Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DCs) classically promote immune responses but can be manipulated to induce antigen-specific hyporesponsiveness. It has been shown that phenotypically "immature" DCs, defined by low levels of costimulatory molecules at the cell surface, are involved in the induction of peripheral immune tolerance in autoimmunity. Paecilomyces hepiali Chen (PHC) mycelium, as a substitute for Cordyceps, has been used extensively as an immunomodulator to treat numerous diseases. In this study, the effects of an ethanol extract of PHC (EEPHC) on the phenotypic and functional maturation of bone marrow-derived DCs (BM-DCs) from NOD mice were evaluated. EEPHC significantly suppressed the expression of major histocompatibility complex (MHC) class II molecules and the costimulatory molecules CD40 and CD86 in NOD BM-DCs. These DCs also exhibited impaired production of the proinflammatory cytokine interleukin-12 (IL-12) and poor stimulatory capacity in the presence of EEPHC. Moreover, inhibition of the activation and differentiation of cultured DCs was associated with reduced DNA binding activity of nuclear factor kappa B (NF- kappaB), a transcription factor recently shown to be responsible for DC maturation. Administration of 3x10(5) EEPHC-treated DCs into NOD mice aged 3-4 weeks effectively prevented the onset of diabetes. Furthermore, splenocytes from the protected mice produced high amounts of IL-4 and IL-10 and low levels of IL-2 and interferon gamma, suggesting that these DCs deficient in NF- kappaB activity are responsible for the apparent shift in type 2 helper T cells. These novel results showed that EEPHC could specifically inhibit NF- kappaB activity and maintain DCs in a potentially tolerogenic state, permitting their use in strategies to induce immune tolerance in type 1 diabetes.
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PMID:Prevention of type 1 diabetes by immature dendritic cells treated with an ethanol extract of Paecilomyces hepiali Chen mycelium. 1885 43

Our goals in this study were to investigate conditions under which T cells from NOD mice express CD40 and to determine how CD40 on autoreactive CD4 T cells contributes to their pathogenicity in T1D. Using CD40-positive diabetogenic T cell clones and CD4 T cells from NOD mice, we examined expression of CD40 upon activation through the TCR and costimulation through either CD28 or CD40. Our results indicate that CD40 expression is increased upon activation with antigen/MHC and that activation of NOD CD4 T cells through TCR/CD40 rapidly induced CD40 expression. Furthermore, CD40 costimulation promoted T cell proliferation to the same extent as costimulation through TCR/CD28. Importantly, costimulation of CD4 T cells through CD40 also interfered with T cell homeostasis by altering regulation of CTLA-4 expression. Through CD40-CD154 blocking studies, we demonstrated that signaling between T cells through CD40 and its ligand contributes to activation of pathogenic T cells and that blocking CD40 on T cells abrogates their ability to transfer diabetes. Thus, costimulation through CD40 on NOD T cells contributes to their pathogenicity by providing additional pathways for activation and by inhibiting upregulation of CTLA-4 during T cell activation.
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PMID:CD40 on NOD CD4 T cells contributes to their activation and pathogenicity. 1895 62

The CD40/CD40 ligand plays a role in the inflammatory and prothrombotic processes in atherosclerosis. We analyzed whether short-term treatment with atorvastatin affects soluble CD40 ligand (sCD40L) plasma levels in subjects at high cardiovascular risk. sCD40L plasma concentrations were measured in 852 subjects from the Atorvastatin on Inflammatory Markers (AIM) Study, a 12-week prospective multicenter, open-label trial which enrolled statin-free subjects with coronary heart disease (CHD), CHD-equivalent (diabetes, peripheral vascular disease, or cerebrovascular disease), or a 10-year CHD risk >20%. Subjects were assigned to atorvastatin (10-80 mg/day) based on LDL-C at screening. Overall, sCD40L levels were not different in patients at high cardiovascular risk compared with healthy subjects. When sCD40L levels were divided in quartiles, patients in the highest quartile (N=213) had higher sCD40L concentrations than age- and gender-matched healthy subjects (N=29) (P<0.0001). Interestingly, all doses of atorvastatin significantly diminished sCD40L levels in subjects at the highest quartile. Furthermore, atorvastatin treatment decreased sCD40L more markedly in subjects with metabolic syndrome compared with those without metabolic syndrome. In conclusion, atorvastatin diminishes sCD40L plasma levels, more markedly so in subjects with metabolic syndrome. Our results indicate that short-term treatment with atorvastatin exhibits anti-inflammatory and antithrombotic effects in subjects at high cardiovascular risk.
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PMID:Atorvastatin decreases elevated soluble CD40L in subjects at high cardiovascular risk. Atorvastatin on inflammatory markers study: a substudy of ACTFAST. 1903 29

Dendritic cells (DCs) are essential in T cell-mediated destruction of insulin-producing beta cells in the islets of Langerhans in type 1 diabetes. In this study, we investigated T cell induction of intra-islet DC maturation during the progression of the disease in both autoimmune-prone NOD and resistant C57BL/6 mice. We demonstrated steady-state capture and retention of unprocessed beta cell-derived proteins by semimature intra-islet DCs in both mouse strains. T cell-mediated intra-islet inflammation induced an increase in CD40 and CD80 expression and processing of captured Ag by resident DCs without inducing the expression of the p40 subunit of IL-12/23. Some of the CD40(high) intra-islet DCs up-regulated CCR7, and a small number of CD40(high) DCs bearing unprocessed islet Ags were detected in the pancreatic lymph nodes in mice with acute intra-islet inflammation, demonstrating that T cell-mediated tissue inflammation augments migration of mature resident DCs to draining lymph nodes. Our results identify an amplification loop during the progression of autoimmune diabetes, in which initial T cell infiltration leads to rapid maturation of intra-islet DCs, their migration to lymph nodes, and expanded priming of more autoreactive T cells. Therapeutic interventions that intercept this process may be effective at halting the progression of type 1 diabetes.
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PMID:Amplification of autoimmune response through induction of dendritic cell maturation in inflamed tissues. 1923 53

Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to diverse reducing sugars. Accumulation of AGEs induces diabetes complications. Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications. Activation of monocytes/macrophages and T cells plays roles in the pathogenesis of atherosclerosis. The activation of T cells requires the enhanced expression of adhesion molecules on monocytes. AGEs activate monocytes by engaging the receptor for AGE (RAGE); however, little is known about the profile of agonist activity of diverse AGE moieties on monocytes. We investigated the effect of four distinct AGE subtypes (AGE-modified bovine serum albumin; AGE-2, AGE-3, AGE-4, and AGE-5) at concentrations ranging from 0.1 to 100 microg/ml on the expression of intercellular adhesion molecule-1, B7.1, B7.2, and CD40 on monocytes and its impact on the production of interferon-gamma and tumor necrosis factor-alpha in human peripheral blood mononuclear cells. Among the AGEs examined, AGE-2 and AGE-3 selectively induced adhesion molecule expression and cytokine production. Antagonism experiments using antibodies against adhesion molecules demonstrated that cell-to-cell interaction between monocytes and T/natural killer cells was involved in AGE-2- and AGE-3-induced cytokine production. AGE-2 and AGE-3 up-regulated the expression of RAGE on monocytes. The effects of AGE-2 and AGE-3 were inhibited by nuclear factor-kappaB and p38 mitogen-activated protein kinase inhibitors. These results indicated that AGE-2 and AGE-3 activated monocytes via RAGE, leading to the up-regulation of adhesion molecule expression and cytokine production.
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PMID:Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. 1938 Jun 3

Advanced glycation end product (AGE) subtypes, proteins or lipids that become glycated after exposure to sugars, induce complications in diabetes. Among the various AGE subtypes, glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) have been indicated to play roles in inflammation in diabetic patients. The engagement of AGEs and receptor for AGEs activates monocytes. Because the engagement of intercellular adhesion molecule-1 (ICAM-1), B7.1, B7.2, and CD40 on monocytes with their ligands on T cells plays roles in cytokine production, we investigated the effects of AGE-2 and AGE-3 on the expressions of ICAM-1, B7.1, B7.2, and CD40 on monocytes, the production of interferon gamma and tumor necrosis factor alpha, and the lymphocyte proliferation in human peripheral blood mononuclear cells and their modulation by prostaglandin E(2) (PGE(2)). AGE-2 and AGE-3 induced the expressions of adhesion molecule, the cytokine production, and the lymphocyte proliferation. PGE(2) concentration-dependently inhibited the actions of AGE-2 and AGE-3. The effects of PGE(2) were mimicked by an E-prostanoid (EP)(2)-receptor agonist, 11,15-O-dimethyl prostaglandin E(2) (ONO-AE1-259-01), and an EP(4) receptor agonist, 16-(3-methoxymethyl)phenyl-omega-tetranor-3,7-dithia prostaglandin E(1) (ONO-AE1-329). An EP(2)-receptor antagonist, 6-isopropoxy-9-oxaxanthene-2-carboxylic acid (AH6809), and an EP(4)-receptor antagonist, (4Z)-7-[(rel-1S,2S,5R)-5-(1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid (AH23848), inhibited the actions of PGE(2). The stimulation of EP(2) and EP(4) receptors is reported to increase cAMP levels. The effects of PGE(2) were reversed by a protein kinase A (PKA) inhibitor, H89, and mimicked by a dibutyryl cAMP and an adenylate cyclase activator, forskolin. These results as a whole indicated that PGE(2) inhibited the actions of AGE-2 and AGE-3 via EP(2)/EP(4) receptors and the cAMP/PKA pathway.
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PMID:Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression, cytokine production, and lymphocyte proliferation in human peripheral blood mononuclear cells. 1970 Jun 29

Cell-to-cell interaction through binding of intercellular adhesion molecule-1 (ICAM-1) and CD40 on monocytes to their ligands on T-cells plays crucial roles in cytokine production. Advanced glycation end products (AGEs) subtypes induce complications in diabetes. In a previous study, we found that glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) at 100 microg/ml induced the expressions of ICAM-1 and CD40 on monocytes and the production of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha in human peripheral blood mononuclear cells. beta(2)-adrenoceptor stimulation has been demonstrated to modulate the production of inflammatory mediators. In the present study, we found that norepinephrine, epinephrine and isoproterenol inhibited AGE-2- and AGE-3-induced adhesion expression and cytokine production in a concentration-dependent manner. The action of these catecholamines was antagonized by beta(2)-adrenoceptor antagonist, but not by alpha(1)-, alpha(2)- and beta(1)-adrenoceptor antagonist. beta(2)-adrenoceptor agonists, salbutanol and terbutaline inhibited AGE-2- and AGE-3-induced adhesion expression and cytokine production, but alpha(1)-, alpha(2)- and beta(1)-adrenoceptor agonist had no effect, indicating that the stimulation of beta(2)-adrenoceptor might improve AGEs-initiated complications in diabetes.
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PMID:Beta2-adrenoceptor stimulation inhibits advanced glycation end products-induced adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. 1985 86

Posttransplant diabetes mellitus (PTDM) is a frequent complication among transplant recipients. Ligation of advanced glycation end products (AGEs) with their receptor (RAGE) on monocytes/macrophages plays roles in the diabetes complications. The enhancement of adhesion molecule expression on monocytes/macrophages activates T-cells, leading to reduced allograft survival. We investigated the effect of four distinct AGE subtypes (AGE-2/AGE-3/AGE-4/AGE-5) on the expressions of intracellular adhesion molecule (ICAM)-1, B7.1, B7.2 and CD40 on monocytes, the production of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha and the proliferation of T-cells during human mixed lymphocyte reaction (MLR). AGE-2 and AGE-3 selectively induced the adhesion molecule expression, cytokine production and T-cell proliferation. The AGE-induced up-regulation of adhesion molecule expression was involved in the cytokine production and T-cell proliferation. AGE-2 and AGE-3 up-regulated the expression of RAGE on monocytes; therefore, the AGEs may activate monocytes, leading to the up-regulation of adhesion molecule expression, cytokine production and T-cell proliferation.
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PMID:Advanced glycation end products enhance monocyte activation during human mixed lymphocyte reaction. 1991 38

The metabolic syndrome (MS) is associated with a systemic inflammatory response that plays an important pathogenetic role in atherothrombotic disease. Increasing evidence indicates that CD40-CD40 ligand interactions constitute an important mediator for vascular inflammation. The purpose of this study was to assess whether high-sensitivity C-reactive protein (hs-CRP) and soluble CD40 ligand (sCD40L) levels were increased in patients with MS. During the study period from January 2004 to August 2004, 312 patients with MS and 98 control subjects were included. Anthropometric measurements, blood pressure assessment, electrocardiography, and blood measurements including fasting blood glucose, postprandial blood glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, glycated hemoglobin, white blood cell (WBC), platelets, hs-CRP, and sCD40L were performed. Patients with MS were divided into 3 groups based upon their glucose tolerance (group 1, normal glucose tolerance; group 2, prediabetic group; and group 3, diabetes mellitus). Patients with MS showed a significant increase of WBC, hs-CRP, and sCD40L levels compared with control subjects. The levels of both hs-CRP and sCD40L were positively correlated with body mass index (BMI). High-sensitivity CRP levels were also positively correlated with waist circumferences, fasting blood glucose, postprandial blood glucose, and glycated hemoglobin, and negatively correlated with high-density lipoprotein cholesterol. In patients with MS, both hs-CRP and sCD40L levels were positively correlated with WBC count. We found a positive correlation between sCD40L and platelets. Among the subgroups of patients with MS, the mean levels of WBC, hs-CRP, and sCD40L did not show any significant differences. In conclusion, elevated levels of WBC, hs-CRP, and sCD40L in MS patients provide further insight into the relationship between MS and inflammation. In our study, positive correlations between BMI and both hs-CRP and sCD40L levels suggest that BMI is an important determinant of a chronic inflammatory state in patients with MS. Moreover, this study reports significantly increased levels of WBC, hs-CRP, and sCD40L not only in diabetic subjects with MS but also in prediabetic subjects and nondiabetic subjects with MS compared with control subjects. Our data suggest that MS patients have proinflammatory state independent of their glucose tolerance status. In our study, the positive correlation between the levels of sCD40L and platelets in patients with MS supports previous reports indicating that sCD40L are derived predominantly from platelets.
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PMID:Enhanced levels of soluble CD40 ligand and C-reactive protein in a total of 312 patients with metabolic syndrome. 2000 62

Dendritic cells (DCs) are powerful antigen-presenting cells capable of maintaining peripheral tolerance. The possibility to generate tolerogenic DCs opens new therapeutic approaches in the prevention or remission of autoimmunity. There is currently no treatment inducing long-term tolerance and remission in type 1 diabetes (T1D), a disease caused by autoimmunity towards beta cells. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow islet regeneration. Apoptotic cells--a source of autoantigens--are cleared rapidly by macrophages and DCs through an immunologically silent process that contributes to maintaining tolerance. Our aims were to prevent T1D and to evaluate the re-establishment of peripheral tolerance using autologous DCs pulsed in vitro with apoptotic bodies from beta cells. Immature DCs derived from bone marrow of non-obese diabetic (NOD) mice were obtained and pulsed with antigen-specific apoptotic bodies from the beta cell line NIT-1. Those DCs that phagocytosed apoptotic cells diminished the expression of co-stimulatory molecules CD40 and CD86 and reduced secretion of proinflammatory cytokines. Moreover, these cells were resistant to increase the expression of co-stimulatory molecules after lipopolysaccharide activation. The administration of these cells to NOD transgenic mice expressing interferon-beta in their insulin-producing cells, a model of accelerated autoimmune diabetes, decreased diabetes incidence significantly and correlated positively with insulitis reduction. DCs pulsed with apoptotic cells that express disease-associated antigens constitutes a promising strategy to prevent T1D.
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PMID:Dendritic cells pulsed with antigen-specific apoptotic bodies prevent experimental type 1 diabetes. 2003 Jun 70


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