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)

The isoprenoid pathway produces three key metabolites-digoxin (membrane sodium-potassium ATPase inhibitor and regulator of intracellular calcium-magnesium ratios), dolichol (regulator of N-glycosylation of proteins) and ubiquinone (free radical scavenger). The pathway was assessed in a rare and specific type of familial basal ganglia calcification described. The family had a coexistence of basal ganglia calcification (six out of 10 cases), schizophrenia, Parkinson's disease, Alzheimer's disease, rheumatoid arthritis, systemic tumours and syndrome X and were all right hemispheric dominant. The isoprenoid pathway was also studied for comparison in right hemispheric dominant, bihemispheric dominant and left hemispheric dominant individuals. The isoprenoid pathway was upregulated with increased digoxin synthesis in familial basal ganglia calcification. Membrane sodium-potassium ATPase inhibition can lead on to increase in intracellular calcium and calcification of the basal ganglia. There was increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was also an increase in dolichol and glycoconjugate levels with reduced lysosomal stability in these patients. The ubiquinone levels were low and free radical levels increased. The cholesterol-phospholipid ratio was increased and glycoconjugate level of the RBC membrane reduced in these group of patients. No significance difference was noted in family members with and without basal ganglia calcification. This findings were correlated with the pathogenesis of syndrome X, immune mediated diseases, degenerations, tumours and psychiatric disorders noted in the familial basal ganglia calcification described. The biochemical patterns obtained in familial basal ganglia calcification correlated with those in right hemispheric dominance.
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PMID:Hypothalamic digoxin related membrane Na+-K+ ATPase inhibition and familial basal ganglia calcification. 1181 7

Alteration in the isoprenoid metabolites--digoxin, ubiquinone, and dolichol--have been reported in neuronal degeneration (Parkinson's disease), oncogenesis (central nervous system glioma), functional neuropsychiatric disorders (schizophrenia and epilepsy), and immune-mediated disorders (multiple sclerosis). The coexistence of these disorders has been documented in literature and a central dysfunction related to digoxin and the isoprenoid pathway may underlie all these disorders. A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome X, rheumatoid arthritis, and epilepsy has been described. The psychological behavioral patterns of the family were: creativity and high IQ, hypersexual behavior, reduced appetite and eating behavior, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less bonding and affectionate behavior, and left handedness/right hemispheric dominance. Digoxin, an endogenous Na(+)-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and red blood cell (RBC) membrane Na(+)-K+ ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine, resulting in increased levels of depolarizng tryptophan catabolites, serotonin, quinolinic acid, strychnine, and nicotine, and decreased levels of hyperpolarizing tyrosine catabolites, dopamine, noradrenaline, and morphine, contributing to membrane Na(+)-K+ ATPase inhibition in all the above disorders and the indexed family. Digoxin-induced membrane Na(+)-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced Mg2+ levels, leading on to glutamate excitotoxicity, oncogene activation, and immune activation. Digoxin-induced altered Ca2+/Mg2+ ratios, reduced ubiquinone, and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure, and mitochondrial function, leading to the diverse disorders described above, including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/LH dominant and left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated hydroxymethylglutarylcoenzyme A reductase activity, with increased serum digoxin and dolichol levels. The serum ubiquinone, serum Mg2+ and RBC Na(+)-K+ ATPase activity were reduced in left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated levels of serum tryptophan, quinolinic acid, serotonin, nicotine, and strychnine. The levels of tyrosine, dopamine, noradrenaline, and morphine were low in left-handed/RH dominant compared to right-handed/LH dominant individuals. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and coordinate the functions of various cellular organelles.
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PMID:Central role of hypothalamic digoxin in conscious perception, neuroimmunoendocrine integration, and coordination of cellular function: relation to hemispheric dominance. 1232 12

Recent data indicate that rheumatoid factors (RFs) that occur in patients with rheumatoid arthritis (RA) are derived from Ig-producing terminally differentiated CD20-, CD38+ plasma cells present in synovial fluids (SFs). Phage antibody display libraries were constructed using CD38+ plasma cells isolated from SFs of two RF-seropositive RA patients. The libraries were enriched for phage antibodies (Phabs) binding to human IgG (HuIgG) Fc fragments and the sequences of their V genes were analysed. These data provided further evidence for an Ag-driven immune response in patients with RA, including expansion of clonally related B cells, selection and isotype switching, all hallmarks of a germinal center reaction. In the present study, the functional characteristics of these HuIgG Fc-binding monoclonal (mo) Phabs were further analysed in order to provide more insight into the specificity of HuIgG Fc-binding Phabs. Remarkably, all HuIgG Fc-binding moPhabs tested (n=48; derived from four different libraries) displayed polyreactivity. Structural analysis of the CDR3 regions revealed characteristic features of polyreactive Igs. Most H chain CDR3 regions harboured tryptophan/tyrosine-rich parts and approximately 60% of the L chain CDR3 regions of both RA patients displayed an identical stretch of amino acids (W/Y-D-S-S). Supportive for a dominant role of VH in specificity, exchange of VL regions with a single VH region yielded moPhabs with similar specificities. All together, the data suggest the presence of an Ag-driven process in the joints of patients with RA, including somatic mutation and clonal selection entailing isotype switching, resulting in the differentiation of B cells into polyreactive RF-secreting plasma cells.
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PMID:Polyreactivity of human IgG Fc-binding phage antibodies constructed from synovial fluid CD38+ B cells of patients with rheumatoid arthritis. 1247 45

A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome-X, rheumatoid arthritis and epilepsy has been described. The psychological behavioural patterns of the family were as follows--creativity and high IQ, hypersexual behaviour, reduced appetite and eating behaviour, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less of bonding and affectionate behaviour and left handedness. Digoxin, an endogenous Na(+)-K(+) ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na(+)-K(+) ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites - serotonin, quinolinic acid, strychnine and nicotine and decreased levels of hyperpolarising tyrosine catabolites dopamine, noradrenaline and morphine contributing to membrane Na(+)-K(+) ATPase inhibition in all the above disorders and the indexed family. Digoxin induced membrane Na(+)-K(+) ATPase inhibition can result in increased intracellular Ca(2+) and reduced Mg(++) levels leading to glutamate excitotoxicity, oncogene activation and immune activation. Digoxin induced altered Ca(++)/Mg(++) ratios, reduced ubiquinone and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure and mitochondrial function leading to the diverse disorders described above including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/left hemispheric dominant and left-handed/right hemispheric dominant individuals. The biochemical patterns in the indexed family and the diverse disorders studied correlated with those obtained in right hemispheric dominance. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and co-ordinate the functions of various cellular organelles.
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PMID:Hypothalamic digoxin--central role in conscious perception, neuroimmunoendocrine integration and coordination of cellular function--relation to hemispheric dominance. 1260 43

Many patients with rheumatoid arthritis (RA) have low plasma pyridoxal-phosphate (PLP) but a normal erythrocyte aspartate aminotransferase activity coefficient (alpha EAST), a measure of vitamin B-6 status in the erythrocytes, compared with healthy subjects. The goal of the present study was to examine the correlations of PLP levels in these two compartments (plasma and erythrocytes) with other established indices of vitamin B-6 status, and to determine which indicator better reflects functional status of vitamin B-6 in patients with RA. Multiple indices of vitamin B-6 status were measured in 33 patients with RA. Plasma PLP, urinary 4-pyridoxic acid (4-PA), net increase in plasma total homocysteine after a methionine load (DeltatHcy) and net increase in urinary xanthurenic acid after a tryptophan load (DeltaXA) were log-transformed to reach normality for statistical analyses. We found that log-plasma PLP levels were inversely correlated with both log-DeltatHcy (r = -0.368, P = 0.035) and log-DeltaXA (r = -0.333, P = 0.05). Plasma PLP was not correlated with alpha EAST or urinary 4-PA excretion. In contrast, erythrocyte PLP was inversely correlated with alpha EAST (r = -0.431, P = 0.012) and positively correlated with log-4-PA (r = 0.475, P = 0.005), but erythrocyte PLP was not correlated with the outcomes of a methionine or tryptophan load test. Erythrocyte PLP and log-4-PA, but not plasma PLP, were correlated with dietary intake of vitamin B-6 after adjusting for protein intake (r = 0.420, P = 0.015 and r = 0.333, P = 0.05, respectively). We suggest that in patients with RA, plasma PLP levels are a better diagnostic indicator of functional vitamin B-6 status than erythrocyte PLP levels.
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PMID:Plasma pyridoxal 5'-phosphate concentration is correlated with functional vitamin B-6 indices in patients with rheumatoid arthritis and marginal vitamin B-6 status. 1267 18

Immusorba TR (IM-TR) and PH (IM-PH) were developed as adsorbents with non-biological materials as affinity ligands to remove pathogenic autoantibodies. The adsorbents of IM-TR and IM-PH are polyvinyl alcohol gel immobilized with tryptophan and phenylalanine as ligand, respectively. IM-TR is clinically applied for treatment of autoimmune neurological diseases such as myasthenia gravis and Guillain-Barre syndrome. IM-PH is used for not only neurological diseases such as GBS and multiple sclerosis but also collagen diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). As many autoantibodies with different specificities have been found to have similar affinities to the ligand of Immusorba, it is expected that Immusorba will be applied to more diseases and contribute to the clarification of the mechanisms of the development of diseases by the identification of adsorbed unknown pathogenic substances with Immusorba.
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PMID:Immusorba TR and PH. 1292 Nov 21

The kynurenine pathway from tryptophan generates compounds which can act on glutamate receptors in peripheral tissues or modulate free radical activity. We have measured the concentrations of several of these compounds in the plasma of patients with rheumatoid arthritis (RA) and osteoporosis (OP) before treatment with drugs and then at monthly intervals for 6 months during treatment. Kynurenine analysis was performed by HPLC. Compared with healthy controls, RA patients showed significantly decreased baseline levels of tryptophan, 3-hydroxykynurenine and 3-hydroxyanthranilic acid and increased levels of kynurenine and xanthurenic acid, while kynurenic acid concentrations were normal. Different results were recorded from patients with OP with only a significant reduction in tryptophan and 3-hydroxyanthranilic acid when compared with healthy controls. During 6 months of treating the RA patients with prednisolone or methotrexate, and the OP patients with raloxifene or etidronate and calcium there were significant therapeutic responses and a significant trend towards a reduction in levels of neopterin in RA patients receiving methotrexate but no changes in the profiles of tryptophan metabolites. The results are consistent with the induction of indoleamine-2,3-dioxygenase (IDO) in both RA and OP but with far greater activation of the pathway in the much more inflammatory condition, i.e. RA. It is concluded that there are changes in the kynurenine pathway, which may modify the activation of tissue glutamate receptors, in RA and OP, but that these are not affected by the drug treatments studied.
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PMID:Kynurenine and neopterin levels in patients with rheumatoid arthritis and osteoporosis during drug treatment. 1520 42

In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.
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PMID:Cytokines and major depression. 1569 27

The aim of this study was to investigate whether the alpha 2 type IX collagen (COL9A2) polymorphism that introduces tryptophan residue into the collagen triple-helix is a marker of susceptibility to, or severity of, rheumatoid arthritis (RA). The study included 749 Japanese patients with RA. One hundred twenty-four unrelated healthy individuals served as the control subjects. The relationship between the COL9A2 gene polymorphism and clinical manifestations of RA was evaluated. For the number of subjects positive for COL9A2 tryptophan polymorphism, there was no statistically significant difference between RA patients and normal controls. Furthermore, we did not detect any association of COL9A2 tryptophan polymorphism with disease status, least erosive subset, more erosive subset, or mutilating disease. The lack of association of COL9A2 tryptophan polymorphism with RA and the clinical findings in our study implies that the polymorphism may not function as a candidate gene marker for screening RA patients.
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PMID:The alpha 2 type IX collagen gene tryptophan polymorphism is not associated with rheumatoid arthritis in the Japanese population. 1624 25

Immune system activation is known to be involved in the progression of rheumatoid arthritis (RA). The proinflammatory cytokine interferon-gamma in various cells, including monocytes, induces the enzyme indoleamine (2,3)-dioxygenase (IDO), which converts tryptophan to kynurenine. In sera of 22 patients (17 women and 5 men) with RA stages 1 to 4 according to Steinbrocker, the concentrations of tryptophan and kynurenine were measured by high-pressure liquid chromatography. To estimate IDO activity, the kynurenine to tryptophan ratio (kyn/trp) was calculated. In parallel, concentrations of the macrophage activation marker neopterin were determined by enzyme-linked immunosorbent assay. Tryptophan concentrations were lower in patients with RA, and the decrease in serum tryptophan correlated with increase in stage (p<0.05). Kyn/trp correlated well with neopterin concentrations, which were elevated in most patients. Whereas higher C-reactive protein concentrations and erythrocyte sedimentation rates were observed in patients with greater disease activity, tryptophan and neopterin concentrations did not differ between patients with different subjective disease activity graded by the physician. Deficiency of the essential amino acid tryptophan in patients with RA most likely results from immune activation involved in the pathogenesis of the disease. It could also be relevant for the mood of patients, as tryptophan is the precursor of serotonin.
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PMID:Tryptophan degradation increases with stage in patients with rheumatoid arthritis. 1626 Dec 83


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