ao-128 and Disease-Models--Animal

The α-glucosidase inhibitor (α-GI) delays the intestinal absorption of glucose, which reduces postprandial hepatic glucose intake. This mechanism is considered to be effective in treating non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of voglibose, an α-glucosidase inhibitor, on high-fat, high-fructose (HFHFr) diet-induced NAFLD models. Seven-week-old male C57BL/6J mice were randomly placed in a chow diet group or an HFHFr diet group. After 10 weeks, mice in the HFHFr group were randomly assigned to one of three groups: HFHFr diet with vehicle, HFHFr with voglibose, or HFHFr with pioglitazone. Each diet and treatment was continued for 10 weeks. The HFHFr diet induced severe NAFLD in terms of steatosis, hepatitis, and fibrosis. Administration of voglibose improved all aspects of NAFLD, comparable to those of pioglitazone, a positive control. In voglibose-treated mice, gene expressions of hepatic lipogenesis markers were significantly downregulated. In the in vitro experiment, reducing the influx of glucose into hepatocytes significantly reduced steatosis and de novo lipogenesis even in the presence of sufficient fructose and fat, demonstrating that the mechanism of voglibose could be effective in treating HFHFr diet-induced NAFLD. These results indicate that voglibose improves HFHFr diet-induced NAFLD by suppressing hepatic de novo lipogenesis.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Fructose; Glucose; Glycoside Hydrolase Inhibitors; Inositol; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Pioglitazone

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Topics: Animals; Antioxidants; Azoxymethane; Biomarkers; Biopsy; Cell Proliferation; Colonic Neoplasms; Cytokines; Diabetes Mellitus, Type 2; Disease Models, Animal; Glycoside Hydrolase Inhibitors; Humans; Inflammation Mediators; Inositol; Intestinal Mucosa; Mice; NF-kappa B; Obesity; Oxidative Stress; Precancerous Conditions

Postprandial hyperglycemia considered to be a major risk factor for cerebrovascular complications.. The current study was designed to elucidate the beneficial role of voglibose via in-silico in vitro to in-vivo studies in improving the postprandial glycaemic state by protection against strokeprone type 2 diabetes.. In-Silico molecular docking and virtual screening were carried out with the help of iGEMDOCK+ Pymol+docking software and Protein Drug Bank database (PDB). Based on the results of docking studies, in-vivo investigation was carried out for possible neuroprotective action. T2DM was induced by a single injection of streptozotocin (90mg/kg, i.v.) to neonates. Six weeks after induction, voglibose was administered at the dose of 10mg/kg p.o. for two weeks. After eight weeks, diabetic rats were subjected to middle cerebral artery occlusion, and after 72 hours of surgery, neurological deficits were determined. The blood was collected for the determination of serum glucose, CK-MB, LDH and lipid levels. Brains were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, ROS parameters, NO levels, and aldose reductase activity.. In-silico docking studies showed good docking binding score for stroke associated proteins, which possibly hypotheses neuroprotective action of voglibose in stroke. In the present in-vivo study, pre-treatment with voglibose showed a significant decrease (p<0.05) in serum glucose and lipid levels. Voglibose has shown significant (p<0.05) reduction in neurological score, brain infarct volume, the difference in brain hemisphere weight. On biochemical evaluation, treatment with voglibose produced significant (p<0.05) decrease in CK-MB, LDH, and NO levels in blood and reduction in Na+-K+ ATPase, oxidative stress, and aldose reductase activity in brain homogenate.. In-silico molecular docking and virtual screening studies and in-vivo studies in MCAo induced stroke, animal model outcomes support the strong anti-stroke signature for possible neuroprotective therapeutics.

Topics: Animals; Cerebrovascular Disorders; Computer Simulation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hyperglycemia; Infarction, Middle Cerebral Artery; Inositol; Lipids; Molecular Docking Simulation; Neuroprotective Agents; Nitric Oxide; Rats; Risk Factors; Sodium-Potassium-Exchanging ATPase; Software; Stroke; User-Computer Interface

Diabetic gastroparesis is a common complication of diabetes mellitus (DM) that is characterized by decreased serum insulin and insulin-like growth factor-1 (IGF-1). Despite the fact that insulin treatment not glycemic control potently accelerated gastric emptying in type 1 DM patients, the role of insulin/InsR and IGF-1/IGF-1R signaling in diabetic gastroparesis remains incompletely elucidated. In the present study, type 1 DM mice were established and treated with insulin or Voglibose for 8 weeks. The gastric emptying was delayed from DM week 4 when the gastric InsR and IGF-1R were declined. Meanwhile, the gastric choline acetyltransferase (ChAT) was significantly reduced and the myenteric cholinergic neurones and their fibers were significantly diminished. The production of stem cell factor (SCF) was dramatically repressed in the gastric smooth muscles in DM week 6. TWereafter, interstitial cells of Cajal (ICC) were clearly lost and their networks were impaired in DM week 8. Significantly, compared with Voglibose, an 8-week treatment with insulin more efficiently delayed diabetic gastroparesis development by protecting the myenteric cholinergic neurones and ICC. In conclusion, diabetic gastroparesis was an aggressive process due to the successive damages of myenteric cholinergic neurones and ICC by impairing the insulin/InsR and IGF-1/IGF-1R signaling. Insulin therapy in the early stage may delay diabetic gastroparesis.

Topics: Animals; Antigens, CD; Choline O-Acetyltransferase; Cholinergic Neurons; Diabetes Complications; Disease Models, Animal; Gastroparesis; Gene Expression Regulation; Humans; Inositol; Insulin; Insulin-Like Growth Factor I; Interstitial Cells of Cajal; Mice; Mice, Inbred NOD; Muscle, Smooth; Receptor, IGF Type 1; Receptor, Insulin; Stem Cell Factor

Sucrose is a major sweetener added to various foods and beverages. Excessive intake of sucrose leads to increases in blood glucose levels, which can result in the development and exacerbation of lifestyle-related diseases such as obesity and diabetes. In this study, we established an in vivo evaluation system using silkworms to explore substances that suppress the increase in blood glucose levels caused by dietary intake of sucrose. Silkworm hemolymph glucose levels rapidly increased after intake of a sucrose-containing diet. Addition of acarbose or voglibose, α-glycosidase inhibitors clinically used for diabetic patients, suppressed the dietary sucrose-induced increase in the silkworm hemolymph glucose levels. Screening performed using the sucrose-induced postprandial hyperglycemic silkworm model allowed us to identify some lactic acid bacteria that inhibit the increase in silkworm hemolymph glucose levels caused by dietary intake of sucrose. The inhibitory effects of the Lactococcus lactis #Ll-1 bacterial strain were significantly greater than those of different strains of lactic acid bacteria. No effect of the Lactococcus lactis #Ll-1 strain was observed in silkworms fed a glucose diet. These results suggest that the sucrose diet-induced postprandial hyperglycemic silkworm is a useful model for evaluating chemicals and lactic acid bacteria that suppress increases in blood glucose levels.

Topics: Acarbose; Animals; Bombyx; Dietary Sucrose; Disease Models, Animal; Glucose; Glycoside Hydrolase Inhibitors; Hemolymph; Humans; Hyperglycemia; Inositol; Lactobacillales; Phylogeny; Postprandial Period

Type 2 diabetes mellitus (DM) has a deleterious effect on dental implant integration into alveolar bone, thought to arise from impaired osteoblast function and consequent reduced bone turnover. However, whether controlling blood glucose with antidiabetic drugs is sufficient to improve implant integration is unclear. This study was designed to evaluate implant integration using diabetic rats with/without an antidiabetic drug.. Titanium screws were surgically implanted in each tibia of 20 Goto-Kakizaki (GK) rats and 5 nondiabetic control rats. After 3 or 9 weeks, osseointegration was determined by testing the removal torque required to displace the screw and by histological analysis of various parameters of bone formation.. Removal torque was significantly higher in the nondiabetic control group than in GK rats, irrespective of whether the GK rats had received voglibose. Histology revealed that single-labeled surface area was still high in the GK rats at 9 weeks but had peaked and diminished in control rats. Bone-implant contact area was reduced in GK rats.. Despite controlling blood glucose, voglibose was unable to reverse the bone metabolic effects of DM.

Topics: Alveolar Process; Animals; Biomechanical Phenomena; Dental Implants; Dental Stress Analysis; Diabetes Mellitus, Type 2; Disease Models, Animal; Hypoglycemic Agents; Inositol; Male; Mice, Inbred Strains; Osteogenesis; Rats; Rats, Wistar

Short-term hypoglycemic effects of single dose voglibose and nateglinide were compared after sucrose loading in spontaneously diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats.. After a 17-h fasting period, the animals received 0.06 mg/kg of voglibose (VOG group, n = 6), 50 mg/kg of nateglinide (NAT group, n = 6), or 0.5% methyl cellulose (control group, n = 6), immediately followed by 2.5 g/kg of sucrose.. Compared to control group values, glucose levels after sucrose loading were significantly decreased in the portal blood in the VOG group and in the peripheral blood in the NAT and VOG groups. The portal glucose AUC0-120 min was significantly lower in the VOG group than in the control and NAT groups, whereas the peripheral glucose AUC0-120 min was significantly lower in the VOG and NAT groups than in the control group. Portal insulin levels in the VOG group were significantly decreased compared to the control group. However, portal insulin levels in the NAT group were acutely increased, peaking 15 min after sucrose loading. Portal FFA levels were decreased in the NAT group 15, 30, and 60 min after sucrose loading; no FFA reductions were seen in the VOG group.. Although both drugs produced similar hypoglycemic effects after sucrose loading in the peripheral blood, these drugs generated vastly different results in portal blood. Reduced FFA in the portal blood, observed after single administration of nateglinide, may have a favorable impact not only on glucose metabolism but also on lipid metabolism.

Topics: Animals; Area Under Curve; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Disease Models, Animal; Enzyme Inhibitors; Fatty Acids, Nonesterified; Hypoglycemic Agents; Inositol; Insulin; Insulin Secretion; Male; Nateglinide; Phenylalanine; Portal Vein; Postprandial Period; Rats; Rats, Inbred OLETF; Secretory Rate; Sucrose

The effect of long-term (6 months) administration of voglibose in a dietary mixture (10 ppm) on intestinal disaccharidase activity was examined in non obese type 2 diabetes model Goto-Kakizaki (GK) rats. The postprandial blood glucose level in voglibose-treated GK rats was significantly lower than in untreated GK rats (190+/-19 vs. 250+/-25 mg/dl, P<0.01; 1 h, 212+/-23 vs. 256+/-20, P<0.05; 2 h), and the activities of maltase, sucrase, and isomaltase remained significantly lower throughout the 6 months of voglibose treatment. The expressions of protein and mRNA of sucrase-isomaltase (SI) complex were significantly higher in voglibose-treated GK rats. Voglibose administration then was stopped after 6 months of treatment. The mRNA level and protein level of the SI complex became normalized during the interruption of drug administration, and disaccharidase activities increased almost to the level of the untreated group 1 month after treatment was stopped. After 1 day of re-administration of the drug, however, disaccharidase activities again became significantly inhibited. These results indicate that voglibose may improve glucose tolerance since it inhibits activities of disaccharidases in spite of increasing the expression of them on intestine, furthermore voglibose may be reversible and reproducible through interruption and re-administration.

Topics: Alkaline Phosphatase; Animals; Blood Glucose; Blotting, Northern; Blotting, Western; Body Weight; Diabetes Mellitus, Type 2; Disaccharidases; Disease Models, Animal; Eating; Enzyme Inhibitors; Inositol; Insulin; Intestinal Mucosa; Male; Rats; Rats, Wistar; RNA, Messenger