UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetically obese Zucker rats exhibit symptoms similar to those of obese patients with insulin-resistance or Type II diabetes; therefore, they have been used as a genetic model to study obesity, as well as a pharmacological model for the discovery of new drugs for the treatment of Type II diabetes and hyperlipidemia. In the present study, we compared the pharmacokinetics of two novel peroxisome proliferator-activated receptor (PPAR) agonists, MRL-I [(2R)-7-[3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy]-2-ethyl-3,4-dihydro-2H-benzopyran-2-carboxylic acid] and MRL-II [(2R)-7-[3-[2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy]propoxy]-3,4-dihydro-2-methyl-2H-benzopyran-2-carboxylic acid], in obese Zucker and lean Sprague-Dawley rats following a single intravenous administration. The plasma clearance of both MRL-I and MRL-II was significantly lower in obese Zucker rats (4- and 2-fold, respectively) compared with Sprague-Dawley rats, but without any significant change in the volume of distribution, which resulted in a dramatic increase in the half-life (7- and 3-fold, respectively). The reversible in vitro plasma protein binding of [(14)C]MRL-I and [(14)C]MRL-II was comparable in the two strains, approximately 96% bound. The expression levels of uridine diphosphate-glucuronosyltransferases 1A1, 1A6, 2B1, and CYP2C11 and 3A1 mRNA in liver were lower (30-50%) in Zucker compared with Sprague-Dawley rats, as were the liver glutathione S-transferases (70%), quinone reductase (30%), organic anion-transporting protein 2 (80%), and multidrug resistance-associated protein 2 (Mrp2) (50%) mRNA levels. However, Mrp3 mRNA levels were similar in both strains. Consistent with these observations, the intrinsic clearance (CL(int)), calculated from the V(max)/K(m) of glucuronidation of [(14)C]MRL-I and [(14)C]MRL-II in liver microsomes, was approximately 2-fold lower in obese Zucker rats; the K(m) values were comparable in the two strains for both compounds. In conclusion, differences in the pharmacokinetics of two novel PPAR agonists, both cleared, predominantly, by conjugation, were evident in genetically obese Zucker rats compared with Sprague-Dawley rats. These differences were consistent with changes in the mRNA levels of hepatic drug-metabolizing enzymes and transporters. This information should be considered when comparing pharmacokinetic and efficacious doses in the obese Zucker rats, used as a pharmacological model, with those in Sprague-Dawley rats, which are used widely for drug metabolism and toxicology studies.
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PMID:Differences in the pharmacokinetics of peroxisome proliferator-activated receptor agonists in genetically obese Zucker and sprague-dawley rats: implications of decreased glucuronidation in obese Zucker rats. 1531 30

Nitric oxide (NO) is synthesized from L-arginine by nitric oxide synthase (NOS). Alternation of NOS expression is implicated in the pathogenesis of numerous secondary complications of diabetes. Aqueous extract of Ginseng radix has traditionally been used for the various disorders including diabetes. In this study, the effect of Ginseng radix on the NOS expression in the hippocampus of streptozotocin (STZ)-induced diabetic rats was investigated via nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Enhanced NOS expression was detected in the hippocampus of diabetic rats and administration of Ginseng radix suppressed NOS expression. Ginseng radix may aid the treatment of central nervous system complications in diabetes.
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PMID:Administration of Ginseng radix decreases nitric oxide synthase expression in the hippocampus of streptozotocin-induced diabetic rats. 1548 40

Summary In this study we investigated the effect of the acetyl-L-carnitine (ALC) supplementation on the myenteric neurons of the jejunum of rats made diabetic at the age of 105 days by streptozotocin (35 mg/kg body weight). Four groups were used: non-diabetic (C), non-diabetic supplemented with ALC (CC), diabetic (D), diabetic supplemented with ALC (DC). After 15 weeks of diabetes induction the blood was collected by cardiac puncture to evaluate glycaemia and glycated haemoglobin. Next the animals were killed and the jejunum was collected and subjected to whole-mount preparation to evidence the myenteric neurons through the histochemical technique of the NADH-diaphorase. The neuronal counts were made in 80 microscopic fields, in tissue samples of five animals of each group. The profiles of the cell bodies of 1000 neurons per group were analysed. Diabetes induced a significant increase in the area of the cell body and decrease in the number of NADH-diaphorase positive myoenteric neurons. ALC suplementation to the diabetic group promoted smaller hypertrophic effects and less neuronal loss than in the myoenteric neurons of the diabetic rats, and in addition diminished the body weight decrease and reduced the fasting glycaemia.
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PMID:Morphometric and quantitative evaluation of the NADH-diaphorase positive myenteric neurons of the jejunum of streptozotocin-diabetic rats supplemented with acetyl-L-carnitine. 1592 29

Diabetes-induced erectile dysfunction is one of the most prevalent complications of diabetes in males. alpha-Lipoic acid (ALA) and its reduced form, dihydrolipoic acid, are powerful antioxidants. Data strongly suggest that, because of its antioxidant properties, ALA is particularly suited to the prevention and/or treatment of diabetic complications that arise from overproduction of reactive oxygen and nitrogen. The aim of this study was to investigate the localization of nitric oxide synthetase (NOS) in normal and diabetic rat cavernous smooth muscles and to examine the effects of ALA on them. Rats were divided into four groups: control, diabetic, diabetic plus ALA, and ALA only. Penile tissues were taken 15 days after drug application and examined histochemically and immunohistochemically. Comparison of the control and diabetic groups revealed that the axons of nerve cells were not identified with Masson trichrome in the diabetic group, whereas in the control group NOS localization and immunostaining (endothelial NOS [eNOS]) were normal. Diabetic rats administered ALA showed improvement in Masson trichrome, nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) and eNOS localization compared with untreated diabetic rats. Although there was no difference between the control group and the group administered ALA only, we observed an increase in NADPH-d and eNOS. In erection, eNOS and neuronal NOS (nNOS) may have a significant role. In pathologic conditions, erectile dysfunction may occur as a result of an increase in inducible macrophage-type NOS (iNOS). ALA plays an important role in treatment of erectile dysfunction by decreasing iNOS and increasing other isoforms of NOS.
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PMID:The effects of alpha-lipoic acid on nitric oxide synthetase dispersion in penile function in streptozotocin-induced diabetic rats. 1637 81

In this work, we investigated the effect of the acetyl-L-carnitine (ALC) supplementation (200 mg/kg/day) on the myenteric neurons of the ileum of rats made diabetic by streptozotocin (35 mg/kg, i.v.). Four groups were used: diabetic (D), diabetic supplemented with ALC (DC), control (C) and control supplemented with ALC (CC). After 15 weeks of diabetes induction the animals were killed and the ileum was collected and subjected to whole-mount preparation to evidence the myenteric neurons through the histochemical technique of the NADH-diaphorase. The density of neurons seen in 12.72 mm2 of ileum showed no difference among the groups, although in group D it was 22% smaller than in group C, while group DC was 9% smaller to group CC. The profiles of the cell bodies (PC) of 1000 neurons per group were analysed. The neurons PC in group D decreased (P < 0.0001) when compared with other groups and increased (P < 0.0001) when compared with group DC. The incidence of neurons with a PC inferior to 200 microm2 was larger in group D. The frequency of neurons with a PC higher than 200 microm2 in group DC was close to those seen in groups C and CC. We concluded that ALC eases the loss of neurons and makes the incidence of myenteric neurons with a PC higher than 200 microm2 similar to the control rats.
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PMID:Morphoquantitative aspects of NADH-diaphorase myenteric neurons in the ileum of diabetic rats treated with acetyl-L-carnitine. 1643 67

Increased generation of reactive oxygen species (ROS) in vascular diseases such as atherosclerosis, diabetes, chronic renal failure and preeclampsia readily leads to impaired endothelium-dependent relaxation and vascular injury. To counteract ROS- and electrophile-mediated injury, cells can induce a number of genes encoding phase II detoxifying enzymes and antioxidant proteins. A cis-acting transcriptional regulatory element, designated as antioxidant response element (ARE) or electrophile response element (EpRE), mediates the transcriptional activation of genes such as heme oxygenase-1, gamma-glutamylcysteine synthethase, thioredoxin reductase, glutathione-S-transferase and NAD(P)H:quinone oxidoreductase. Other antioxidant enzymes such as superoxide dismutase and catalase and non-enzymatic scavengers such as glutathione are also involved in scavenging ROS. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the Cap nno Collar family of basic region-leucine zipper (bZIP) transcription factors, plays an important role in ARE-mediated antioxidant gene expression. Kelch-like ECH-associated protein-1 (Keap1) normally sequesters Nrf2 in the cytoplasm in association with the actin cytoskeleton, but upon oxidation of cysteine residues Nrf2 dissociates from Keap1, translocates to the nucleus and binds to ARE sequences leading to transcriptional activation of antioxidant and phase II detoxifying genes. Protein kinase C (PKC), mitogen-activated protein kinases (MAPKs) and phosphotidylinositol 3-kinase (PI3K) have been implicated in the regulation of Nrf2/ARE signaling. We here review the evidence that the Nrf2/ARE signaling pathway plays an important role in vascular homeostasis and the defense of endothelial and smooth muscle cells against sustained oxidative stress associated with diseases such as atherosclerosis and preeclampsia.
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PMID:Nrf2/ARE regulated antioxidant gene expression in endothelial and smooth muscle cells in oxidative stress: implications for atherosclerosis and preeclampsia. 1743 32

Curcumin (diferuloylmethane), a component of turmeric, has been shown to have therapeutic properties. Induction of phase 2 detoxifying enzymes is a potential mechanism through which some of the actions of curcumin could proceed. Heme oxygenase-1 (HO-1), an antioxidant phase 2 enzyme, has been reported to have cytoprotective effects in pancreatic beta-cells. Curcumin on further purification yields demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC). The objective of the present study was to determine the mechanism by which these purified curcuminoids induce HO-1 in MIN6 cells, a mouse beta-cell line. Demethoxy curcuminoids induced HO-1 promoter linked to the luciferase reporter gene more effectively than curcumin. The induction was dependent on the presence of antioxidant response element (ARE) sites containing enhancer regions (E1 and E2) in HO-1 promoter and nuclear translocation of nuclear factor-E2-related factor (Nrf2), the transcription factor that binds to ARE. Curcuminoids stimulated multiple signaling pathways that are known to induce HO-1. Inhibition of specific signaling pathways with pharmacological inhibitors and cotransfection experiments suggested the involvement of phosphotidylinositol 3-kinase and Akt. Real-time quantitative RT-PCR analysis showed significant elevation in the mRNA levels of HO-1 and two other phase 2 enzymes, the regulatory subunit of glutamyl cysteine ligase, which is needed for the synthesis of glutathione, and NAD(P)H:quinone oxidoreductase, which detoxifies quinones. DMC and BDMC induced the expression of HO-1 and translocated Nrf2 to nucleus in beta-cells of mouse islets. Our observations suggest that demethoxy curcuminoids could be used to induce a cellular defense mechanism in beta-cells under conditions of stress as seen in diabetes.
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PMID:Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase/Akt-mediated pathway in mouse beta-cells. 1753 57

alpha-Lipoic acid (LA) is a naturally-occurring micronutrient that has been actively investigated for the treatment and management of various chronic medical conditions including neurodegenerative diseases, diabetes and hepatic disorders. However, relatively few studies have examined the effects of LA as a chemopreventive agent, particularly in regard to its ability to modulate homeostasis of oxidoreductive state and to regulate detoxification enzymes such as quinone reductase NQO1 in LA-responsive cells. We tested the hypothesis that LA affects the intracellular redox status and induces NQO1 expression using the human promyelocytic HL-60 leukemia cells. We showed that treatment by LA maintains HL-60 cells in a relatively reduced state, supported by the dose/time-dependent increase in the activities of glutathione peroxidase and glutathione reductase and decrease in the activity of catalase. Moreover, LA significantly increased the activity and protein expression of NQO1. The induction of NQO1 was accompanied by the nuclear accumulation of transcription factor Nrf2, which was correlated with a decreased level of Nrf2 in the cytosol as well as the concomitant reduction in the expression of cytoplasmic repressor of Nrf2, Keap1.
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PMID:Control of cellular redox status and upregulation of quinone reductase NQO1 via Nrf2 activation by alpha-lipoic acid in human leukemia HL-60 cells. 1881 98

We investigated the effects of chronic administration of vitamin E on nitric oxide (NO)-producing neurons in the brains of streptozotocin (STZ)-induced diabetic rats using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. We further evaluated the effects of diabetes and vitamin E treatment on experimental anxiety and memory processes using the elevated plus maze (EPM) Trial 1/2 protocol. Wistar rats were divided into four groups: normoglycemics (N), normoglycemics treated with vitamin E (NVE), diabetics (D), and diabetics treated with vitamin E (DVE). Diabetes mellitus was induced by a single intraperitoneal injection of STZ (35mg/kg). Vitamin E (100mg/kg) or vehicle was administered orally by gavage (1ml/kg) once each day for 7 weeks. After behavioral testing, the dentate gyrus of the hippocampus (DG), striatum, paraventricular nucleus of the hypothalamus (PVN), supraoptic nucleus (SON), and dorsolateral periaqueductal grey (DLPAG) were analyzed for NADPH-d histochemistry. STZ-induced diabetic rats exhibited decreased locomotor activity and cognitive impairment compared with normoglycemic controls. The number of NADPH-d-positive neurons was increased in the DG, striatum, and DLPAG of diabetic rats. An increase in soma area was detected in all structures analyzed (DG, striatum, PVN, SON, and DLPAG) of STZ-induced diabetic animals. The present study showed that chronic administration of vitamin E ameliorates memory in STZ-induced diabetic rats and revealed that NOS-producing neurons have an increased soma area which can be restored, at least partially, by vitamin E treatment. These results suggest the potential use of vitamin E as an adjuvant therapy for the prevention and treatment of diabetic conditions.
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PMID:Vitamin E improves learning performance and changes the expression of nitric oxide-producing neurons in the brains of diabetic rats. 2013 20

Hyperglycemia in diabetes mellitus promotes oxidative stress in endothelial cells, which contributes to development of cardiovascular diseases. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor activated by oxidative stress that regulates expression of numerous reactive oxygen species (ROS) detoxifying and antioxidant genes. This study was designed to elucidate the homeostatic role of adaptive induction of Nrf2-driven free radical detoxification mechanisms in endothelial protection under diabetic conditions. Using a Nrf2/antioxidant response element (ARE)-driven luciferase reporter gene assay we found that in a cultured coronary arterial endothelial cell model hyperglycemia (10-30 mmol/l glucose) significantly increases transcriptional activity of Nrf2 and upregulates the expression of the Nrf2 target genes NQO1, GCLC, and HMOX1. These effects of high glucose were significantly attenuated by small interfering RNA (siRNA) downregulation of Nrf2 or overexpression of Keap-1, which inactivates Nrf2. High-glucose-induced upregulation of NQO1, GCLC, and HMOX1 was also prevented by pretreatment with polyethylene glycol (PEG)-catalase or N-acetylcysteine, whereas administration of H(2)O(2) mimicked the effect of high glucose. To test the effects of metabolic stress in vivo, Nrf2(+/+) and Nrf2(-/-) mice were fed a high-fat diet (HFD). HFD elicited significant increases in mRNA expression of Gclc and Hmox1 in aortas of Nrf2(+/+) mice, but not Nrf2(-/-) mice, compared with respective standard diet-fed control mice. Additionally, HFD-induced increases in vascular ROS levels were significantly greater in Nrf2(-/-) than Nrf2(+/+) mice. HFD-induced endothelial dysfunction was more severe in Nrf2(-/-) mice, as shown by the significantly diminished acetylcholine-induced relaxation of aorta of these animals compared with HFD-fed Nrf2(+/+) mice. Our results suggest that adaptive activation of the Nrf2/ARE pathway confers endothelial protection under diabetic conditions.
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PMID:Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. 2121 61

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