BACKGROUND: O-GlcNAcylation is a highly dynamic post-translational modification that plays a key role in regulating phosphorylation of protein and cell survival. The proteins O-GlcNAcylation level is regulated dynamically by O-GlcNAc transferase (OGT) and β-N-acetylglucosaminidase (O-GlcNAcase, OGA). Although previous studies have suggested the role of O-GlcNAcylation in neurodegenerative diseases, the mechanism of O-GlcNAcylation in Alzheimer's disease (AD) remains unclear. METHODS: The decrease of O-GlcNAcylation by alloxan, an OGT inhibitor, and increase by NAG-thiazolines (NAG-Ae), an O-GlcNAcase inhibitor were tested to investigate the effects of O-GlcNAc alteration on AD like neurodegeneration in SK-N-SH cells. RESULTS: The level of O-GlcNAcylation was decreased in alloxan treated cells and increased in NAG-Ae treated cells. Meanwhile, it was observed that both abnormal phosphorylation of NFs in cell bodies and apoptosis induced by alloxan treatment can be resisted by pretreatment or simultaneous treatment with appropriate NAG-Ae. CONCLUSION: These results demonstrated that increasing O-GlcNAc with NAG-Ae protected AD like neurodegeneration from NFs hyperphosphorylation and the cell loss, suggesting the role of O-GlcNAc in the pathogenesis and therapy of AD.
- MeSH
- Acetylation MeSH
- Alloxan pharmacology MeSH
- Alzheimer Disease enzymology etiology MeSH
- Apoptosis physiology MeSH
- beta-N-Acetylhexosaminidases antagonists & inhibitors MeSH
- Cell Death physiology MeSH
- Phosphorylation physiology MeSH
- Enzyme Inhibitors pharmacology MeSH
- Humans MeSH
- N-Acetylglucosaminyltransferases antagonists & inhibitors metabolism MeSH
- Cell Line, Tumor MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
AIM: The present study was designed to investigate the activity of two glibenclamide derivatives on glucose concentration. An additionalAIM was to identify the biodistribution of glibenclamide derivatives in different organs in a diabetic animal model. METHODS: The effects of two glibenclamide derivatives on glucose concentration were evaluated in a diabetic animal model. In addition, glibenclamide derivatives were bound to Tc-99m using radioimmunoassay methods. To evaluate the pharmacokinetics of the glibenclamide derivatives over time (15, 30, 45 and 60 min) the Tc-99m-glibenclamide conjugates were used. RESULTS: The results showed that glibenclamide-pregnenolone had greater hypoglycemic activity than glibenclamide or glibenclamide-OH. The data also showed that the biodistribution of Tc-99m-glibenclamide-OH in all organs was less than that of the Tc-99m-glibenclamide-pregnenolone derivative. CONCLUSIONS: The glibenclamide-pregnenolone derivative had greater hypoglycemic effects and its biodistribution was wider than glibenclamide-OH. The data suggest that the steroid nucleus may be important to the hypoglycemic activity of the glibenclamide-pregnenolone derivative and this could be related to the degree of lipophilicity induced by the steroid nucleus in the chemical structure of glibenclamide-pregnenolone.
- MeSH
- Alloxan MeSH
- Diabetes Mellitus, Experimental blood MeSH
- Drug Combinations MeSH
- Glyburide analogs & derivatives pharmacokinetics therapeutic use MeSH
- Hypoglycemic Agents pharmacokinetics metabolism MeSH
- Blood Glucose metabolism MeSH
- Rats MeSH
- Metformin therapeutic use MeSH
- Rats, Wistar MeSH
- Pregnenolone pharmacokinetics therapeutic use MeSH
- Tissue Distribution MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Cardiac repolarization is prolonged in diabetes mellitus (DM), however the distribution of repolarization durations in diabetic hearts is unknown. We estimated the ventricular repolarization pattern and its relation to the ECG phenomena in diabetic mice. Potential mapping was performed on the anterior ventricular surface in healthy (n=18) and alloxan-induced diabetic (n=12) mice with the 64-electrode array. Activation times, end of repolarization times, and activation-recovery intervals (ARIs) were recorded along with limb lead ECGs. ARIs were shorter in the left as compared to right ventricular leads (P<0.05). The global dispersion of repolarization, interventricular and apicobasal repolarization gradients were greater in DM than in healthy animals (P<0.03). The increased dispersion of repolarization and apicobasal repolarization gradient in DM correlated with the prolonged QTc and Tpeak-Tend intervals, respectively. The increased ventricular repolarization heterogeneity corresponded to the electrocardiographic markers was demonstrated in DM.
- MeSH
- Action Potentials MeSH
- Alloxan pharmacology MeSH
- Diabetes Mellitus physiopathology MeSH
- Electrocardiography MeSH
- Diabetes Mellitus, Experimental physiopathology MeSH
- Mice MeSH
- Ventricular Function physiology MeSH
- Heart Ventricles metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Keywords
- beta buňky, glukóza, diabetes, experimentální model, GLUT2,
- MeSH
- Alloxan administration & dosage pharmacology MeSH
- Insulin-Secreting Cells drug effects MeSH
- Diabetes Mellitus, Experimental chemically induced MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Streptozocin administration & dosage pharmacology MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
Diabetes mellitus is associated with a variety of cardiovascular complications including impaired cardiac muscle function. The effects of insulin treatment on heart rate, body temperature and physical activity in the alloxan (ALX)-induced diabetic rat were investigated using in vivo biotelemetry techniques. The electrocardiogram, physical activity and body temperature were recorded in vivo with a biotelemetry system for 10 days before ALX treatment, for 20 days following administration of ALX (120 mg/kg) and thereafter, for 15 days whilst rats received daily insulin. Heart rate declined rapidly after administration of ALX. Pre-ALX heart rate was 321+/-9 beats per minute, falling to 285+/-12 beats per minute 15-20 days after ALX and recovering to 331+/-10 beats per minute 5-10 days after commencement of insulin. Heart rate variability declined and PQ, QRS and QT intervals were prolonged after administration of ALX. Physical activity and body temperature declined after administration of ALX. Pre-ALX body temperature was 37.6+/-0.1 °C, falling to 37.3+/-0.1 °C 15-20 days after ALX and recovering to 37.8+/-0.1 °C 5-10 days after commencement insulin. ALX-induced diabetes is associated with disturbances in heart rhythm, physical activity and body temperature that are variously affected during insulin treatment.
- MeSH
- Alloxan administration & dosage pharmacology MeSH
- Diabetes Mellitus, Experimental metabolism physiopathology MeSH
- Financing, Organized MeSH
- Hypoglycemic Agents administration & dosage pharmacology MeSH
- Insulin administration & dosage pharmacology MeSH
- Blood Glucose MeSH
- Rats MeSH
- Motor Activity drug effects MeSH
- Rats, Wistar MeSH
- Heart Rate drug effects MeSH
- Body Temperature drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
Aerva lanata known as Polpala, is prostrate or decumbent to erect herb. The objective of the present investigation was to study the antihyperglycaemic activity of alcoholic extract of Aerva lanata (called AL-alc) leaves on serum glucose levels, and on the oral glucose tolerance test (OGTT) in alloxan induced diabetic mice. AL-alc (100, 200 and 400 mg/kg) and glyburide (10 mg/kg) were administered orally in alloxan (70 mg/kg, i.v.) induced diabetic mice. In the acute study, the serum glucose level was estimated at 0,2,4,6 and 24 h after the administration of the drug. The subacute study involved repeated administration of the drugs for 28 days and then a rest period of 7 days, serum glucose level estimation at 7, 14, 21, 28 and 35 days by the glucose oxidase / peroxidase method and the recording of the body weights of the mice. In the oral glucose tolerance test (OGTT), D-glucose (2.5 g/kg) was administered to nondiabetic and diabetic mice half an hour after pretreatment with AL-alc (100, 200 and 400 mg/kg) and glyburide (10 mg/kg). Serum glucose levels were estimated 30 min prior to glucose administration and at 0, 30, 60 and 120 min after glucose loading. In AL-alc (400 mg/kg), the onset was 4 h, the peak effect was 6 h but the effect waned at 24 h. In the subacute study, repeated administration (once a day for 28 days) of the glyburide and AL-alc caused a significant reduction in the serum glucose level as compared to the vehicle treated group. AL-alc (400 mg/kg) treatment prevented a decrease in the body weight of the diabetic mice. In the OGTT, AL-alc (400 mg/kg) increased the glucose threshold at 60 min after the administration of glucose. The AL-alc (400 mg/kg) showed significantly more antihyperglycaemic activity than AL-alc (100 and 200 mg/kg).
- MeSH
- Alloxan metabolism MeSH
- Amaranthaceae metabolism drug effects MeSH
- Diabetes Mellitus, Experimental metabolism MeSH
- Glucose Tolerance Test methods statistics & numerical data utilization MeSH
- Hypoglycemic Agents pharmacokinetics metabolism MeSH
- Blood Glucose metabolism MeSH
- Mice blood metabolism MeSH
- Plant Extracts pharmacokinetics metabolism MeSH
- Body Weight drug effects MeSH
- Check Tag
- Mice blood metabolism MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
106 l. : il., tab. ; 30 cm
Experimentálně bude testována antidiabetická aktivita extraktů z několika rostlin, využívaných v tradiční medicíně. U účinných extraktů bude provedena frakcionace, separace a identifikace aktivních látek a vypracovány metody jejich standardizace. Cílem je získání ověřených poznatků o antidiabetické aktivitě vybraných léčivých rostlin.; The antidiabetic activity of selected herbal drugs and extracts, used in traditional medicine will be experimentally verified. The active extract will underwent the fractionation process and active constituents will be isolated. The methods for standardization of content and activity of several herbal drugs and extracts will be developed. The aim of the study is obtaining of verified experimental data about the proposed antidiabetic activity of selected medicinal plants.
- MeSH
- Alloxan pharmacokinetics MeSH
- Diabetes Mellitus drug therapy MeSH
- Ethnopharmacology MeSH
- Diabetes Mellitus, Experimental MeSH
- Glyburide pharmacokinetics MeSH
- Hypoglycemic Agents pharmacokinetics pharmacology MeSH
- Blood Glucose analysis MeSH
- Rats MeSH
- Plants, Medicinal chemistry immunology MeSH
- Malondialdehyde blood urine MeSH
- Medicine, Traditional MeSH
- Check Tag
- Rats MeSH
- Conspectus
- Farmacie. Farmakologie
- NML Fields
- diabetologie
- farmacie a farmakologie
- alternativní lékařství
- NML Publication type
- závěrečné zprávy o řešení grantu IGA MZ ČR
Mushrooms are a low calorie food with very little fat and are highly suitable for obese persons. The objective of the present investigation was to study the interaction of aqueous extract of P. pulmonarius (called PP-aqu) with acarbose on serum glucose levels, and on the oral glucose tolerance test (OGTT) in alloxan induced diabetic mice. PP-aqu (500 mg/kg), acarbose (50 mg/kg) and their combination were administered orally in alloxan (70 mg/kg,i.v.) induced diabetic mice. In the acute study, the serum glucose level was estimated at 0, 2, 4, 6 and 24 h after drug administration. The sub acute study involved repeated administration of the drugs for 28 days, a serum glucose level estimation at 7, 14, 21 and 28 days and recording of the body weights of the mice. In the OGTT, d-glucose (2.5 g/kg) was administered in diabetic mice half an hour after pre-treatment with PP-aqu (500 mg/kg), acarbose (50 mg/kg) and their combination. Serum glucose levels were estimated 30 min prior to glucose administration and at 0, 30, 60 and 120 min after glucose loading. The antihyperglycaemic effects of PP-aqu and acarbose alone were similar; i.e. the onset was 2 h, the peak effect was 6 h but the effect waned at 24 h. The effect of the combination of PP-aqu with acarbose was however different, as serum glucose was lower at 24 h. In the subacute study, repeated administration (once a day for 28 days) of the acarbose, PP-aqu and combination caused a significant (P<0.001) reduction in the serum glucose level as compared to the vehicle treated group. Combination treatment prevented a decrease in the body weight of the diabetic mice. In the OGTT test, the combination of PP-aqu with acarbose increased the glucose threshold at 120 min after the administration of glucose. The combination treatment of PP-aqu with acarbose produced a more synergistic antihyperglycaemic effect than either drug alone.
- MeSH
- Acarbose metabolism therapeutic use MeSH
- Alloxan metabolism MeSH
- Diabetes Mellitus, Experimental metabolism MeSH
- Glucose Tolerance Test methods utilization MeSH
- Blood Glucose metabolism drug effects MeSH
- Mice MeSH
- Pleurotus physiology growth & development MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
The relationship between the pharmacokinetics of gliclazide and its antidiabetic efficacy were evaluated on the basis of experimental determination of changes with time in the plasma levels of this antidiabetic agent and those of glucose. The experiment included rats with both initial normal glycaemia and alloxan-induced hyperglycaemia (glycaemia increased by a minimum of 30%). Pharmacokinetic and pharmacodynamic parameters were examined in the interval of 30 to 180 min after p.o. administration of a single dose of 25 mg/kg of gliclazide. The drug was administered on day 4, following a single i.v. dose of either 50 mg/kg of alloxan (hyperglycaemic group) or the injection vehicle (control group). Even though the biological availability of gliclazide was similar in both normoglycaemic and hyperglycaemic animals, the gliclazide-induced hypoglycaemizing response was not uniform: until 60 min, the decrease of glycaemia was smaller in animals with alloxan hyperglycaemia (23% decrease at 60 min) in contrast to the normoglycaemic animals (36% decrease at 60 min), at later times, the intensity of this hypoglycaemizing effect of gliclazide persisted in the hyperglycaemic animals, while in the normoglycaemic ones, a reversal of the hypoglycaemizing effect occurred. Copyright (c) 2007 John Wiley & Sons, Ltd.
- MeSH
- Alloxan administration & dosage toxicity MeSH
- Administration, Oral MeSH
- Time Factors MeSH
- Financing, Organized MeSH
- Gliclazide pharmacokinetics blood therapeutic use MeSH
- Hyperglycemia drug therapy chemically induced blood MeSH
- Hypoglycemic Agents administration & dosage pharmacokinetics therapeutic use MeSH
- Injections, Intravenous MeSH
- Insulin blood MeSH
- Blood Glucose metabolism MeSH
- Rats MeSH
- Area Under Curve MeSH
- Rats, Wistar MeSH
- Chromatography, High Pressure Liquid MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
The present study aims to investigate the antidiabetic as well as the effect on lipid peroxidation of three different doses (50, 100, and 200 mg/kg) of Cleome droserifolia aerial parts methanolic extract in comparison with glibenclamide in alloxan-induced diabetic rats. Forty-two rats (35 diabetic and 7 normal) were included in this study. Oral administration of 100 and 200 mg/kg of the methanolic extract for 3 weeks significantly (P < 0.05) restored the blood glucose level, plasma malondialdehyde and urine sugar to near the physiological values whereas the effect of 50 mg/kg was not significant. Furthermore, from the HPLC chromatograms, we identified the presence of three flavonoids (quercetin, kaempferol, and isorhamnetin) together with three phenolic acids (sinapinic acid, ferulic acid and 4-coumaric acid) which may explain at least in part some of the antidiabetic and antioxidative properties observed in this study.
