Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maharasnadhi Quathar (MRQ) is a polyherbal preparation recommended by Ayurvedic medical practitioners for treatment of arthritic conditions. An investigation has been carried out with rats and human rheumatoid arthritis (RA) patients, to determine the anti-inflammatory and analgesic potential of MRQ. Results obtained demonstrate that MRQ can significantly and dose-dependently inhibit carrageenan-induced rat paw oedema (the inhibition at 3h was greater than at 1h after induction of oedema). MRQ could also increase the reaction time of rats in the hot-plate test (by 57% after the first hour of treatment), although it had no effect on the reaction time in the tail-flick test, indicating that MRQ possesses analgesic activity that is probably mediated via a supra-spinal effect.MRQ also exerted a dose-dependent (a) protective effect on heat-induced erythrocyte lysis, and (b) inhibition of 5-lipoxygenase activity. In RA patients, after 3 months of MRQ treatment, there was a marked improvement in the pain and inflammation experienced by the patients as well as in the mobility of the affected joints. From the overall results obtained, it may be concluded that MRQ possesses significant anti-inflammatory and analgesic activities. Alteration in synthesis of prostaglandins and leukotrienes, membrane stabilization and anti-oxidant activity are some of the possible mechanisms through which MRQ mediates its anti-arthritic effects.
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PMID:Anti-inflammatory and analgesic activity in the polyherbal formulation Maharasnadhi Quathar. 1263 50

The immune system is involved in host defense against infectious agents, tumor cells, and environmental insults. Inflammation is an important component of the early immunologic response. Inappropriate or dysfunctional immune responses underlie acute and chronic inflammatory diseases. The n-6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds that have important roles in inflammation and in the regulation of immunity. Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators, through several mechanisms, including decreased availability of AA, competition for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, and decreased expression of COX-2 and 5-LOX. This alone is a potentially beneficial anti-inflammatory effect of n-3 FA. However, n-3 FA have a number of other effects that might occur downstream of altered eicosanoid production or might be independent of this effect. For example, dietary fish oil results in suppressed production of proinflammatory cytokines and can modulate adhesion molecule expression. These effects occur at the level of altered gene expression. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease and to protect against the effects of endotoxin. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some asthmatics, supporting the idea that the n-3 FA in fish oil are anti-inflammatory. There are indications that the inclusion of fish oil in enteral and parenteral formulae is beneficial to patients.
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PMID:N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. 1284 78

Tinospora smilacina Benth. has been used in Australian indigenous medicine for the treatment of headache, rheumatoid arthritis and other inflammatory disorders. As part of an investigation into the anti-inflammatory potential of plants using an ethnopharmacological approach, the present study sought to evaluate the efficacy and safety of Tinospora smilacina. An ethanol extract of this plant was evaluated in vitro for anti-inflammatory activities on cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LO) and phospholipase A(2) (PA(2)). The ethanol extract of Tinospora smilacina showed inhibitory activities on COX-1, COX-2, 5-LO and PA(2) with the IC(50) values of 63.5, 81.2, 92.1 and 30.5 micro g/mL respectively. Cytotoxic effect of the extracts of Tinospora smilacina was investigated in vitro using ATP-based luminescence assay and the results showed no cytotoxic effect on cell lines of skin fibroblasts (1BR3), human Caucasian hepatocyte carcinoma (Hep G2) and human Caucasian promyelocytic leukaemia (HL-60). This paper also describes the results of fractionations and bioassay guided chemical studies, suggesting that the anti-inflammatory activity is due to triterpene-fatty acid esters and free fatty acids.
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PMID:Anti-inflammatory activity, cytotoxicity and active compounds of Tinospora smilacina Benth. 1475 Feb 6

Leukotrienes play a part in inflammatory response. The unique role of the enzyme 5-lipoxygenase (5-LOX) in the production of leukotrienes makes it a likely therapeutic target for inflammatory conditions like asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD). The aim of the present study was to evaluate the effect of zileuton, an orally active selective 5-LOX inhibitor against the events associated with dextran sodium sulphate-induced colitis in a rat model of IBD. The animals were administered simultaneously zileuton (100mg/kg) or sulphasalazine (100mg/kg) orally for 7 days. On day eight, rats were sacrificed, and distal colon isolated to determine myeloperoxidase activity, in vivo superoxide dismutase activity, prostaglandin E2 levels and histological examination. Both zileuton and sulphasalazine significantly prevented the development of inflammatory events associated with colitis. The effect of zileuton was more pronounced towards reducing myeloperoxidase activity and increasing PGE2 levels in distal colon. The results show that chemotactic leukotrienes are responsible for inflammatory surge in damaged colon and, zileuton, significantly improved healing by inhibition of neutrophil recruitment and indirectly through increase in prostaglandins at the site of inflammation. It is suggested that inhibitors of 5-LOX enzyme may have useful therapeutic role in the treatment of chronic intestinal inflammation.
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PMID:Effect of 5-lipoxygenase inhibition on events associated with inflammatory bowel disease in rats. 1533 30

Nuclear factor-kappa B (NF-kappaB) is a transcription factor that resides in the cytoplasm of every cell and translocates to the nucleus when activated. Its activation is induced by a wide variety of agents including stress, cigarette smoke, viruses, bacteria, inflammatory stimuli, cytokines, free radicals, carcinogens, tumor promoters, and endotoxins. On activation, NF-kappaB regulates the expression of almost 400 different genes, which include enzymes (e.g., COX-2, 5-LOX, and iNOS), cytokines (such as TNF, IL-1, IL-6, IL-8, and chemokines), adhesion molecules, cell cycle regulatory molecules, viral proteins, and angiogenic factors. The constitutive activation of NF-kappaB has been linked with a wide variety of human diseases, including asthma, atherosclerosis, AIDS, rheumatoid arthritis, diabetes, osteoporosis, Alzheimer's disease, and cancer. Several agents are known to suppress NF-kappaB activation, including Th2 cytokines (IL-4, IL-13, and IL-10), interferons, endocrine hormones (LH, HCG, MSH, and GH), phytochemicals, corticosteroids, and immunosuppressive agents. Because of the strong link of NF-kappaB with different stress signals, it has been called a "smoke-sensor" of the body.
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PMID:Transcription factor NF-kappaB: a sensor for smoke and stress signals. 1638 90

Leukotrienes (LTs), a family of lipid mediators, play a key role in the pathogenesis of inflammation. They are synthesized in the leucocytes from arachidonic acid (AA) via the actions of 5-lipoxygenase (5-LO). LTs are classified into two classes: LTB(4) and cysteinyl LTs (CysLTs). LTB(4) is one of the most potent chemoattractant mediators of inflammation. It exerts its actions through a seven transmembrane-spaning G protein receptors, LTB4 R-1 and LTB4 R-2. CysLTs (LTC(4), LTD(4), and LTE(4)) are potent bronchoconstrictors that play an important role in asthma. They induce their actions through G protein coupled receptors, CysLT R-1 and CysLT R-2. LTs are involved in the pathogenesis of inflammatory disorders specially asthma, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Therefore, LTs modifiers, LTs inhibitors or antagonists, represent important therapeutic advance in the management of inflammatory diseases. Zileuton, zafirlukast and montelukast are LTs modifiers that are approved to use for the treatment of inflammatory disorders.
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PMID:The role of leukotrienes in the pathophysiology of inflammatory disorders: is there a case for revisiting leukotrienes as therapeutic targets? 1698 90

Oleogum resins from BOSWELLIA species are used in traditional medicine in India and African countries for the treatment of a variety of diseases. Animal experiments showed anti-inflammatory activity of the extract. The mechanism of this action is due to some boswellic acids. It is different from that of NSAID and is related to components of the immune system. The most evident action is the inhibition of 5-lipoxygenase. However, other factors such as cytokines (interleukins and TNF-alpha) and the complement system are also candidates. Moreover, leukocyte elastase and oxygen radicals are targets. Clinical studies, so far with pilot character, suggest efficacy in some autoimmune diseases including rheumatoid arthritis, Crohn's disease, ulcerative colitis and bronchial asthma. Side effects are not severe when compared to modern drugs used for the treatment of these diseases.
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PMID:Boswellic acids in chronic inflammatory diseases. 1702 88

The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA (4) by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA (4) yields LTB (4) and the cysteinyl-LTs C (4), D (4) and E (4). LTs have prominent functions in pathophysiology and are connected to numerous disorders including bronchial asthma, allergic rhinitis, inflammatory bowel and skin diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovascular diseases. Pharmacological and genetic interruption of the 5-LO pathway or blockade of LT receptors, serving as means for intervention with LTs, may be of therapeutic value for certain related disorders. Natural or plant-derived substances were among the first 5-LO inhibitors identified in the early 1980 s. To date, a huge number of diverse plant-derived compounds have been reported to interfere with 5-LO product synthesis. However, many investigations have addressed the efficacy of a given compound solely in cellular test systems and analysis of direct interference with 5-LO has been neglected. In the first part of this review, the biology and molecular pharmacology of the 5-LO pathway is summarized in order to understand its overall regulation and complexity as well as to comprehend the possible points of attack of compounds that eventually lead to inhibition of 5-LO product formation in intact cells. In the second part, natural compounds that interfere with 5-LO product formation are compiled and grouped into structural classes, and the underlying molecular mechanisms and structure-activity relationships are discussed.
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PMID:Inhibition of 5-lipoxygenase product synthesis by natural compounds of plant origin. 1793 2

We have investigated the mechanisms underlying IL-15-induced neutrophil migration into inflamed tissues. IL-15 induced neutrophil migration to the peritoneal cavity in mice in a time- and dose-dependent manner. The cell migration was not induced in IL-18-/-, MIP-1alpha (CCL3)-/-, TNFR1-/- or 5-LOX-/- mice but was normal in IFN-gamma-/- mice. IL-15-induced neutrophil migration was inhibited by anti-MIP-2 (CXCL2) antibody or MK886 (leukotriene synthesis inhibitor). IL-18-induced neutrophil migration was also dependent on TNFR1, MIP-1alpha, MIP-2 and leukotriene. Consistent with this observation, IL-15 induced IL-18 production, and IL-15 or IL-18 injection induced the production of MIP-2, MIP-1alpha, TNF-alpha and LTB4. In an antigen-specific inflammation model, ovalbumin (OVA)-induced neutrophil migration was completely inhibited by soluble IL-15Ralpha (sIL-15Ralpha) or anti-MIP-2 antibody. Furthermore, cell migration was absent in IL-18-/-, MIP-1alpha-/-, TNFR1-/-, or 5-LOX-/- mice. OVA challenge induced the release of MIP-2, MIP-1alpha, TNF-alpha and LTB4 in the peritoneal cavity in an IL-15- and IL-18-dependent manner. We also found that neutrophils from the peripheral blood and synovial fluid of patients with rheumatoid arthritis produced substantial amounts of IL-18 and LTB4 following activation by IL-15. Together, these results demonstrate that IL-15 plays an important role in antigen-induced neutrophil migration during inflammation, triggering a sequential OVA, IL-15, IL-18, MIP-2, MIP-1alpha, TNF-alpha, LTB4 and neutrophil migration signaling cascade.
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PMID:IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production. 1797 56

The 5-lipoxygenase (5-LOX) pathway has been associated with a variety of inflammatory diseases including asthma, atherosclerosis, rheumatoid arthritis, pain, cancer and liver fibrosis. Several classes of 5-LOX inhibitors have been identified, but only one drug, zileuton, a redox inhibitor of 5-LOX, has been approved for clinical use. To better evaluate the efficacy of 5-LOX inhibitors for pharmacological intervention, a rat model was modified to test the in vivo efficacy of 5-LOX inhibitors. Inflammation was produced by adding carrageenan into a newly formed air pouch and prostaglandins produced. While macrophages and neutrophils are present in the inflamed pouch, little 5-LOX products are formed. Cellular 5-LOX activation was obtained by adding calcium ionophore (A23187) into the pouch thus providing a novel model to evaluate the efficacy and selectivity of 5-LOX inhibitors. Also, we described modifications to the in vitro 5-LOX enzyme and cell assays. These assays included a newly developed fluorescence-based enzyme assay, a 5-LOX redox assay, an ex vivo human whole blood assay and an IgE-stimulated rat mast cell assay, all designed for maximal production of leukotrienes. Zileuton and CJ-13,610, a competitive, non-redox inhibitor of 5-LOX, were evaluated for their pharmacological properties using these assays. Although both compounds achieved dose-dependent inhibition of 5-LOX enzyme activity, CJ-13,610 was 3-4 fold more potent than zileuton in all-assays. Evaluation of 5-LOX metabolites-by LC/MS/MS and ELISA confirmed that both compounds selectively inhibited all products downstream of 5-hydroperoxy eicosatetraenoic acid (5-HPETE), including 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxoETE), without inhibition of 12-lipoxygenase (12-LOX), 15-lipoxygenase (15-LOX), or cyclooxygenase (COX) products. In the rat air pouch model, oral dosing of CJ-13,610 and zileuton resulted in selective inhibition 5-LOX activity from pouch exudate and ex vivo rat whole blood with similar potency to in vitro assay. These data show that the rat air pouch model is a reliable and useful tool for evaluating in vivo efficacy of 5-LOX inhibitors and may aid in the development of the next generation of 5-LOX inhibitors, such as the non-redox inhibitors similar to CJ-13,610.
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PMID:A rat air pouch model for evaluating the efficacy and selectivity of 5-lipoxygenase inhibitors. 1829 98


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