responsible for inflammatory symptoms and pain in periodontitis, we investigated whether the inflammatory and algesic effects of a sonic extract from P. gingivalis (PGSE) could be inhibited by the potent bradykinin B2 receptor antagonist, icatibant (Hoe 140). 2. In anaesthetized rats, the subplantar injection of PGSE (0.1 and 1.0 mg) caused a dose-dependent oedema of the hind paws. The net increase of the paw volume 60 min after the injection was 23 +/- 5% and 77 +/- 12%, respectively. The oedema was rich in plasma proteins as determined by the Evans blue method. Pretreatment with icatibant (300 nmol kg-1, s.c.) significantly reduced the effect of 1.0 mg of PGSE whereas the effects of 0.1 mg of PGSE remained unaffected. 3. The subplantar injection of 1.0 mg of PGSE in unanaesthetized rats caused nociceptive behavioural responses which started about 5 min after the injection and lasted for about 10-15 min. These responses were completely prevented by pretreatment with icatibant (300 nmol kg-1, s.c.). 4. The present results show that the plasma extravasation induced by non-algesic doses of a sonic extract from P. gingivalis are caused by mechanisms other than B2 kinin receptor activation whereas inflammatory effects of algesic doses are due to the action of kinins. The pain elicited by the extract is solely mediated by kinins and can be prevented by icatibant. The bradykinin antagonist could thus have a potential for a clinical use against pain associated with periodontal inflammation.
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PMID:Anti-inflammatory and analgesic activity of the bradykinin antagonist, icatibant (Hoe 140), against an extract from Porphyromonas gingivalis. 795 58

To elucidate the mechanism of production of an inflammatory exudate, gingival crevicular fluid (GCF), from periodontal pockets in periodontitis, we examined the vascular permeability enhancement (VPE) activity induced by an arginine-specific cysteine proteinase, Arg-gingipain-1 (RGP-1), produced by a major periopathogenic bacterium, Porphyromonas gingivalis. Intradermal injections into guinea pigs of RGP-1 (> 10(-8) M), or human plasma incubated with RGP-1 (> 10(-9) M), induced VPE in a dose- and activity-dependent manner but with different time courses for the two routes of production. VPE activity induced by RGP-1 was augmented by kininase inhibitors, inhibited by a kallikrein inhibitor and unaffected by an antihistamine drug. The VPE activity in human plasma incubated with RGP-1 also correlated closely with generation of bradykinin (BK). RGP-1 induced 30-40% less VPE activity in Hageman factor-deficient plasma and no VPE in plasma deficient in either prekallikrein (PK) or high molecular weight kininogen (HMWK). After incubation with RGP-1, plasma deficient in PK or HMWK, reconstituted with each missing protein, caused VPE, as did a mixture of purified PK and HMWK, but RGP-1 induced no VPE from HMWK. The VPE of extracts of clinically isolated P. gingivalis were reduced to about 10% by anti-RGP-1-IgG, leupeptin, or tosyl-L-lysine chloromethyl ketone, which paralleled effects observed with RGP-1. These results indicate that RGP-1 is the major VPE factor of P. gingivalis, inducing this activity through PK activation and subsequent BK release, resulting in GCF production at sites of periodontitis caused by infection with this organism.
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PMID:Pathogenesis of periodontitis: a major arginine-specific cysteine proteinase from Porphyromonas gingivalis induces vascular permeability enhancement through activation of the kallikrein/kinin pathway. 804 Feb 77

We isolated an enzyme from a major periodontal pathogen, Porphyromonas gingivalis (also called Bacteroides gingivalis), that is capable of initially increasing the coagulant activity of high molecular weight kininogen (HK), releasing bradykinin from HK and low molecular weight kininogen (LK), and destroying the light chain (coagulant portion) of HK. This enzyme, a membrane-bound thiol proteinase that preferentially cleaves the P1-Lys position of tripeptide substrates, is also able to rapidly render fibrinogen nonclottable. We will refer to this enzyme as lys-gingivain because of its origin from P. gingivalis, its classification as a thiol proteinase, and its action as a lysyl-amidase. The activity of lys-gingivain is enhanced by beta-mercaptoethanol, and the enzyme has a molecular mass of 68-70 kDa, a pH optimum of 7.4, and is not inactivated by plasma protease inhibitors. The second-order rate constant for the destruction of the coagulant activity of the HK light chain (surface-binding domain) at 23 degrees C is 2.3 x 10(7) M-1 s-1, and, for cleavages that render fibrinogen unclottable, is 2.05 x 10(6) M-1 s-1. These data suggest that lys-gingivain is a very potent proteinase that would be fully functional in anaerobic periodontal crevices and might participate in the pathogenesis of periodontitis. Lys-gingivain appears to be the most potent kininogenase and fibrase to be described to date.
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PMID:Purification and characterization of a potent 70-kDa thiol lysyl-proteinase (Lys-gingivain) from Porphyromonas gingivalis that cleaves kininogens and fibrinogen. 838 28

The initiation and progression of adult-onset periodontitis has been associated with infection of the gingival sulcus by Porphyromonas gingivalis. This organism utilizes a multitude of virulence factors to evade host defenses as it establishes itself as one of the predominant pathogens in periodontal pockets. A feature common to many other oral pathogens is the production of ammonia due to its protective effect during acidic cleansing cycles in the mouth. Additionally, ammonia production by P. gingivalis has been proposed as a virulence factor due to its negative effects on neutrophil function. In this study, we describe the first purification of a peptidylarginine deiminase (PAD) from a prokaryote. PAD exhibits biochemical characteristics and properties that suggest that it may be a virulence agent. PAD deiminates the guanidino group of carboxyl-terminal arginine residues on a variety of peptides, including the vasoregulatory peptide-hormone bradykinin, to yield ammonia and a citrulline residue. The soluble protein has an apparent mass of 46 kDa, while the DNA sequence predicts a full-length protein of 61.7 kDa. PAD is optimally active at 55 degrees C, stable at low pH, and shows the greatest activity above pH 9.0. Interestingly, in the presence of stabilizing factors, PAD is resistant to limited proteolysis and retains significant activity after short-term boiling. We propose that PAD, acting in concert with arginine-specific proteinases from P. gingivalis, promotes the growth of the pathogen in the periodontal pocket, initially by enhancing its survivability and then by assisting the organism in its circumvention of host humoral defenses.
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PMID:Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. 1037 98

Recently accumulated large bodies of evidence have strongly implicated proteolytic enzymes released by subgingival plaque bacteria in the pathogenicity of periodontal disease. With regard to proteolytic power, however, the contribution from different microbial species considered as periodontal pathogens is not equal. Two of these bacteria, P. gingivalis and T. denticola, have developed an elaborate proteolytic systems composed of several surface-located or secreted enzymes, which apparently serve a role to provide bacteria with nutrients in the form of small peptides and amino acids. Of these two species, proteinases of P. gingivalis are the most intensively studied, and during the last decade an impressive array of information has been accumulated with respect to the biochemical characterization of purified proteinases and structure of the genes encoding them, the regulation of expression and the effects of these enzymes on host systems. In addition, studies on proteinase-deficient isogenic mutants has shed light on both their housekeeping functions and potential role(s) in the pathogenicity of periodontitis. Among several proteinases produced by P. gingivalis, the cysteine proteinases, referred to as gingipains, are clearly in the spotlight. They are the subject of several recent reviews and generally considered as the major virulence factors of this periodontal pathogen (59, 105, 139, 182, 183, 186, 281, 284, 286, 289). Gingipains seem to be key players in subverting host defense systems with, significantly, the complement and neutrophils being the main target. In addition, through uncontrolled activation of kallikrein/kinin pathway and coagulation cascade they contribute to local generation of bradykinin and thrombin, two synergistically working pro-inflammatory reagents with a strongly, although indirectly, stimulatory effect on bone resorption. Furthermore, the ability to interact with the cytokine networking systems has the potential to dysregulate the local inflammatory reaction. Finally, gingipains have a strong effect on mechanisms controlling host matrix metalloproteinase activity at the level of gene expression and zymogen activation (Fig. 10). Collectively, at the periodontal lesion site, the non-restrained action of gingipains, supported by other proteinases locally produced by subgingival plaque bacteria, would dysregulate most mechanisms controlling inflammatory reaction. Although successful in limiting infection to the periodontium, the ultimate effect of uncontrolled inflammatory processes would be the destruction of periodontal connective tissue, certainly the hallmark of periodontitis.
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PMID:Role of bacterial proteinases in matrix destruction and modulation of host responses. 1127 66


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