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: UMLS:C0030193 (pain)
261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rheumatoid arthritis is known to afflict the temporomandibular joint (TMJ) with common symptoms including pain during function, tenderness on palpation, stiffness, and crepitus. New evidence suggests that metalloproteinases may be responsible for tissue changes that occur in rheumatoid arthritis. These enzymes are collagenase, gelatinase, and proteoglycanase. Antiinflammatory drugs are the first line of management for pain and inflammation in rheumatoid arthritis. This paper, however, suggests that because increased joint load is believed to cause a greater expression of destructive metalloproteinase, it is appropriate to assess even the asymptomatic temporomandibular joint and the muscles of mastication for early objective signs of dysfunction or discomfort. Interceptive management, by the use of load-reducing appliance therapy, may enable reduction of the expression of destructive metalloproteinase within the joint, thereby reducing joint destruction.
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PMID:Rheumatoid arthritis and its implications in temporomandibular disorders. 130 53

In this study, lavage fluid was fractionated from the superior joint space in patients with temporomandibular joint (TMJ) dysfunction. A hide powder azure protease assay was used to assess protease activity in lavage fluid. No correlation between a patient's pain and the level of protease activity was demonstrated. Latent as well as active proteases were detected in the sample lavage fluid. Latent matrix metalloproteinases (MMPs) were activated using trypsin. Stromelysin-1 was detected in an active form in lavage fluid by immunozymography. The presence of high molecular weight species with protease activity was also demonstrated. This study validates the presence of stromelysin-1 as well as other MMPs in TMJ lavage fluid and proposes a mechanism for their physiologic activation.
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PMID:Detection and preliminary characterization of matrix metalloproteinase activity in temporomandibular joint lavage fluid. 980 7

Clinical trials with monoclonal antibodies directed against TNF alpha (anti-TNF mAbs) and soluble TNF receptor fusion proteins (sTNFR-IgGs) have demonstrated that systemic and synovial trapping of TNF alpha results in long lasting anti-inflammatory and anti-nociceptive effects in patients with rheumatoid arthritis. Clinical indices of inflammatory synovitis and laboratory parameters (CRP and ESR) respond to single and repeated administrations of anit-TNF alpha therapies in a dose-dependent fashion. Studies on the immuno-pharmacological profile in patients suggest evidence that TNF alpha trapping down-regulates the effector mechanisms involved in the immuno-inflammatory response in rheumatoid arthritis. Inhibition of PLA 2- and COX-2-derived pathways of mediators of inflammation (prostanoids and leukotrienes) decreases signs and symptoms of inflammatory synovitis such as joint swelling, tenderness and pain. Down-regulating of the cytokine-inducible adhesion molecules ICAM-1, VCAM-1 and ELAM-1 in endothelial cells and synoviocytes results in a marked inhibition of transendothelial migration of inflammatory and immune cells. A decrease of cytokine-regulated metalloproteinase expression results in normalization of circulating MMP-1 and MMP-3 levels. The effect of TNF alpha neutralization on mechanisms of rheumatoid joint destruction has the long-term potential for preventing or decreasing the rate of erosive changes of cartilage and bone.
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PMID:[Immunopharmacologic profile and therapeutic prospects of anti-TNF-alpha therapy]. 986 33

We measured matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP) in temporomandibular joint (TMJ) disorders. All patients were fully investigated, by visual analogue pain scores, plain radiographs and double-contrast arthrotomograms. The patients were grouped according to whether or not they were in pain. There were 35 patients with painful joints; 16 painless crepitating joints and 10 with chronic closed locked joints. A further group of 9 volunteers with no symptoms of TMJ abnormalities were used as controls. We found that synovial fluid concentration of MMP-3 was significantly increased (1117.2 (164.0) ng/ml) (P< 0.05) in the painful group compared with controls (436.2 (94.8) ng/ml) and with the two groups with painless TMJ (475.0 (113. 0) ng/ml/crepitation, and 516.0 (115.1) ng/ml/closed locked joints). MMP-1 and TIMP-1 were not recordable in most joints, and the serum concentrations of MMP-1, MMP-3, and TIMP-1 were similar to those in controls in all groups. There was no correlationship between MMP-3 concentration and joint morphology as shown by plain radiographs and double contrast arthrotomograms. These findings indicate that the synovia of painful joints are inflamed.
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PMID:Matrix metalloproteinase and tissue inhibitor of metalloproteinase in serum and lavage synovial fluid of patients with temporomandibular joint disorders. 1092 68

Nimesulide (Aulin) refers to the class of sulphonanilides, which is unique among the non-steroidal antiinflammatory drugs (NSAIDs), being also the first drug on the market of pharmaceuticals, which preferentially inhibits the enzyme cyclooxygenase-2 (COX-2). This enzyme takes part in the synthesis of prostaglandin, which is produced in the course of the cascade of the inflammation process and has relation to the pathogenesis of pain, inflammation and fever, while the COX-1 enzyme forms prostaglandin, which projects the gastro-intestinal mucosis. Many newly found factors, together with the preferential inhibition of COX-2, are also contributing to the therapeutic effects of Nimesulide. The therapeutic concentration of non-combined active substance in blood-circulation reduces the following indicators: the activity of the myeloperoxidase; the release of cytokines; the histamine effects; the synthesis of stromelysin and collagenase, which pull down the proteoglicans and collagen. It is also characteristic of Nimesulide its antioxidant activity and suppression of: the synthesis of superoxidic ions from the neutrophils; also, the synthesis of platelet activating factor. Nimesulide shows good tolerability and is safe with patients having respiratory problems due to treatment with other NSAIDs.
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PMID:[Nimesulide - a non-steroidal anti-inflammatory drug, a preferential cyclooxygenase-2 inhibitor]. 1119 95

Total hip arthroplasty (THA) has provided dramatic pain relief and improvement in function for millions of patients with end-stage arthritis; however, periprosthetic osteolysis following THA has become increasingly recognized as a major clinical problem in both cemented and cementless reconstructions. An aggressive granulomatous tissue (interfacial membrane) consisting predominantly of fibroblasts, aggregates of macrophages, and foreign body giant cells develops at the interface of bone/prostheses or bone/cement. It is believed that particulate wear debris from prosthetic materials and/or bone cement are phagocytized by histiocytic cells of interfacial membrane and then these cells produce inflammatory mediators and proteolytic enzymes to provoke a cascade of osteolytic events. In this paper, we studied in vitro responsiveness of various cell types to particulate wear debris. Although titanium and titanium alloys demonstrate excellent biocompatibility in bulk from, titanium in particulate form can provoke a variety of cellular responses. We have found that small-sized Ti particles of phagocytosable size, a commonly encountered particle species in the periprosthetic tissues of failed THAs, stimulate macrophages to secrete various mediators of bone resorption (prostaglandin E(2), interleukin-1, interleukin-6, and tumor necrosis factor-alpha from macrophages and cause bone resorption in organ culture. In addition, we have shown that phagocytosable titanium particles stimulate fibroblasts to up-regulate the expression of matrix metalloproteinases (stromelysin and collagenase) without a substantial effect on the tissue inhibitor of these enzymes (TIMP). Titanium particulates also have a suppressive effect on procollagen synthesis by osteoblast-like cell line. Thus, titanium particulates have the capacity to stimulate bone resorption and inhibit bone matrix formation. In this series of experiments, we have also shown in vitro inhibitory effect of certain pharmaceutical components (indomethacin, misoprostol) upon bone resorption in organ culture, which may indicate a potential therapeutic intervention to prevent or treat particulate-induced pathological bone resorption in total joint arthroplasties.
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PMID:Particulate-Induced, Prostaglandin- and Cytokine-Mediated Bone Resorption in an Experimental System and in Failed Joint Replacements. 1185 95

In osteoarthritis (OA) the balance between cartilage degeneration and repair is disturbed. The aim of this pilot clinical study was to examine the effects of a nonsteroidal anti-inflammatory drug, nimesulide, on the synthesis of matrix metalloproteinases (MMPs) which are important enzymes in cartilage proteolysis. Cartilage oligomeric matrix protein (COMP), a component of the extracellular matrix, was used as an indicator of accelerated joint erosion. Radiologically proven painful OA of the knee or hip was treated with 100 mg nimesulide twice daily for 3 weeks. MMP-1, -3 and -8 and COMP were measured by immunoassays, and clinical investigations were made on pain, and on disease intensity using the WOMAC scale. During treatment with nimesulide, in addition to clinical improvement and less pain, serum levels of MMP-3, MMP-8 and COMP fell indicating a beneficial effect on cartilage catabolism.
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PMID:Effect of nimesulide on metalloproteinases and matrix degradation in osteoarthritis: a pilot clinical study. 1216 16

The purpose of this study was to examine whether glucosamine has an antirheumatic effect in a randomized placebo-controlled study. The subjects were 51 rheumatoid arthritis (RA) patients: 25 patients in the glucosamine group and 26 patients in the placebo group. Glucosamine hydrochloride at a daily dose of 1,500 mg and placebo, respectively, were administered for 12 weeks along with conventional medication. While significant improvement was not found in joint counts and in the rate of ACR20 responders, the face scale and a visual analogue scale pain were significantly in favor of the glucosamine group. ESR and CRP levels did not change, but serum MMP-3 levels decreased in the glucosamine group. Results of the patients' self-evaluations and the physicians' global evaluations indicated that the glucosamine treatment produced noticeable improvements in symptoms. Although glucosamine administration had no antirheumatic effect evaluated by conventional measures, it seemed to have some symptomatic effects on RA.
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PMID:Effects of glucosamine administration on patients with rheumatoid arthritis. 1695 94

Buerger's disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American), compared to 21 age-gender-race matched healthy controls, 5A/6A stromelysin- 1 homozygosity was present in 7 of 21 (33%) BD cases versus 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5-3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) BD cases versus 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3-26.6). C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in 7 of 21 cases (33%) versus 11 of 21 controls (52%) (risk ratio 0.6; 95% CI 0.3-1.3). In 18 patients who stopped and 3 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, superficial phlebitis, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In 15 patients, to increase vasodilatory NO via endothelial NO synthase, l-arginine (15 g/day) was given, along with folic acid (5 mg), vitamin B6 (100 mg), and B12 (2000 mg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months receiving l-arginine-folic acid, 11 of 15 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo/heterozygous for stromelysin-1 5A/6A and eNOS T-786C mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by l-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.
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PMID:Stromelysin-1 5A/6A and eNOS T-786C polymorphisms, MTHFR C677T and A1298C mutations, and cigarette-cannabis smoking: a pilot, hypothesis-generating study of gene-environment pathophysiological associations with Buerger's disease. 1700 Aug 87

Osteoarthritis is an inflammatory disease of load-bearing synovial joints that is currently treated with drugs that exhibit numerous side effects and are only temporarily effective on pain, the main symptom of the disease. Consequently, there is an acute need for novel, safe and more effective chemotherapeutic agents for the treatment of osteoarthritis and related arthritic diseases. Resveratrol is a phytoalexin stilbene produced naturally by plants including red grapes, peanuts and various berries. Recent research in various cell models has demonstrated that resveratrol is safe and has potent anti-inflammatory properties. However, its potential for treating arthritic conditions has not been explored. In this study we provide experimental evidence that resveratrol inhibits the expression of VEGF, MMP-3, MMP-9 and COX-2 in human articular chondrocytes stimulated with the pro-inflammatory cytokine IL-1beta. Since these gene products are regulated by the transcription factor NF-kappaB, we investigated the effects of resveratrol on IL-1beta-induced NF-kappaB signaling pathway. Resveratrol, like N-Ac-Leu-Leu-norleucinal (ALLN) suppressed IL-1beta-induced proteasome function and the degradation of IkappaBalpha (an inhibitor of NF-kappaB) without affecting IkappaBalpha kinase activation, IkappaBalpha-phosphorylation or IkappaBalpha-ubiquitination which suppressed nuclear translocation of the p65 subunit of NF-kappaB and its phosphorylation. Furthermore, we observed that resveratrol as well as ALLN inhibited IL-1beta-induced apoptosis, caspase-3 activation and PARP cleavage in human articular chondrocytes. In summary, our results suggest that resveratrol suppresses apoptosis and inflammatory signaling through its actions on the NF-kappaB pathway in human chondrocytes. We propose that resveratrol should be explored further for the prophylactic treatment of osteoarthritis in humans and companion animals.
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PMID:Resveratrol suppresses interleukin-1beta-induced inflammatory signaling and apoptosis in human articular chondrocytes: potential for use as a novel nutraceutical for the treatment of osteoarthritis. 1860 98


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