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

To evaluate whether G-CSF improves an impaired production of oxygen-derived free radicals in diabetic neutrophils, we studied the effect of G-CSF on chemiluminescence amplified by a luciferin analog (CLA-DCL) and luminol (L-DCL) in response to fMLP in neutrophils from STZ-induced diabetic rats. Both CLA-DCL and L-DCL in diabetic neutrophils were significantly reduced, and L-DCL was more sensitive to this inhibition than CLA-DCL. G-CSF did not change the basal chemiluminescence in either control or diabetic neutrophils, but it apparently primed CLA-DCL and L-DCL. Although, in diabetic neutrophils, the priming effect of G-CSF to both CLA-DCL and L-DCL was less compared with that in control neutrophils, L-DCL was more sensitive than CLA-DCL to this priming effect. Because bacterial infection is still an important cause of morbidity and mortality in diabetic patients, these data suggest that G-CSF may be useful as a drug to prevent the aggravation of bacterial infection in diabetic patients.
Diabetes 1993 Mar
PMID:Granulocyte-colony stimulating factor improves an impaired bactericidal function in neutrophils from STZ-induced diabetic rats. 767 62

To evaluate whether granulocyte-colony stimulating factor (G-CSF) improves an impaired production of oxygen-derived free radicals by neutrophils from poorly controlled NIDDM patients, we studied the effect of G-CSF on myeloperoxidase (MPO) activity and chemiluminescence amplified by a Cypridina luciferin analog (CLA-DCL), which is dependent on O2 generation, and luminol (L-DCL), which is dependent on OCl(-) generation, in response to formyl-methonyl-leucyl-phenylalanine. Both CLA-DCL and L-DCL by neutrophils from the diabetic group (n = 15, HbA(1c) >10%) were significantly decreased (26 and 37%, respectively: P < 0.01) compared with the age-matched normal control group (n = 15), and L-DCL was more sensitive to this inhibition than CLA-DCL (P < 0.05). In both control and diabetic neutrophils, G-CSF significantly enhanced both CLA-DCL (175% in control and 156% in diabetic) and L-DCL (283% in control and 346% in diabetic). In diabetic neutrophils, the enhancing effect of G-CSF on L-DCL was more sensitive than on CLA-DCL (P < 0.001). There was a positive correlation between HbA(1c) and the enhancing effect of G-CSF on L-DCL in diabetic patients (P < 0.05), but not on CLA-DCL. MPO activity was also decreased in the diabetic group (63%, P < 0.05), and G-CSF improved this impaired MPO activity (184%, P < 0.01). Furthermore, there was a positive correlation between HbA(1c) and the improving effect of G-CSF on MPO activity (P < 0.05). Because bacterial infection still accounts for an important cause of morbidity and mortality in diabetic patients, these data suggest that G-CSF may be useful as a drug to prevent the aggravation of bacterial infection by improving neutrophil function, especially through H2O2-MPO-OCl(-) mechanism, in poorly controlled diabetic patients.
Diabetes 1997 Jan
PMID:Effect of granulocyte-colony stimulating factor on generation of oxygen-derived free radicals and myeloperoxidase activity in neutrophils from poorly controlled NIDDM patients. 897 Oct 93

Neutrophil function is impaired by a known mechanism in diabetic patients, thus increasing susceptibility to infections. We studied the effect of epalrestat, an aldose reductase inhibitor, on the generation of oxygen-derived free radicals and cytosolic sorbitol concentration in neutrophils from streptozotocin-induced diabetic rats. There were four groups: treated and untreated control and diabetic rats. Treated groups were given 0.075% epalrestat in their diet for 4 weeks from the induction of diabetes and were untreated for the subsequent 4 weeks. Oxygen radicals were measured as chemiluminescence amplified by a luciferin analog [Cypridina luciferin analog-dependent chemiluminescence (CLA-DCL), which is dependent on O2- generation] and luminol (L)-DCL, which is highly dependent on OCl- generation) in response to formyl-methonyl-leucyl-phenylalanine. Diabetes resulted in a significant decrease in CLA/L-DCL and a significant increase in sorbitol (P < 0.01); there was a negative correlation between sorbitol and CLA-DCL (P < 0.05) in diabetic groups. The 4-week treatment with epalrestat in the diabetic group completely prevented the increase in sorbitol and partially improved the CLA-DCL, although L-DCL was not significantly affected. After 4 weeks off treatment, CLA-DCL decreased and sorbitol increased. Treatment had no effect on serum insulin or glucose concentration. We conclude that an increase in sorbitol in neutrophils causes, in part, an impaired generation of O2-. Epalrestat improves the impaired O2- generation by preventing the sorbitol increase in streptozotocin-induced diabetic rats.
 ...
PMID:Effect of epalrestat, an aldose reductase inhibitor, on the generation of oxygen-derived free radicals in neutrophils from streptozotocin-induced diabetic rats. 968 89

Breakdown of protective tissue barrier systems characterizes the chronic diabetic complications affecting the retina, and peripheral and central nerve tracts. The progressive damages to the blood-retina-, blood-nerve-, and paranodal ion channel barriers have pathophysiological consequences for the relentless progression of these complications. The continuing damage to the paranodal ion channel barrier in the spontaneously diabetic BB/W rat is associated with an increasingly irreversible nerve conduction defect, due to impaired nodal Na+ currents associated with displacement of nodal Na+ channels across the damaged paranodal barrier. The structural substrate for the mechanical barrier of the paranode is provided by electron-dense junctional complexes made up by a moiety of neural cell adhesive-(N-CAM), neural-glial adhesive (Ng-CAM), substrate adhesive molecules (SAMs) and polysialic acid (PSA). To further explore the mechanism underlying the protective barrier defect in diabetic neuropathy we examined the expression and immunolocalization of these molecules in peripheral nerve. In 6-month diabetic BB/W rats, direct and indirect ELISAs revealed significantly up-regulated N-CAM (P < 0.05), tenascin (Ng-CAM), (P < 0.001) and N-cadherin (A-CAM) (P < 0.03). On the other hand, SAMs showed little change, except for PSA which showed a significantly (P < 0.03) decreased concentration in the diabetic nerve. Immunocytochemical identification of these molecules revealed no visually detectable differences between diabetic and control rats. In conclusion, these data suggest that imbalances between highly interactive molecules responsible for the adhesiveness between terminal Schwann cell loops and the paranodal axolemma may underlie the critical paranodal barrier defect in diabetic neuropathy.
Diabetes Res Clin Pract 1998 Jun
PMID:Imbalances in N-CAM, SAM and polysialic acid may underlie the paranodal ion channel barrier defect in diabetic neuropathy. 971 18

Leukocytes infiltrate the pancreatic islets of nonobese diabetic mice, causing beta-cell destruction and autoimmune Type I diabetes. Here, we completely blocked adoptive transfer of diabetes and reduced spontaneous disease incidence from 71% to 17% by simultaneously administering a combination of antibodies directed against alpha4, beta2, and beta7 integrins and their ligands VCAM-1, MAdCAM-1, and ICAM-1 for 52 and 28 days, respectively. CD4 and CD8 T cells and macrophages were excluded from islets and remained entrapped in a peri-islet location as inactive exiles, no longer expressing normal levels of interferon-gamma, interleukin-4, and iNOS. Only IL-10 expression was retained, which could aid immunosuppression. Infiltrating leukocytes retained a peri-islet location, even 215 days following suspension of antibody treatment, potentially forming a barrier to the entry of active, autoantigen-reactive T cells. Combination treatment was effective against spontaneous disease when administered from 7 days of age but ineffective when initiated late in the prediabetic period (day 40 or 70). Nevertheless, anti-alpha4 subunit mAb monotherapy alone was very effective, reducing insulitis to levels similar to those obtained with combinational antibody treatment, suggesting that alpha4 integrins are major receptors contributing to leukocyte infiltration. Treatment with anti-alpha4 integrin antibody retained some therapeutic benefit when administered from days 7, 40, or 70 of age. The results have implications for the treatment of diabetes and provide a unique insight into the fate of disease-forming leukocytes following anti-CAM therapy.
 ...
PMID:Leukocytes infiltrating the pancreatic islets of nonobese diabetic mice are transformed into inactive exiles by combinational anti-cell adhesion therapy. 1159 Jan 86

We have reviewed the published literature regarding the effects of CLA on body composition and immune cell functions in humans and in animal models. Results from studies in mice, hamsters, rats, and pigs generally support the notion that CLA reduced depot fat in the normal or lean strains. However, in obese rats, it increased body fat or decreased it less than in the corresponding lean controls. These studies also indicate that t10,c12-CLA was the isomer that reduced adipose fat; however, it also increased the fat content of several other tissues and increased circulating insulin and the saturated FA content of adipose tissue and muscle. Four of the eight published human studies found small but significant reductions in body fat with CLA supplementation; however, the reductions were smaller than the prediction errors for the methods used. The other four human studies found no change in body fat with CLA supplementation. These studies also report that CLA supplementation increased the risk factors for diabetes and cardiovascular disease including increased blood glucose, insulin, insulin resistance, VLDL, C-reactive protein, lipid peroxidation, and decreased HDL. Most studies regarding the effects of CLA on immune cell functions have been conducted with a mixture of isomers, and the results have been variable. One study conducted in mice with the purified c9,t11-CLA and t10,c12-CLA isomers indicated that the two isomers have similar effects on immune cell functions. Some of the reasons for the discrepancies between the effects of CLA in published reports are discussed. Although significant benefit to humans from CLA supplementation is questionable, it may create several health risks in both humans and animals. On the basis of the published data, CLA supplementation of adult human diets to improve body composition or enhance immune functions cannot be recommended at this time.
 ...
PMID:Modulation of body composition and immune cell functions by conjugated linoleic acid in humans and animal models: benefits vs. risks. 1284 82

Oxidative stress may play a critical role in the pathogenesis of endothelial dysfunction in patients with diabetes or hypertension. An angiotensin II type 1 receptor(AT1) antagonist candesartan is now a widely used antihypertesive drug, and AT1 activation is a predominant source of oxidative stress. We studied the effect of a 12-week treatment of candesartan(4-12 mg-day) on oxidative stress markers [lipid peroxidation(LPO), malondialdehyde-modified LDL(MDA-LDL), 8-epi-PGF2 alpha, and the generation of superoxide anion by monocytes(CLA-DCL)] in 30 type 2 diabetic patients with hypertension (> 140/85 mmHg). Both MDA-LDL and CLA-DCL were significantly decreased, although the others were not changed. These data suggest that candesartan clinically improves oxidant stress, probably lowering the generation of superoxide anion from blood monocytes.
 ...
PMID:[Effect of angiotensin II type 1 receptor antagonist on oxidative stress markers in type 2 diabetic patients with hypertension]. 1287 92

The endothelium represents an important therapeutic target for containment of oxidative stress, thrombosis and inflammation involved in a plethora of acute and chronic conditions including cardiovascular and pulmonary diseases and diabetes. However, rapid blood clearance and lack of affinity to the endothelium compromise delivery to target and restrict medical utility of antioxidant enzymes (e.g., catalase) and fibrinolytics. The use of "stealth" PEG-liposomes prolongs circulation, whereas conjugation with antibodies to endothelial determinants permits targeting. Constitutive endothelial cell adhesion molecules (CAM, such as ICAM-1 and PECAM-1, which are stably expressed and functionally involved in oxidative stress and thrombosis) are candidate determinants for targeting of antioxidants and fibrinolytics. CAM antibodies and compounds conjugated with anti-CAM bind to endothelial cells and accumulate in vascularized organs (preferentially, lungs). Pathological stimuli enhance ICAM-1 expression in endothelial cells and facilitate targeting, whereas PECAM-1 expression and targeting are stable. Endothelial cells internalize 100-300 nm diameter conjugates possessing multiple copies of anti-CAM, but not monomolecular antibodies or micron conjugates. This permits size-controlled sub-cellular targeting of antioxidants into the endothelial interior and fibrinolytics to the endothelial surface. Targeting catalase to PECAM-1 or ICAM-1 protects endothelial cells against injury by oxidants in culture and alleviates vascular oxidative stress in lungs in animals. Anti-CAM/catalase conjugates are active for a few hours prior to lysosomal degradation, which can be delayed by auxiliary drugs. Conjugation of fibrinolytics to monovalent anti-ICAM permits targeting and prolonged retention on the endothelial surface. Therefore, CAM targeting of antioxidants and fibrinolytics might help to contain oxidative and thrombotic stresses, with benefits of blocking CAM. Avenues for improvement and translation of this concept into the clinical domain are discussed.
 ...
PMID:Targeting of antioxidant and anti-thrombotic drugs to endothelial cell adhesion molecules. 1602 67

Data from a number of studies and trials have shown that different conjugated linoleic acids (CLA's) may produce beneficial effects on cancer, atherosclerosis, hypertension, diabetes and changes in body composition. Despite the increasing knowledge about CLA's implications on health, the mechanism of action of these fatty acids is not completely understood. Moreover, human studies indicate that some of these beneficial effects are considerably less evident than anticipated from mice studies, while the efficacy and safety of dietary supplements containing CLA have been questioned in some intervention trials. Recently, it has been suggested that the anti-carcinogenic and anti-atherosclerosis effects of CLA's stem from its anti-inflammatory properties. Because inflammatory responses are associated with the pathophysiology of many diseases, including obesity and the metabolic syndrome, the investigation in this area is of growing interest in recent years.
 ...
PMID:Inflammation and conjugated linoleic acid: mechanisms of action and implications for human health. 1644 Jun 2

More than half of the U.S. population has a body mass index of 25 kg/m2 or more, which classifies them as overweight or obese. Obesity is often associated with comorbidities such as diabetes, cardiovascular diseases, and cancer. CLA and chromium have emerged as major dietary supplements that reduce body weight and fat mass, and increase basal metabolic rate in animal models. However, studies show that CLA induces insulin resistance in mice and in humans, whereas Cr improves insulin sensitivity. Hence, we designed the present study to examine the combined effect of CLA and Cr on body composition and insulin sensitivity in a Balb/c mice (n = 10/group) model of high-fat-diet-induced obesity. CLA alone lowered body weight, total body fat mass, and visceral fat mass, the last of which decreased further with the combination of CLA and Cr. This effect was accompanied by decreased serum leptin levels in CLA-fed and CLA + Cr-fed mice, and by higher energy expenditure (EE) and oxygen consumption (OC) in CLA + Cr-fed mice. Serum levels of glucose, insulin, the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6), as well as insulin resistance index (IRI), decreased with CLA, whereas CLA and Cr in combination had significant effects on insulin and IL-6 concentrations and IRI. In summary, CLA + Cr decreased body weight and fat mass in high-fat-diet-fed mice, which may be associated with decreased leptin levels and higher EE and OC.
 ...
PMID:Conjugated linoleic acid and chromium lower body weight and visceral fat mass in high-fat-diet-fed mice. 1693 88


1 2 3 Next >>