Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mycophenolate mofetil (MMF, CellCept) is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5'-monophosphate dehydrogenase. MPA depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation. MPA also inhibits the glycosylation and expression of adhesion molecules, and the recruitment of lymphocytes and monocytes into sites of inflammation. MPA depletes tetrahydrobiopterin and decreases the production of nitric oxide by inducible NO synthase without affecting the activity of constitutive NO synthases. Activated macrophages produce NO and superoxide, which combine to generate tissue-damaging peroxynitrite. By these two mechanisms MMF exerts anti-inflammatory activity. Unlike calcineurin inhibitors, MMF is not nephrotoxic and does not induce the production of TGFbeta, which is fibrogenic. MMF does not increase blood pressure, cholesterol levels or triglyceride levels in recipients. MMF reduces acute and chronic rejection in allograft recipients and is efficacious in some nephropathies. Evidence is accumulating that MMF may have clinical utility in some autoimmune disorders.
Lupus 2005
PMID:Mechanisms of action of mycophenolate mofetil. 1580 24

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5'-monophosphate dehydrogenase, has several immunosuppressant actions. MPA depletes guanosine and deoxyguanosine nucleotides preferentially in T and B lymphocytes, inhibiting proliferation and suppressing cell-mediated immune responses and antibody formation, major factors in acute and chronic rejection. MPA also can induce T-lymphocyte apoptosis. MPA suppresses dendritic cell maturation and can induce human monocyte-macrophage cell line differentiation, decreasing the expression of interleukin (IL)-1 and enhancing expression of the IL-1 receptor antagonist. In addition, MPA inhibits adhesion molecule glycosylation and expression and lymphocyte and monocyte recruitment. Activated macrophages produce nitric oxide (NO) and superoxide, which combine to generate tissue-damaging peroxynitrite. MPA depletes tetrahydrobiopterin and decreases NO production by inducible NO synthase without affecting constitutive NO synthase activity. By these mechanisms, MMF exerts anti-inflammatory activity, which could attenuate both acute and chronic rejection. Unlike calcineurin inhibitors, MMF is nonnephrotoxic and does not induce transforming growth factor-beta production, which is fibrogenic. MMF inhibits arterial smooth muscle cell proliferation, a contributor to graft proliferative arteriopathy, and does not increase blood pressure, cholesterol, or triglyceride levels. By decreasing high-density lipoprotein oxidation and macrophage recruitment, MMF also may delay onset/progression of graft atherosclerosis. Thus, MMF may prevent chronic rejection by several mechanisms. MMF activity is synergistic with that of other agents such as valganciclovir for treating cytomegalovirus infection. MMF also has synergistic activity with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists in the treatment of some nephropathies in experimental animals. This combination may prevent progression toward end-stage renal disease in humans with chronic allograft, lupus, and diabetic nephropathies.
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PMID:Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. 1625 60

Systemic lupus erythematosus (SLE) presents various clinical features; however, underlying mechanisms remain unclear. In the immunity of SLE, impaired T cell receptor (TCR) signaling and altered cytokine production are in the center of pathogenesis, although, little is known about NFAT (nuclear factor of activated T cells) in lupus T lymphocytes. TCR stimulation activates NFAT1 through Ca2+/calcineurin (Cn) pathway, facilitating nuclear translocation of NFAT1 from cytosol. Therefore, we investigated relationship of disease activity/features and intracellular NFAT1 localization in T lymphocytes from active lupus patients by fractionation. Results showed no significant relationship between disease activity and NFAT1 distribution. However, interestingly, we observed skewed NFAT1 distribution in pellet in patients with active lupus nephritis or pleuritis. In vitro cyclosporin A treatment suggested autonomously activated Ca2+/Cn pathway in lupus T lymphocytes. Considering these results, NFAT1 might be presenting the clinical heterogeneity in SLE.
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PMID:Abnormal intracellular distribution of NFAT1 in T lymphocytes from patients with systemic lupus erythematosus and characteristic clinical features. 1650 1

Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women in childbearing age. SLE tissue damage is mediated by autoantibodies, complement activation and immune complexes deposition. The disease is diagnosed on the basis of its clinical manifestations and the demonstration of characteristic immunological phenomena, especially antinuclear antibodies. Management of the disease includes regular monitoring of disease activity, avoidance of predisposing factors and therapy guided by the activity and severity of the leading organ manifestation. Treatment ranges from nonsteroidal antirheumatic drugs to intensive treatment with cytotoxic agents. Corticosteroids form the basis of all regimens. Antimalarials and azathioprine are important for treating mild and moderate SLE cases, especially for the long time. Cyclophosphamide given intravenously is the current gold standard for severe lupus nephritis. More recently new strategies for immunosuppression in SLE, that interfere with the syntesis of DNA and nucleotides have been developed (such as mycophenolate mofetil, fludarabine and cladribine). Other agents like cyclosporine and tacrolimus inhibit effect of the activation signals for T cells by inhibition of calcineurin. Some monoclonal antibodies against cytokines or components of the complement system interfere with the effector phase of the immune response. Abetimus (LJP-394) inhibits the production of anti-dsDNA antibodies and may prevent glomerulonephritis caused by anti-DNA containing immune complexes. Somatic gene therapy is also a novel approach in autoimmune disorders and my be a valuable method of SLE therapy in the future. The adrenal steroid prasterone (DHEA) has also shown benefitial effects in mild to moderate SLE. Finally, autologous stem cell transplantation can induce tolerance to self-antigens and cause significant improvement in SLE patients. However, new therapeutic strategies must be tested according to the established principles of clinical trial methods.
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PMID:[Progress and perspectives in the treatment of systemic lupus erythematosus]. 1654 25

With improved disease survival, arterial thromboembolism has become an important cause of morbidity in patients with systemic lupus erythematosus (SLE). A number of conventional and non-conventional risk factors are associated with accelerated atherosclerosis. Regular surveillance and control of traditional risk factors is mandatory, and so is the appropriate use of the statins, anti-malarial agents, anti-platelet agents, and anti-coagulation for primary and secondary prevention of arterial thromboembolism in SLE patients. Judicious use of corticosteroids, calcineurin inhibitors, hormonal replacement therapy, and the cyclooxygenase 2 inhibitors is equally important.
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PMID:Accelerated atherosclerosis, arterial thromboembolism, and preventive strategies in systemic lupus erythematosus. 1664 Oct 40

Haemolytic uraemic syndrome (HUS) is the most common cause of acute renal failure in children. The syndrome is defined by triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure (ARF). Incomplete HUS is ARF with either haemolytic anaemia or thrombocytopenia. HUS is classified into two subgroups. Typical HUS usually occurs after a prodrome of diarrhoea (D+HUS), and atypical (sporadic) HUS (aHUS), which is not associated with diarrhoea (D-HUS). The majority of D+HUS worldwide is caused by Shiga toxin-producing Esherichia coli (STEC), type O157:H7, transmitted to humans via different vehicles. Currently there are no specific therapies preventing or ameliorating the disease course. Although there are new therapeutic modalities in the horizon for D+HUS, present recommended therapy is merely symptomatic. Parenteral volume expansion may counteract the effect of thrombotic process before development of HUS and attenuate renal injury. Use of antibiotics, antimotility agents, narcotics and non-steroidal anti-inflammatory drugs should be avoided during the acute phase. Prevention is best done by preventing primary STEC infection. Underlying aetiology in many cases of aHUS is unknown. A significant number may result from underlying infectious diseases, namely Streptococcus pneumoniae and human immunedeficiency virus. Variety of genetic forms include HUS due to deficiencies of factor H, membrane cofactor protein, Von Willebrand factor-cleaving protease (ADAMTS 13) and intracellular defect in vitamin B12 metabolism. There are cases of aHUS with autosomal recessive and dominant modes of inheritance. Drug-induced aHUS in post-transplantation is due to calcineurin-inhibitors. Systemic lupus erythematosus and catastrophic antiphospholipid syndrome may also present with aHUS. Therapy is directed mainly towards underlying cause.
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PMID:Haemolytic uraemic syndrome: an overview. 1675 34

T cells from patients with systemic lupus erythematosus (SLE) are characterized by heightened TCR-initiated free intracytoplasmic calcium responses. We demonstrate that activated T cells from SLE patients, but not from rheumatoid arthritis patients, displayed higher levels of the calcineurin-dependent transcription factor NF-ATc2 in the nucleus compared with control T cells. DNA NF-AT-binding activity was also increased, as was the amount of NF-ATc2 bound to the promoters of CD154 (CD40L) and IL-2 genes. Nevertheless, although high NF-ATc2 levels translated into higher CD154 transcription in SLE, IL-2 transcription was decreased. The absence of important transcriptional activators (AP-1, NF-kappaBeta) and the presence of transcriptional repressors (cAMP response element modulator) on the IL-2 promoter explain this dichotomous effect.
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PMID:Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus. 1723 47

Facial and flexural psoriasis may impair the quality of life of psoriatic patients considerably. For the adequate management of psoriasis it is important to pay attention to lesions at these sensitive sites, which require an approach different to that for lesions on other sites in several respects. An extensive literature search was carried out to collect evidence-based data on facial and flexural psoriasis with respect to epidemiology, clinical aspects, pathogenetic factors and various treatments. Subsequently, a panel of experts, the Copenhagen Psoriasis Working Group (CPWG), discussed these aspects and several recommendations were formulated reconciling the evidence-based data. Facial psoriasis occurs in 17-46% of psoriatics and flexural psoriasis is experienced by 6.8-36% of patients with psoriasis. Therefore, psoriasis at these sites cannot be regarded as a rare manifestation. Facial psoriasis is a prognostic marker indicating a poor prognosis of psoriasis. Facial and flexural psoriasis cannot be regarded as distinct disease entities but rather as site variations. The clinical features of facial psoriasis suggest that there are three subtypes: hairline psoriasis, sebo-psoriasis and true facial psoriasis. Otitis externa and ocular manifestations should not be neglected. Evidence that microbiological factors may be relevant to facial and flexural psoriasis is virtually absent. For facial psoriasis the response to UV radiation is variable. At least 5% of psoriatics have photosensitive psoriasis. In these patients photosensitive diseases such as lupus erythematodes and polymorphic light eruption have to be excluded. Based on the literature assessment and working group discussions the CPWG concluded the following. (1) Low-potency topical corticosteroids, vitamin D3 analogues and calcineurin inhibitors are first choice treatments in facial and flexural psoriasis. Evidence for the efficacy of the first two modalities is at level 3 while it is at level 1 for the third one. An individualized approach is indicated; for example, in case of corticosteroid side effects in the past the other two modalities should be selected and in unstable psoriasis prone to irritation, monotherapy with vitamin D3 analogues should be avoided. (2) Antimicrobial treatments are not indicated for facial and flexural psoriasis. (3) Dithranol and tar treatment are not indicated as first-line treatment but only if the first-line options fail. (4) In case topical therapies are not effective, phototherapy and systemic treatments are indicated. (5) For future drug development the combination of vitamin D3 analogues with low strength corticosteroids is recommended.
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PMID:Psoriasis of the face and flexures. 1790 13

Increased Ca(2+) influx is found in mononuclear cells (MNC) of patients with systemic lupus erythematosus (SLE). The role of calcineurin and potential implication of calcium channel blocker to suppress the abnormal Ca(2+) influx in SLE remain to be determined. In the present study, we found that the expression and phosphatase activity of calcineurin, but not calcineurin inhibitor in SLE-MNC were greater than normal MNC. Functionally, 1 microM nifedipine could suppress SLE-MNC IFN-gamma secretion but 10 microM nifedipine was required for suppressing that of normal MNC. IL-10 secretion by both SLE-MNC and normal MNC was suppressed by 1 microM nifedipine. However, high dose of nifedipine (50 microM) suppressed NFATc1 activation in SLE-MNC and enhanced apoptosis of anti-CD3 + anti-CD28-activated SLE-MNC irrelevant to expression of Fas ligand. These data suggest that SLE-MNC overexpressed calcineurin and hyper-responded to L-type Ca(2+) channel blocker-mediated apoptosis and cytokine suppression. We proposed that L-type Ca(2+) channel blocker maybe a potential medication for controlling SLE.
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PMID:Nifedipine suppresses Th1/Th2 cytokine production and increased apoptosis of anti-CD3 + anti-CD28-activated mononuclear cells from patients with systemic lupus erythematosus via calcineurin pathway. 1879 Jun 72

Protein phosphatase 2A (PP2A) is a major serine/threonine protein phosphatase in eukaryotic cells and is involved in many essential aspects of cell function. The catalytic subunit of the enzyme (PP2Ac), a part of the core enzyme, has two isoforms, alpha (PP2Ac alpha) and beta (PP2Ac beta), of which PP2Ac alpha is the major form expressed in vivo. Deregulation of PP2A expression has been linked to several diseases, but the mechanisms that control the expression of this enzyme are still unclear. We conducted experiments to decipher molecular mechanisms involved in the regulation of the PP2Ac alpha promoter in human primary T cells. After preparing serially truncated PP2Ac alpha promoter luciferase constructs, we found that the region stretching around 240 bases upstream from the translation initiation site was of functional significance and included a cAMP response element motif flanked by three GC boxes. Shift assays revealed that CREB/phosphorylated CREB and stable protein 1 could bind to the region. Furthermore, we demonstrated that methylation of deoxycytosine in the CpG islands limited binding of phosphorylated CREB and the activity of the PP2Ac alpha promoter. In contrast, the binding of stable protein 1 to a GC box within the core promoter region was not affected by DNA methylation. Primary T cells treated with 5-azacitidine, a DNA methyltransferase inhibitor, showed increased expression of PP2Ac alpha mRNA. We propose that conditions associated with hypomethylation of CpG islands, such as drug-induced lupus, permit increased PP2Ac expression.
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PMID:Methylation status of CpG islands flanking a cAMP response element motif on the protein phosphatase 2Ac alpha promoter determines CREB binding and activity. 1915 97


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