Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biodegradable microspheres containing cyclosporin A (CyA, cyclosporine) were prepared using poly(L-lactic acid) (PLA) and poly(lactide-co-glycolide)(PLGA) by a solvent evaporation method. CyA was efficiently entrapped in PLA, PLGA(50/50) and PLGA(75/25) microspheres in a range of 81-85%. CyA released constantly from PLA microspheres without any lag time, whereas the drug from PLGA(50/50) and PLGA(75/25) microspheres was released after lag time of about 1 and 3 weeks, respectively. Addition of fatty acid esters enhanced the release rates of CyA from PLA microspheres. In-vivo study was performed using rats with adjuvant-induced arthritis. PLA microspheres with ethyl myristate sustained high blood levels of CyA compared with the microspheres with no additives over 4 weeks. In addition, the PLA microspheres improved the symptoms such as the decrease in body weight and the increase in paw swelling occurred by adjuvant-induced arthritis in rats. Consequently, the release rate of CyA from PLA microspheres can be improved by adding fatty acid esters and PLA microspheres with fatty acid esters seem to be a useful dosage form for autoimmune disease therapy.
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PMID:Modification of release rates of cyclosporin A from polyl(L-lactic acid) microspheres by fatty acid esters and in-vivo evaluation of the microspheres. 1005 86

Prostaglandins (PGs) are important mediators of acute and chronic inflammation. The production of PGs in synovial tissues is catalyzed by an enzyme cascade that includes phospholipase A(2)s (PLA(2)s), cyclooxygenases (COXs), and terminal PG synthases. There are two isoforms of COX expressed in synovial tissues. COX-1 is constitutively expressed in synovia, particularly in synovial lining cells. COX-2, on the other hand, is localized most strikingly to the vascular endothelial cells, mononucler inflammatory cells, and subsynovial fibroblasts. There are no significant differences in immunostaining of COX-1 in vivo in inflammatory compared with non-inflammatory arthritis. COX-2 expression is increased in inflammatory arthritis. In-vitro, COX-2 expression in synovial cells is dramatically increased by proinflammatory cytokines, phorbol ester, and stimulation of certain cell surface receptors. A number of different transcription factors are likely to be involved in the up-regulation of COX-2 in synovial tissues. Expression of COX-2 is inhibited by glucocorticoids in synovial cells as in other cell types. Taken together, these data suggest that COX-2 is likely to be responsible for increased local PG production during inflammation of synovial tissues.
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PMID:COX-2 in synovial tissues. 1041 82

Secreted phospholipase A(2) (sPLA(2)) regulates a variety of cellular functions. The present investigation was undertaken to elucidate the potential role of sPLA(2) in endothelial cell (EC) migration. Bovine aortic endothelial cells (BAECs) exposed to sPLA(2) placed in the lower compartment of a modified Boyden chamber displayed increased migration compared to cells exposed to vehicle. The effect of sPLA(2) on EC migration was time and dose dependent. Migration of BAECs was observed at 30 minutes, increased over 1 to 2 hours, and declined thereafter. At 2 hours of stimulation, sPLA(2) (0.01-2 micromol/L) induced 1.2- to 3-fold increased cell migration compared with media alone. Among the different sPLA(2)s tested, bee venom, Naja naja, and porcine and human pancreatic PLA(2)s all evoked a migratory response in ECs. Moreover, human synovial fluid, obtained from patients with arthritis and containing sPLA(2) activity, induced EC migration. Migration of ECs was significantly reduced after exposure to a catalytic site mutant of pancreatic sPLA(2) with decreased lipolytic activity as compared to wild-type sPLA(2). Similarly, pretreatment of human synovial fluid with p-bromophenacyl bromide, an irreversible inhibitor of sPLA(2), markedly decreased the ability of human synovial fluid to stimulate EC migration. Moreover, migration of ECs was stimulated on exposure to hydrolytic products of sPLA(2) activity including arachidonic acid, lysophosphatidic acid, and lysophosphatidylcholine. These findings suggest that sPLA(2) plays a physiologic role in induction of EC migration. Moreover, the effects of sPLA(2) on EC migration are mediated, at least in part, by its catalytic activity. (Blood. 2000;96:3809-3815)
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PMID:Secreted phospholipase A(2) induces vascular endothelial cell migration. 1109 64

Rapanone (2,5-dihydroxy-3-tridecyl-1,4-benzoquinone), a natural compound isolated from Myrsine guianensis growing in the Andean highlands of Colombia, was studied in different in vitro and in vivo models as a potential antioxidant and anti-inflammatory drug. Rapanone showed a mild anti-lipoperoxidative profile in rat liver microsomes and inhibited potently degranulation (IC(50) of 9.8 microM) and superoxide chemiluminescence (IC(50) of 3.0 microM) in human neutrophils. In addition, rapanone is a selective and potent human synovial PLA(2) inhibitor (IC(50) of 2.6 microM). In vivo experiments using the carrageenan paw oedema and the zymosan air pouch model in mice as well as the adjuvant arthritis model in rats have proved that rapanone is very efficient in controlling the inflammatory process by different administration routes.
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PMID:Inhibition of acute and chronic inflammatory responses by the hydroxybenzoquinonic derivative rapanone. 1174 12

Arachidonic acid (AA) mainly released from the cell membrane by phospholipase A(2) (PLA(2)) is converted to eicosanoids by the action of cyclooxygenase (COX) and lipoxygenase (LO). In order to find the specific inhibitors of AA metabolism especially PLA(2) and COX-2, 300 plant extracts were evaluated for their inhibitory activity on PGD(2) production from cytokine-induced mouse bone marrow-derived mast cells in vitro. From this screening procedure, the methanol extract of Salvia miltiorrhiza was found to inhibit PGD(2) production and the ethyl acetate subfraction gave the strongest inhibition of five subfractions tested. From this ethyl acetate subfraction, an activity-guided isolation finally gave tanshinone I as an active principle. This investigation deals with the effects of tanshinone I on AA metabolism from lipopolysaccharide (LPS)-induced RAW 264.7 cells and in vivo antiinflammatory activity. Tanshinone I inhibited PGE(2) formation from LPS-induced RAW macrophages (IC(50) = 38 microM). However, this compound did not affect COX-2 activity or COX-2 expression. Tanshinone I was found to be an inhibitor of type IIA human recombinant sPLA(2)(IC(50) = 11 microM) and rabbit recombinant cPLA(2) (IC(50) = 82 microM). In addition, tanshinone I showed in vivo antiinflammatory activity in rat carrageenan-induced paw oedema and adjuvant-induced arthritis.
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PMID:Effects of tanshinone I isolated from Salvia miltiorrhiza bunge on arachidonic acid metabolism and in vivo inflammatory responses. 1241 May 40

Phospholipase A(2) (PLA(2); EC 3.1.1.4) is a key enzyme involved in the production of proinflammatory mediators known as eicosanoids. The binding of the substrate to PLA(2) occurs through a well-formed hydrophobic channel. To determine the viability of PLA(2) as a target molecule for the structure-based drug design against inflammation, arthritis, and rheumatism, the crystal structure of the complex of PLA(2) with a known anti-inflammatory compound oxyphenbutazone (OPB), which has been determined at 1.6 A resolution. The structure has been refined to an R factor of 0.209. The structure contains 1 molecule each of PLA(2) and OPB with 2 sulfate ions and 111 water molecules. The binding studies using surface plasmon resonance show that OPB binds to PLA(2) with a dissociation constant of 6.4 x 10(-8) M. The structure determination has revealed the presence of an OPB molecule at the binding site of PLA(2). It fits well in the binding region, thus displaying a high level of complementarity. The structure also indicates that OPB works as a competitive inhibitor. A large number of hydrophobic interactions between the enzyme and the OPB molecule have been observed. The hydrophobic interactions involving residues Tyr(52) and Lys(69) with OPB are particularly noteworthy. Other residues of the hydrophobic channel such as Leu(3), Phe(5), Met(8), Ile(9), and Ala(18) are also interacting extensively with the inhibitor. The crystal structure clearly reveals that the binding of OPB to PLA(2) is specific in nature and possibly suggests that the basis of its anti-inflammatory effects may be due to its binding to PLA(2) as well.
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PMID:Phospholipase A2 as a target protein for nonsteroidal anti-inflammatory drugs (NSAIDS): crystal structure of the complex formed between phospholipase A2 and oxyphenbutazone at 1.6 A resolution. 1554 28

Triptolide (TP), which has potent immunosuppressive effects, anti-inflammatory and severe toxicity on digestive, urogenital, blood circulatory system, was used as a model drug in this study. The aim of this study was to investigate the anti-inflammatory effect of complete Freund's adjuvant-induced arthritis in rats treated with TP-loaded poly(D,L-lactic acid) (PLA) nanoparticles (TP-PLA-NPs) by gavage. TP-PLA-NPs were prepared by the modified spontaneous emulsification solvent diffusion method (modified-SESD). Nanoparticles were shown to be small particle size (149.7 nm), low polydispersity index (0.088), a fine spherical shape with smooth surfaces determined by dynamic light scattering (DLS) and transmission electron microscope (TEM). Encapsulation efficiency and the in vitro release of TP from nanoparticles were measured by the reverse phase high-performance liquid chromatography (RP-HPLC). The in vitro release profile of TP from nanoparticles exhibited a typical biphasic release phenomenon, namely initial burst release and consequently slow release. The potential therapeutic arthritic method of TP-PLA-NPs was established. The results obtained in experiments indicated that TP-PLA-NPs significantly inhibited the adjuvant-induced arthritis, and had preferable anti-inflammatory effect with the long-time administration.
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PMID:Anti-inflammatory effects of triptolide loaded poly(D,L-lactic acid) nanoparticles on adjuvant-induced arthritis in rats. 1570 56

Phospholipase A(2) (PLA(2); EC 3.1.3.4) catalyzes the first step of the production of proinflammatory compounds collectively known as eicosanoids. The binding of phospholipid substrates to PLA(2) occurs through a well formed hydrophobic channel. Surface plasmon resonance studies have shown that niflumic acid binds to Naja naja sagittifera PLA(2) with an affinity that corresponds to a dissociation constant (K(d)) of 4.3 x 10(-5) M. Binding studies of PLA(2) with niflumic acid were also carried out using a standard PLA(2) kit that gave an approximate binding constant, K(i), of 1.26 +/- 0.05 x 10(-6) M. Therefore, in order to establish the viability of PLA(2) as a potential target molecule for drug design against inflammation, arthritis and rheumatism, the three-dimensional structure of the complex of PLA(2) with the known anti-inflammatory agent niflumic acid [2-[3-(trifluoromethyl)anilino]nicotinic acid] has been determined at 2.5 Angstroms resolution. The structure of the complex has been refined to an R factor of 0.187. The structure determination reveals the presence of one niflumic acid molecule at the substrate-binding site of PLA(2). It shows that niflumic acid interacts with the important active-site residues His48 and Asp49 through two water molecules. It is observed that the niflumic acid molecule is completely buried in the substrate-binding hydrophobic channel. The conformations of the binding site in PLA(2) as well as that of niflumic acid are not altered upon binding. However, the orientation of the side chain of Trp19, which is located at the entry of the substrate-binding site, has changed from that found in the native PLA(2), indicating its familiar role.
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PMID:Non-steroidal anti-inflammatory drugs as potent inhibitors of phospholipase A2: structure of the complex of phospholipase A2 with niflumic acid at 2.5 Angstroms resolution. 1630 91

The accumulation of uric acid, an end-product of purine metabolism, is responsible for the many deleterious effects observed in gouty arthritis, including renal injury. Here, we present evidence that under conditions of hyperuricemia (>10(-4) M uric acid) [(3)H]thymidine incorporation into primary renal proximal tubule cells (PTCs) is inhibited, and we delineate the signaling pathways involved. Elevated uric acid was observed to stimulate MAPK phosphorylation. The uric acid induced p38 MAPK phosphorylation was also blocked by H-7 (a PKC inhibitor), indicating that p38 MAPK was a downstream target of PKC. Evidence that cytoplasmic phospholipase A(2) (cPLA(2)) was involved further downstream included 1) the stimulatory effect of uric acid on [(3)H]-labeled arachidonic acid (AA) release; 2) the stimulation of AA release in response to uric acid was blocked by the PKC inhibitor H-7 as well as by the p38 MAPK inhibitor SB 203580; and 3) the uric acid-induced inhibition of [(3)H]thymidine incorporation was prevented by SB 203580, as well as by the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone, and mepacrine (another PLA(2) inhibitor). Evidence of a uric acid-induced activation of NF-kappaB as well as PLA(2) was obtained. Moreover the uric acid-induced inhibition of [(3)H]thymidine incorporation was also blocked by two NF-kappaB inhibitors, pyrrolidine dithiocarbamate and SN 50. However, SN 50 did not block the uric acid induced [(3)H]AA release. Thus the inhibition of [(3)H]thymidine incorporation caused by uric acid can be explained by two distinct mechanisms, the activation of NF-kappaB as well as the activation of PLA(2).
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PMID:Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-kappaB. 1698 15

The antiinflammatory effect of the aqueous leaf extract of Byrsocarpus coccineus was evaluated using the carrageenan and egg albumin induced rat paw edema, xylene induced mouse ear edema and formaldehyde induced arthritis inflammation tests. The extract administered orally at doses of 50, 100, 200 and 400 mg/kg b.w produced a significant (P<0.05) dose dependent inhibition of edema formation in all four methods used. The results obtained suggest that the aqueous leaf extract of B. coccineus is endowed with effective antiinflammatory activity mediated via either inhibition of phospholipase A(2) (PLA(2)) activity or cyclooxygenase cascade and by blocking the release of vasoactive substances (histamine, serotonin and kinins). These findings seem to justify the use of the plant in traditional African medicine in the treatment of inflammation, including arthritic conditions.
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PMID:Antiinflammatory activity of the aqueous leaf extract of Byrsocarpus coccineus. 1711 72


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