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

The aim of this study was to determine whether tripterine, isolated from Tripterygium wilfordii Hoog f. in China, had beneficial effects on experimental systemic lupus erythematosus induced by active chromatin in BALB/c mice. BALB/c mice were immunized with active chromatin isolated from concanavalin A-activated syngenetic spleno-lymphocytes on day 0. Tripterine 6 or 12 mg kg(-1) day(-1), or prednisone 5 mg kg(-1) day(-1) was given to BALB/c mice intragastrically from day 35 to day 50. Treatment with tripterine 12 mg kg(-1) day(-1) for 15 days protected renal from glomerular injury with a concomitant reduction of serum autoantibodies and total immunoglobulin G (IgG) also with a improvement of splenocyte proliferation stimulated with concanavalin A and lipopolysaccharide. The effects were associated with reduced interleukin-10 production and serum nitric oxide (NO) level but not interferon-gamma compared with vehicle-treated control group. Tripterine 6 mg kg(-1) day(-1) had no significant protective effect against glomerular injury. It inhibited autoantibodies and interleukin-10 production but had no effect on splenocyte proliferation, serum NO level, and interferon-gamma production. These findings suggested that tripterine had a beneficial effect on systemic lupus erythematosus induced by active chromatin in BALB/c mice.
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PMID:Beneficial effect of tripterine on systemic lupus erythematosus induced by active chromatin in BALB/c mice. 1584 Apr 9

Endothelial function, measured noninvasively by brachial artery flow-mediated dilatation (FMD), has been shown to be impaired in patients with systemic lupus erythematosus (SLE). We hypothesized that depressed FMD in SLE patients is associated with increased levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis and regulator of vasoactivity. In this cross-sectional study of female SLE patients under the age of 55, putative markers of cardiovascular disease (CVD) such as PAI-1 were measured in addition to lupus-related disease activity (SLEDAI). The primary outcome, FMD, was measured using high-resolution ultrasound of the brachial artery gated to the R wave to determine endothelial-dependent vasomotion. Endothelial-independent vasomotion was measured in response to nitroglycerin (NMD). Seventy-six female SLE patients, mean age 38.3 +/- 9.4 years, were included. All patients demonstrated normal NMD responses, indicating that depression of FMD was related to decreased endothelial nitric oxide production. Increased PAI-1 was related to depressed FMD by univariate regression (P = 0.004). In a multivariable regression model adjusting for t-PA (tissue plasminogen activator)/PAI-1 ratio, SLEDAI, age at visit, family history of cardiovascular disease, SLE disease duration and body mass index, every 1 ng/mL increase in PAI-1 was associated with a reduction of 0.07 units FMD (P = 0.039). PAI-1 was associated with impaired endothelial dysfunction, after controlling for several potential confounders. Given the high incidence of cardiovascular disease in SLE, further investigation of the role of subclinical markers of CVD is needed.
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PMID:Plasminogen activator inhibitor-1 is associated with impaired endothelial function in women with systemic lupus erythematosus. 1612 68

Engagement of T cell receptors by antigen-presenting cells or stimulation by cytokines determine whether the cell will become activated, anergic or die via apoptosis or necrosis. Ca2+ is a key second messenger that delivers signal from the cell surface, reactive oxygen intermediates and nitric oxide are recently recognized as important mediators of T cell activation. Nitric oxide is a multifunctional intracellular and intercellular messenger induces mitochondrial biogenesis in many cell types, such as lymphocytes. Mitochondria produce reactive oxygen intermediates and store and release Ca2+ in response to activation and death signals. Rapid Ca2+ fluxing is increased while sustained Ca2+ signaling is decreased in lupus T cells. Lupus T cells contain increased numbers and mass of mitochondria. Serum nitric oxide levels and production of nitric oxide by monocytes is increased in patients with systemic lupus erythematosus. Lupus T cells exhibit mitochondrial hyperpolarization and increased mitochondrial mass, which confer predisposition to necrosis rather than apoptosis in response to repetitive activation and death signals. Exposure of normal T cells to nitric oxide dose-dependently increase the mitochondrial mass and mimic rapid and sustained Ca2+ signal abnormalities observed in lupus T cells. Thus increased mitochondrial biogenesis may account for altered Ca2+ handling and represents novel targets for pharmacological intervention in SLE.
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PMID:[Signal transduction abnormalities in systemic lupus erythematosus]. 1615 11

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

Nitric oxide (NO) production increases with age in the lupus-prone MRL/lpr mouse, paralleling disease activity. One mechanism for excess NO production in MRL/lpr mice may be a defect in down-regulatory mechanisms of the iNOS pathway. A potential modulator of NO is the nuclear hormone receptor peroxisome proliferation activated receptor gamma (PPARgamma). We demonstrate that renal PPARgamma protein expression was altered as disease progressed in MRL/lpr mice, which paralleled increased iNOS protein expression. Additionally, MRL/lpr-derived primary mesangial cells expressed less PPARgamma than BALB/c mesangial cells and produced more NO in response to LPS and IFNgamma. Furthermore, PPARgamma activity was reduced in mesangial cells following exposure to inflammatory mediators. This activity was restored with the addition of a NOS enzyme inhibitor. These results indicate that the activation of inflammatory pathways may lead to reduced activity and expression of PPARgamma, further exacerbating the disease state.
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PMID:Inflammatory modulation of PPAR gamma expression and activity. 1630 34

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by production of antinuclear autoantibodies and diverse array of clinical manifestations. T cells from patients with SLE have been shown to be activated in vivo and provide help to autoreactive B cells. Lupus T cells exhibit enhanced spontaneous and diminished activation-induced apoptosis and predisposition to necrosis. Persistent mitochondrial hyperpolarization and ATP depletion - associated with significantly increased mitochondrial mass - characterize T lymphocyte dysfunction in SLE. In addition to cell death abnormalities, mitochondrial dysfunction is associated with altered signal transduction through the T cell receptor and Ca2+ fluxing. Exposure of normal T cell to nitric oxide induces mitochondrial hyperpolarization and biogenesis and regenerates the Ca2+ signaling profile of lupus T cells. This article reviews a novel understanding of the role of nitric oxide in signal transduction and cell death abnormalities in SLE.
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PMID:The role of nitric oxide in abnormal T cell signal transduction in systemic lupus erythematosus. 1640 40

Recently a method to measure nitric oxide (NO) concentration in exhaled air has been developed. The method is non-invasive and easy to perform and it provides information on a fascinating molecule, with such extensive respiratory functions, ranging from bronchial and vascular dilation to ciliary motion and antibacterial defense. Nasal and sinus cavities are the site of major NO production, followed by airway and alveolar compartment. A very low nasal NO production is associated with ciliary dyskinesia, a disease characterized by severe chronic sinusitis and bronchiectasis. An increased concentration of NO in exhaled air has been reported in airway diseases, characterized by airway inflammation, such as bronchial asthma, where its concentration is related to bronchial hyperresponsiveness and sputum eosinophilia. Exhaled NO concentration in asthma is a sensitive marker of airway inflammation that reacts rapidly in response to treatment or exacerbation of disease. Clinical application of exhaled NO measurement include monitoring compliance and response to treatment, disease activity, diagnosis of asthma, and the prediction of acute exacerbations. Exhaled NO concentration may be increased also in other diseases, as COPD, bronchiectasis and some connective tissue diseases (SLE and systemic sclerosis). An increased NO production from alveolar source has been shown to be involved in oxygenation impairment of patients with liver disease, particularly in case of hepato-pulmonary syndrome.
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PMID:[Exhaled nitric oxide as a marker of diseases]. 1649 51

New concepts in the field of atherothrombosis include the human potential to repair and regenerate areas of vascular damage through endogenous growth factors, and the identification of uncommon arterial thrombophilias that promote atherothrombosis. The endogenous factors erythropoietin and insulin-like growth factor-1 are emerging as robust opponents of the vascular and hemostatic alterations that occur in atherothrombosis. Both factors activate the intracellular Akt pathway and the biosynthesis of constitutive nitric oxide, with anti-apoptotic, insulin-sensitizing, vasodilator, anti-inflammatory, antioxidant and antiplatelet effects, all of which oppose arterial degeneration and occlusion. Additionally, erythropoietin and insulin-like growth factor-1 induce the mobilization of stem cells that can differentiate and repair areas of vascular damage thereby halting the progression towards established disease. In selected patients with an arterial thrombotic event, we believe it is justified to search for an uncommon acquired or inherited thrombophilic condition in the presence of at least one of the following: young age, recurrent events, lack of traditional metabolic or acquired vascular risk factors, and no significant artery stenoses at angiography. In these groups of patients, and in those with a marked family history of thrombosis, the prevalence of several functional polymorphisms of genes involved in the hemostatic system is significantly higher compared with controls. Acquired thrombophilias that should be searched for include the antiphospholipid syndrome, systemic lupus erythematosus, and myeloproliferative disorders.
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PMID:[Recent advances in atherothrombotic diseases]. 1672 85

Chloroquine is one of the antimalaria drugs, also used to treat rheumatoid arthritis and systemic lupus erythematosus (SLE). Although well tolerated in most individuals, it was suggested that chloroquine can exert a profound influence on renal function, especially in individuals with compromised body fluid status. However, epidemiological studies are still lacking. The renal actions of chloroquine are further exacerbated by co-administration of other commonly used drugs such as paracetamol. The following discussion will focus on the evidence that chloroquine is a stimulator of nitric oxide (NO), which mediates many of its renal actions (diuresis, natriuresis and an increase in both glomerular filtration rate (GFR) and plasma vasopressin). Chloroquine appears to modulate the renal tubular response to vasopressin either by directly inhibiting cAMP generation or indirectly via NO.
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PMID:Why does chloroquine impair renal function?: chloroquine may modulate the renal tubular response to vasopressin either directly by inhibiting cyclic AMP generation, or indirectly via nitric oxide. 1691 90


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